1. 胰岛素抵抗的病理机制与治疗靶点新认知
1.1 核心病理机制的更新
胰岛素抵抗（IR）作为多种代谢性疾病，如2型糖尿病（T2D）和代谢综合征（MetS）的核心病理生理学基础，其机制的深入理解对于开发有效治疗策略至关重要1。近年来，对胰岛素抵抗核心机制的认知不断更新，尤其是在异位脂质堆积、慢性低级别炎症、内质网（ER）应激与氧化损伤以及肠道菌群和脂肪组织异质性方面取得了显著进展。
异位脂质堆积：异位脂质，即在非脂肪组织中（如肝脏、骨骼肌）积累的脂肪，是导致胰岛素抵抗的关键因素之一2。研究表明，即使在BMI正常的亚洲人群中，肌细胞内的胰岛素抵抗也可能与肝脏脂肪积累和肝酶升高有关3。在肥胖人群中，肝脏和骨骼肌中的异位脂质沉积已被证实与胰岛素抵抗密切相关4。脂毒性，即脂质代谢产物的积累，能够干扰胰岛素信号通路，导致胰岛素敏感性下降15。
慢性低级别炎症：肥胖引起的脂肪组织（AT）慢性低级别炎症是胰岛素抵抗和代谢功能障碍的关键驱动因素67。脂肪组织中的巨噬细胞从M2（抗炎）表型向M1（促炎）表型的极化是这一过程的核心6。M1型巨噬细胞会分泌大量促炎细胞因子（如IL-1β, TNF-α），这些因子直接抑制胰岛素信号传导，导致胰岛素抵抗68。近期研究指出，IL-33等细胞因子在肥胖引起的脂肪组织炎症中可能发挥保护作用，通过诱导Th2细胞积累和巨噬细胞向M2型极化，从而改善胰岛素敏感性9。此外，研究还发现，多部位组织炎症，包括脂肪组织、肝脏、骨骼肌和胃肠道，都与胰岛素抵抗和代谢并发症的发展有关10。
内质网应激与氧化损伤：在代谢功能障碍相关脂肪性肝病（MASLD）的发生发展中，肝脏脂质积累会引发脂毒性，并通过介导内质网应激、氧化应激和线粒体功能障碍等机制，促进肝细胞损伤和炎症，最终导致胰岛素抵抗1511。这些应激反应会激活细胞内的信号通路，干扰胰岛素受体底物（IRS）的磷酸化，从而削弱胰岛素的正常生理作用。
肠道菌群碳水化合物代谢：肠道微生物群在胰岛素抵抗的发生发展中扮演着越来越重要的角色12。2023年的研究表明，肠道菌群的碳水化合物代谢与胰岛素抵抗密切相关13。胰岛素抵抗个体粪便中的碳水化合物，特别是宿主可利用的单糖含量增加，这与微生物的碳水化合物代谢及宿主炎症细胞因子相关联13。研究还发现，与胰岛素敏感性相关的细菌能改善小鼠模型中的胰岛素抵抗表型，提示肠道菌群作为潜在的治疗靶点13。此外，肠道菌群对宿主整体能量提取的贡献高达10%，其在肥胖和糖尿病前期发病机制中的作用不容忽视13。门静脉富集的肠道来源代谢物，能够通过影响肝脏代谢，进而调控胰岛素抵抗14。
脂肪组织异质性：肥胖个体代谢表型的巨大异质性推动了对脂肪组织功能障碍的深入研究。2024年的一项单细胞RNA测序研究揭示了肥胖个体中代谢健康与不健康状态下脂肪组织的细胞组成和基因表达差异15。该研究发现，间皮细胞、脂肪细胞和脂肪细胞祖细胞与代谢疾病的关联最为密切15。特别是，间皮细胞向间充质表型的转变可能与代谢健康型肥胖（MHO）的发生机制有关15。此外，脂肪细胞祖细胞在支持脂肪细胞周转和维持脂肪组织完整性方面发挥重要作用，其功能障碍被认为是脂肪功能失调的关键事件7。有研究指出，瞬时饮食干预通过诱导健康的脂肪组织扩张，可能在小鼠中实现代谢健康型肥胖，这与酮体抑制脂肪组织成纤维细胞活化有关16。而抑制脂肪细胞中的ABHD6酶活性，可以促进抗炎和促脂肪生成程序，从而在肥胖中维持脂肪组织的健康，减少代谢并发症17。多囊卵巢综合征（PCOS）患者的脂肪组织功能障碍也显示出其对胰岛素敏感性和炎症的重要影响，即使在无明显肥胖的PCOS患者中，脂肪组织的储存能力、缺氧、增生异常、脂肪生成受损以及胰岛素信号传导障碍等机制也普遍存在18。
1.2 关键分子靶点的挖掘
胰岛素抵抗的核心在于细胞对胰岛素信号响应能力的下降，这通常表现为胰岛素信号通路（IRS-PI3K/Akt）的异常以及葡萄糖转运蛋白4（GLUT4）转运障碍。深入理解这些关键分子的调控机制，对于开发新的治疗策略至关重要。
胰岛素信号通路与GLUT4转运的调控异常：
胰岛素通过与受体结合，激活下游信号通路，其中磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（Akt）通路是调节葡萄糖摄取和代谢的关键。Akt激活后，能促进GLUT4从细胞内囊泡向细胞膜转运，从而增加细胞对葡萄糖的摄取。在胰岛素抵抗状态下，该通路常受到抑制。例如，在ob/ob小鼠模型中，HM-chromanone（一种均异黄酮化合物）通过增加IRS-1酪氨酸磷酸化、PI3K和Akt的磷酸化，并促进骨骼肌中质膜GLUT4（PM-GLUT4）的表达，显著改善了胰岛素抵抗，这表明对PI3K/Akt通路的有效激活是改善胰岛素敏感性的重要途径 19。此外，Sirtuin-3（Sirt3）作为一种线粒体脱乙酰酶，其激活剂Honokiol（HNK）能促进胰岛素受体β（IRβ）和PI3K/Akt/mTOR通路的活化，增加脂肪细胞的葡萄糖摄取和转运，从而改善胰岛素抵抗 20。二甲双胍作为一线胰岛素增敏剂，其作用机制也与增加GLUT4的表达和向细胞膜转运密切相关，这涉及胰岛素信号通路介质、AMPK以及多种GLUT4转运介质的调控 21。还有研究发现，Baicalin（黄芩苷）通过激活Akt/AS160/GLUT4通路，并上调GLUT4的mRNA表达，有效改善肥胖诱导的胰岛素抵抗 22。此外，近期研究表明，蛋白磷酸酶1γ（PP1γ）能够通过调控AKT2-AS160-GLUT4轴，影响神经元的胰岛素信号传导和胰岛素抵抗 23。
脂毒性与神经酰胺：
脂毒性是胰岛素抵抗发展中的一个重要因素，指非脂肪组织中脂质积累及其代谢产物（如神经酰胺、二酰基甘油）对细胞的有害影响 24。神经酰胺是一类鞘脂，其异常积累已被证实能够直接损伤胰岛素信号通路，加剧胰岛素抵抗和肝脏脂肪变性。2019年的研究发现，通过基因工程小鼠缺失二氢神经酰胺去饱和酶1（DES1），该酶负责在神经酰胺骨架中插入一个双键，能够解决瘦素缺乏或肥胖饮食引起的肝脏脂肪变性和胰岛素抵抗 25。这一发现提示，靶向神经酰胺合成途径中的特定酶可能是治疗代谢性疾病的有效策略。此外，最近一项2025年的研究指出，神经酰胺积累会诱导非经典、非分泌型成纤维细胞生长因子13（FGF13）的表达，FGF13反过来会损害脂肪细胞功能，进而全身性地影响代谢健康。FGF13通过抑制线粒体含量和功能、代谢弹性以及小窝形成来损害葡萄糖利用和产热，提示FGF13可能是一个新的治疗靶点 26。
肌因子（Myokines）：
肌因子是由骨骼肌分泌的一类肽类物质，通过内分泌、旁分泌或自分泌方式调控其他器官的代谢。近年来，肌因子在胰岛素敏感性调节中的作用受到广泛关注。例如，FAM132b（肌生蛋白，myonectin）被鉴定为一种运动诱导的肌因子，具有调节脂质代谢的激素活性 2728。一项2022年的研究通过腺相关病毒（AAV9）在小鼠体内过表达密码子优化的FAM132b（coFAM132b），显著改善了高脂饮食诱导的葡萄糖不耐受和胰岛素抵抗，并减少了体重、脂肪堆积和脂肪细胞大小。该研究发现，coFAM132b可能通过阻断肾上腺素能反应和胰岛素作用来发挥其治疗肥胖的潜力，通过结构分析预测FAM132b突变体可能与β2肾上腺素受体（ADRB2）形成弱键，并对胰岛素及其受体复合物具有更高的亲和力 27。这表明FAM132b及其类似物可能成为治疗胰岛素抵抗的新型分子。
肝因子（Hepatokines）：
肝因子是由肝脏分泌的具有激素样作用的蛋白质，在全身能量代谢和器官间的通讯中扮演关键角色 2829。成纤维细胞生长因子21（FGF21）是其中一个重要成员，在肝脏应激条件下表达上调，并能改善胰岛素敏感性、减轻肝脏脂肪变性。例如，中链脂肪酸（MCFA）通过激活CREBH-FGF21轴来减少肝脏脂肪堆积，从而改善葡萄糖耐受和胰岛素敏感性 30。此外，肝细胞特异性GDF15过表达可诱导肝脏FGF21，进而改善高脂饮食诱导的肥胖和肝脏脂肪变性，GDF15通过促进eIF2α磷酸化和XBP1剪接来诱导FGF21 31。这表明FGF21在肝脏胰岛素抵抗的改善中具有重要治疗潜力。GLP1-Ras-FGF21-Fetuin-A的串扰也被提出作为代谢功能障碍相关脂肪性肝病（MASLD）的治疗靶点，强调了肝因子在MASLD和代谢疾病中的关键作用 32。
棕色脂肪因子（Brown Adipose Tissue-derived Factors）：
棕色脂肪组织（BAT）不仅通过产热消耗能量，还通过分泌多种生物活性分子（棕色脂肪因子）影响全身代谢 33。近期研究发现，冷暴露或β3-肾上腺素受体激动剂（如Mirabegron）激活BAT能提高人体的胰岛素敏感性，并伴随着血浆中脂质介质水平的升高 34。其中，Maresin 2（MaR2）作为一种促分辨率脂质介质，被发现由BAT在冷刺激和β3-肾上腺素刺激下产生。MaR2通过靶向肝脏中的巨噬细胞来减轻肥胖引起的炎症，从而改善胰岛素抵抗和葡萄糖耐受 33。这表明BAT及其分泌的因子，特别是MaR2，可能是治疗肥胖相关炎症和胰岛素抵抗的新策略。
2. 传统药物治疗的优化与临床证据升级
2.1 经典药物的疗效再评估
经典药物在胰岛素抵抗的治疗中仍占据重要地位，随着研究的深入，其疗效机制和应用场景正不断被优化和拓展。其中，二甲双胍和噻唑烷二酮类药物（TZDs）是两大核心药物，其在不同患者群体中的临床证据持续更新。
二甲双胍（Metformin）的疗效再评估
二甲双胍作为治疗2型糖尿病和胰岛素抵抗的一线药物，其主要作用机制包括抑制肝脏糖异生、增加外周组织对葡萄糖的摄取和利用、以及改善胰岛素敏感性。除了在2型糖尿病中的广泛应用，二甲双胍在多囊卵巢综合征（PCOS）合并胰岛素抵抗的女性中也显示出重要疗效。一项2022年发表的三臂随机对照试验（RCT）比较了针灸、二甲双胍（0.5g每日三次）和假针灸在PCOS合并胰岛素抵抗女性中的疗效 35。研究结果显示，经过4个月的治疗，二甲双胍组的HOMA-IR（稳态模型评估胰岛素抵抗指数）改善幅度（下降25.0%）优于真针灸组（下降14.7%）和假针灸组（下降8.6%），表明二甲双胍在改善胰岛素敏感性方面比真针灸更有效 35。
然而，二甲双胍的临床应用也伴随着其特有的副作用。该RCT研究发现，二甲双胍组患者胃肠道副作用（如腹泻、恶心、食欲不振、疲劳、呕吐和胃部不适）的发生率更高，分别为31.6%、13.2%、11.4%、8.8%、14.0%和8.8% 35。相比之下，真针灸组的主要副作用是瘀伤（14.9%），但胃肠道反应较少 35。这提示在PCOS患者中，对于无法耐受二甲双胍胃肠道副作用的个体，针灸可能作为一种非药物替代疗法来改善胰岛素抵抗，尽管其在HOMA-IR改善方面不如二甲双胍有效 35。
此外，二甲双胍在PCOS患者中的应用价值不仅体现在改善胰岛素抵抗，还在于提高临床妊娠率和排卵率 3637。然而，对于肥胖的PCOS女性，二甲双胍的活产率可能低于克罗米芬 36。尽管二甲双胍的胃肠道副作用发生率较高，但严重不良事件罕见，且没有致畸性证据 37。值得一提的是，一项针对2型糖尿病患者的早期研究也发现，小檗碱（berberine）在降糖和改善脂代谢方面的效果与二甲双胍相似，并且也能显著降低HOMA-IR指数，但同样有约34.5%的患者出现短暂性胃肠道副作用 38。
噻唑烷二酮类药物（TZDs）在NAFLD合并胰岛素抵抗中的应用进展
噻唑烷二酮类药物（TZDs），包括罗格列酮和吡格列酮，是过氧化物酶体增殖物激活受体-γ（PPAR-γ）的激动剂 39。PPAR-γ在脂肪组织、肝脏和肌肉等多个组织中广泛表达，其激活能够促进脂肪细胞分化、增加脂肪存储、改善胰岛素敏感性，并具有抗炎作用 3940。因此，TZDs被广泛应用于治疗2型糖尿病患者的胰岛素抵抗。
在非酒精性脂肪性肝病（NAFLD）合并胰岛素抵抗的患者中，TZDs显示出显著的治疗潜力。NAFLD通常被认为是代谢综合征的肝脏表现，与胰岛素抵抗和2型糖尿病密切相关 4142。TZDs通过激活PPAR-γ，可以改善肝脏脂肪变性、减轻肝脏炎症和纤维化，并提高全身胰岛素敏感性 394043。
例如，吡格列酮已被证实可以改善NAFLD患者的肝脏组织学，包括脂肪变性、炎症和气球样变，甚至可能逆转部分纤维化 42。一项系统评价和贝叶斯网络Meta分析指出，吡格列酮在NAFLD合并2型糖尿病患者中对糖化血红蛋白（HbA1c）的降低具有高度的可信度 44。此外，双重PPAR-α/γ激动剂，如Saroglitazar，也为NAFLD/NASH的治疗提供了新的选择。一项随机对照II期临床试验显示，Saroglitazar 4mg能显著改善NAFLD/NASH患者的丙氨酸转氨酶（ALT）、肝脏脂肪含量（LFC）、胰岛素抵抗和动脉粥样硬化性血脂异常 45。它通过同时作用于PPAR-α和PPAR-γ，更全面地调控脂质和糖代谢，从而发挥疗效 45。
尽管TZDs在改善胰岛素抵抗和NAFLD方面表现出色，但其潜在的副作用，如体重增加、水钠潴留和骨折风险增加，限制了其广泛应用。因此，未来的研究将更侧重于开发具有更优安全性特征的PPAR激动剂，或者与其他药物联用以发挥协同作用并减少不良反应。例如，一些中药成分如Antrodan通过调节AMPK/Sirt1/PPARγ/SREBP-1c信号通路，也能有效缓解高脂高果糖饮食诱导的NAFLD 46，这为探索传统药物与现代药物的结合提供了思路。
2.2 新型代谢调节药物的突破
近年来，以胰高血糖素样肽-1（GLP-1）受体激动剂为代表的新型代谢调节药物，在胰岛素抵抗的治疗中取得了突破性进展，展现出超越传统药物的多重疗效。此外，双重和三重受体激动剂的出现，进一步拓宽了治疗视野。
GLP-1受体激动剂（GLP-1RAs）的多效性
GLP-1受体激动剂，如司美格鲁肽（Semaglutide）和利拉鲁肽（Liraglutide），通过模拟天然GLP-1的作用，促进胰岛素分泌、抑制胰高血糖素分泌、延缓胃排空、增加饱腹感，从而有效控制血糖和减轻体重。其在改善胰岛素抵抗中的多效性日益得到证实：
减重效应：GLP-1RAs通过中枢神经系统作用于食欲中枢，减少食物摄入，从而显著减轻体重。体重的下降是改善胰岛素抵抗的关键因素之一。例如，司美格鲁肽被发现能显著降低高脂饮食诱导的肥胖小鼠的体重、体脂、空腹血糖和胰岛素水平，并改善胰岛素抵抗和敏感性损伤 47。有研究表明，司美格鲁肽治疗能使超重受试者的体重下降5% 48。
抗炎作用：GLP-1RAs具有直接或间接的抗炎特性，这有助于缓解胰岛素抵抗相关的慢性低级别炎症。司美格鲁肽被发现可以减少白色和棕色脂肪组织的重量，并降低GLP-1表达巨噬细胞中的促炎标志物，从而减轻炎症 49。
肝脏脂肪减少：代谢功能障碍相关脂肪性肝病（MASLD，旧称NAFLD）与胰岛素抵抗密切相关。GLP-1RAs在改善MASLD方面表现出色。司美格鲁肽能够显著降低肝脏脂肪含量。一项研究显示，经过16周的司美格鲁肽治疗，肥胖非糖尿病患者的肝脏脂肪含量下降了三分之一 48。这种改善与体重和身体脂肪测量的变化不相关，也与胰岛素敏感性的改善无关，提示司美格鲁肽可能通过抑制从头脂肪生成（de novo lipogenesis）来发挥作用，表现为VLDL-甘油三酯中棕榈酸和棕榈油酸比例的降低 4849。另一项针对2型糖尿病和NAFLD患者的研究也显示，司美格鲁肽联合二甲双胍治疗组在肝脏炎症标志物（ALT、AST）、纤维化（FIB-4指数）和胰岛β细胞功能（Matsuda指数）方面均优于单用二甲双胍组 50。多项研究，包括一项开放标签对照试验，均证实口服和注射用司美格鲁肽能改善NAFLD患者的血脂、肝酶、BMI，以及纤维化-4评分（FIB-4）、肝脏硬度测量（LSM）和受控衰减参数（CAP）等指标，尤其在注射用司美格鲁肽组中效果更为显著 5152。
改善胰岛β细胞功能和胰岛素敏感性：GLP-1RAs直接作用于胰岛β细胞，增强葡萄糖依赖性胰岛素分泌，并能改善胰岛素敏感性 5354。
MASH治疗的临床进展：对于代谢功能障碍相关脂肪性肝炎（MASH，旧称NASH）的治疗，GLP-1RAs已进入III期临床试验。例如，司美格鲁肽在III期试验中显示出改善MASH的潜力 55。虽然司美格鲁肽能有效改善MASH，但其在组织学纤维化缓解方面的效果仍有待进一步明确，并且其对MASH的益处是直接作用还是继发于体重减轻、胰岛素抵抗和血糖控制的改善，目前仍在争论中 49。
双/三重受体激动剂对胰岛素敏感性的协同提升
为了进一步增强治疗效果，研究人员开发了针对多种肠促胰素受体或与胰高血糖素受体协同作用的双重或三重激动剂。这些新型药物通过多靶点作用机制，有望提供更全面的代谢改善。
GLP-1/GIP双重激动剂：替尔泊肽（Tirzepatide）是一种葡萄糖依赖性促胰岛素多肽（GIP）和GLP-1受体的双重激动剂。临床研究表明，替尔泊肽在改善胰岛素敏感性和β细胞功能方面比单一GLP-1RA杜拉鲁肽（dulaglutide）更优 5356。替尔泊肽对胰岛素敏感性的改善部分归因于其显著的体重减轻效应，但其双重激动作用还通过独特的机制，提供了超越体重减轻的额外益处 5356。例如，替尔泊肽在糖尿病小鼠模型中，通过调节肠道菌群和胆汁酸代谢，有效减轻肝脏脂肪变性，甚至比司美格鲁肽表现出更优越的肝脏脂质积累减少效果 57。一项研究表明，替尔泊肽不仅显著改善了胰岛素敏感性，还提高了β细胞功能，同时对餐后血糖波动的影响也优于司美格鲁肽 53。
GLP-1/胰高血糖素双重激动剂：考塔杜肽（Cotadutide）是GLP-1和胰高血糖素受体的双重激动剂。在饮食诱导的肥胖小鼠模型中，考塔杜肽能够控制体重增加、改善葡萄糖耐受和胰岛素抵抗，并对血浆标志物（如甘油三酯、总胆固醇、ALT、AST）和肝脏脂肪堆积、炎症以及内质网应激具有有益作用 58。此外，它还能改善白色脂肪组织的脂质代谢基因表达，减少脂肪细胞肥大和凋亡 58。这类药物在管理脂肪性肾脏疾病和慢性肾病方面也显示出潜在价值 59。
GLP-1/FGF21双重激动剂：成纤维细胞生长因子21（FGF21）是一种重要的代谢调节因子，能够改善胰岛素敏感性并减轻肝脏脂肪变性 60。HEC88473是一种新型GLP-1/FGF21双重激动剂，在针对MASLD和2型糖尿病患者的临床Ib/IIa期研究中，经过5周治疗，HEC88473以剂量依赖性方式显著降低了肝脏脂肪含量（MRI-PDFF最大相对平均变化达-47.21%），并显著降低了HbA1c、空腹和餐后血糖水平，同时改善了血脂状况 61。这表明GLP-1/FGF21双重激动剂在全面改善代谢综合征方面具有广阔前景 61。
GLP-1RA/PPARɑ/ɣ双重激动剂偶联物：为了克服PPAR激动剂（如噻唑烷二酮类）的副作用，研究人员探索了将GLP-1RA与PPARɑ/ɣ双重激动剂（如替格列扎）偶联，形成GLP-1RA/替格列扎分子。这种偶联物通过GLP-1R介导的细胞递送，能在肥胖小鼠中比单独使用GLP-1RA或替格列扎更有效地改善体重、食物摄入和葡萄糖代谢，且在GLP-1R敲除小鼠中失去作用 62。这提示通过靶向递送策略，有望提高药物疗效并减少副作用 62。
总之，新型代谢调节药物，特别是多靶点激动剂，通过整合多种代谢通路的调控，为胰岛素抵抗的治疗带来了革新。它们不仅在减重、降糖和改善肝脏脂肪变性方面表现出卓越疗效，还可能通过抗炎、改善肠道菌群等机制，提供更全面的代谢健康益处。
3. 非药物干预的创新模式与实践验证
非药物干预，尤其是饮食和运动，是胰岛素抵抗管理的基础，也是核心组成部分。近年来，随着对个体代谢差异和干预机制的深入理解，非药物干预模式呈现出精准化和协同化的趋势，为胰岛素抵抗的治疗提供了更多创新路径。
3.1 饮食干预的精准化探索
饮食干预在改善胰岛素抵抗方面发挥着至关重要的作用。随着研究的深入，针对不同碳水化合物摄入量的饮食模式，如低碳饮食、地中海饮食等，在改善胰岛素抵抗和相关代谢指标方面的效果、机制及其长期依从性挑战，正成为精准化营养探索的热点。
低碳饮食（Low-Carbohydrate Diets, LCDs）的剂量效应：
低碳饮食通常定义为每日碳水化合物摄入量低于130克，或占总能量摄入的26%以下。这种饮食模式通过减少碳水化合物摄入，进而降低餐后血糖和胰岛素反应，从而改善胰岛素抵抗。多项研究证实了低碳饮食在改善胰岛素抵抗方面的有效性。
一项针对2型糖尿病患者的系统评价和Meta分析（2021年）发现，持续6个月的低碳饮食能显著提高糖尿病缓解率。在定义为HbA1c < 6.5%（无论是否用药）的缓解标准下，低碳饮食组的缓解率高达57%（76/133），显著高于对照组的31%（41/131），风险差异为0.32 63。这项研究强调了低碳饮食在短期内（6个月）对糖尿病缓解的积极作用，同时伴随着体重减轻、甘油三酯水平降低和胰岛素敏感性改善等临床重要益处 63。
对于胰岛素抵抗性血脂异常（Insulin-Resistant Dyslipoproteinemia）患者，低碳饮食也表现出显著优势。一项随机对照喂养试验（2022年）比较了不同碳水化合物和饱和脂肪比例的饮食对体重维持期心血管疾病风险因素的影响。结果显示，低碳饮食组（碳水化合物占20%，饱和脂肪占21%）的脂蛋白胰岛素抵抗（LPIR）评分平均降低5.3分（95% CI: -9.2, -1.5），显著优于中碳饮食组（LPIR平均变化-0.02）和高碳饮食组（LPIR平均变化3.6），呈现出剂量依赖性效应（P = 0.009）64。此外，低碳饮食组的脂蛋白(a)水平也显著下降14.7%，甘油三酯和高密度脂蛋白胆固醇（HDL-C）也得到有利改善，且未对低密度脂蛋白胆固醇（LDL-C）产生不良影响 64。这表明，即使含有相对较高的饱和脂肪，低碳饮食也能通过改善胰岛素抵抗性血脂异常，独立于体重减轻而降低心血管疾病风险 64。
在非酒精性脂肪性肝病（NAFLD）患者中，低碳水化合物高纤维饮食结合健康教育，在2个月后显著降低了体重、体脂、腹围、内脏脂肪面积、空腹血糖、胰岛素抵抗指数以及ALT、AST、尿酸和胰岛素水平 65。这进一步支持了低碳饮食在改善胰岛素抵抗相关代谢紊乱方面的广泛应用潜力。
地中海饮食（Mediterranean Diet）的益处：
地中海饮食以其富含水果、蔬菜、全谷物、豆类、坚果、橄榄油以及适量鱼类、家禽和乳制品，限制红肉和加工食品的特点，被广泛认为是健康的饮食模式。其对胰岛素抵抗的改善作用主要通过其抗炎、抗氧化和对肠道菌群的积极影响来实现。
一项系统评价（2019年）综合分析了多种饮食模式对2型糖尿病管理的影响。结果显示，地中海饮食在体重减轻和HbA1c水平降低方面表现出显著优势，并能延缓对糖尿病药物的需求 66。另一项针对生殖年龄女性的研究（2020年）发现，地中海饮食评分的增加与卵巢体积的减小相关，这种关联主要通过减少腰围、改善胰岛素抵抗（通过葡萄糖耐量试验后的葡萄糖反应）和降低游离雄激素指数来介导 67。这提示地中海饮食通过多重机制间接改善了与胰岛素抵抗相关的多囊卵巢综合征（PCOS）等女性健康问题。
极低碳水饮食（Very Low-Carbohydrate Diets, VLCDs）的长期依从性挑战：
极低碳水饮食通常指碳水化合物摄入量低于总能量的10%，或每日少于20-50克，旨在诱导身体进入酮症状态。虽然VLCDs在快速减重和短期内显著改善血糖控制方面表现出色，但其长期依从性却是一个重大挑战。
2021年的Meta分析指出，尽管VLCDs在6个月时对体重减轻效果显著，但在12个月时，这种效果会减弱 63。研究还发现，VLCDs的有效性在很大程度上取决于患者的依从性：依从性高的VLCD患者体重减轻效果显著，而依从性差的患者则不然 63。此外，与限制性较小的低碳饮食相比，VLCDs在6个月时对体重减轻的效果反而更差，这可能与更严格的限制导致依从性下降有关 63。
长期严格限制碳水化合物可能导致营养不均衡、纤维摄入不足，并可能引发便秘、电解质紊乱、酮症流感等副作用。同时，其社会适应性也较差，难以长期坚持。因此，在推荐VLCDs时，需要充分评估患者的健康状况、生活方式和依从性，并提供专业的营养指导和长期监测，以确保其安全性和有效性。对于大多数胰岛素抵抗患者而言，选择可持续且均衡的低碳或中等碳水化合物饮食，如地中海饮食，可能更具长期依从性和健康效益。
3.2 运动与间歇性禁食的协同效应
运动和间歇性禁食（Intermittent Fasting, IF）是两种独立的非药物干预措施，已被广泛证实对改善胰岛素抵抗和代谢健康具有益处。近年来，研究发现将这两种干预手段相结合，可能产生协同效应，尤其是在处理非酒精性脂肪性肝病（NAFLD）等胰岛素抵抗相关疾病方面。
间歇性禁食（IF）对胰岛素抵抗的影响
间歇性禁食模式包括多种形式，如隔日禁食（Alternate-Day Fasting, ADF）、限时进食（Time-Restricted Eating, TRE）和5:2饮食法。这些模式通过限制进食时间和/或减少卡路里摄入，启动身体的代谢转换，促进脂肪分解和能量代谢重塑。
多项研究证实了间歇性禁食对改善胰岛素抵抗的积极作用：
- 一项针对NAFLD患者的系统回顾和Meta分析（2024年）显示，IF方案（包括5:2饮食、16/8限时进食和隔日禁食）能显著降低NAFLD患者的肝脏脂肪变性评分（WMD: -33.22 CAP dB/m, 95% CI: -50.72 to -15.72）、体重指数（WMD: -0.77 kg/m²）、体重（WMD: -3.16 kg）、腰围（WMD: -1.90 kg），以及丙氨酸转氨酶（ALT）、甘油三酯、总胆固醇和糖化血红蛋白（HbA1c）水平，同时HOMA-IR指数也显著降低（WMD: -1.21, 95% CI: -2.08 to -0.34）68。
- 2019年的一项研究发现，限时进食（每日进食窗口限制在10小时）在代谢综合征患者中，即使在大多数患者正在接受他汀类药物和/或降压治疗的情况下，也能改善心脏代谢健康，包括体重、血压和致动脉粥样硬化脂质水平69。
- 间歇性禁食被认为通过诱导代谢重编程、促进自噬、改善昼夜节律、调节肠道菌群以及减少炎症和氧化应激来发挥作用，这些机制共同有助于提升胰岛素敏感性7071。
运动对胰岛素抵抗的影响
规律的体育锻炼，特别是结合有氧运动和抗阻训练，是改善胰岛素敏感性的有效策略。运动通过增加葡萄糖摄取、改善胰岛素信号通路、增加肌肉质量、减少脂肪堆积以及释放肌因子等多种机制发挥作用。
- 运动可直接促进骨骼肌葡萄糖转运蛋白GLUT4向细胞膜的转位，即使在胰岛素水平较低的情况下也能增加葡萄糖摄取。
- 长期运动有助于减少内脏脂肪，降低全身炎症水平，从而间接改善胰岛素敏感性。
- 一些肌因子，如鸢尾素（Irisin），在运动时释放，能够促进白色脂肪棕色化，增加能量消耗，从而改善代谢健康。
运动与间歇性禁食的协同效应
将间歇性禁食与运动结合起来，旨在通过不同的生理途径共同优化代谢健康，从而可能带来超越单一干预的协同效益。
一项2023年针对NAFLD患者的随机对照试验（RCT）研究了隔日禁食（ADF）联合有氧运动（每周5次，每次60分钟中等强度）对肝内甘油三酯（IHTG）含量和胰岛素敏感性的影响7273。该研究将肥胖和NAFLD患者（n=80）随机分为四组：ADF+运动组合组、ADF单独组、运动单独组和无干预对照组。
- 对肝内甘油三酯（IHTG）的影响：经过3个月的干预，组合组的IHTG含量显著降低了5.48%（95% CI, -7.77%至-3.18%），与运动单独组（-1.30%）和对照组（-0.17%）相比差异显著（p=0.02和p<0.01）。尽管组合组的IHTG下降幅度大于ADF单独组（-2.25%），但统计学上无显著差异（p=0.05）。这表明，组合干预在降低肝脏脂肪方面具有强大潜力，虽然其相对于ADF单独使用是否能提供额外的显著益处仍需进一步探讨72。
- 对胰岛素敏感性的提升：该研究还发现，与对照组相比，组合组的体重、脂肪量、腰围和ALT水平显著降低，而胰岛素敏感性显著增加72。这提示运动与禁食的结合可能通过多重机制，包括脂肪分解和能量代谢重塑，全面改善代谢状况。
- 机制探讨：IF结合运动可能通过以下机制发挥协同作用：运动可以增加肌肉对葡萄糖的利用，而IF则通过延长禁食期促进脂肪酸氧化，两者共同减少异位脂肪积累，从而减轻肝脏和肌肉的胰岛素抵抗。IF诱导的代谢转换可能增强运动训练带来的线粒体生物发生和功能改善。此外，两者都可能影响肠道菌群，进一步改善代谢调节71。
另一项系统回顾和Meta分析（2024年）评估了限时进食（TRF）结合抗阻训练（RT）的协同效应。结果显示，与对照组（常规饮食+抗阻训练）相比，TRF+RT显著减少了体重（WMD -2.90 kg）、脂肪量（WMD -1.52 kg）、胰岛素（SMD -0.72）、总胆固醇（WMD -9.44 mg/dL）和低密度脂蛋白胆固醇（LDL-C）（WMD -9.94 mg/dL），并且显著降低了能量摄入，而对肌肉量和力量没有负面影响74。这表明，结合TRF和RT是一种有效的方法，可以同时改善身体成分和代谢健康，特别是在不损害肌肉性能的前提下。
尽管运动与间歇性禁食的结合显示出显著的潜力，但长期依从性、个体差异以及针对不同疾病状态的最佳组合方案仍需进一步深入研究。例如，一项研究指出，ADF联合运动虽然能显著减重和降低IHTG，但并未改善NAFLD患者的睡眠质量、睡眠时长或阻塞性睡眠呼吸暂停的风险73。这提示在设计综合干预方案时，需要考虑其对不同健康结局的全面影响。
4. 新兴治疗技术的突破性进展
4.1 基因与细胞治疗的临床转化
随着分子生物学和细胞工程技术的飞速发展，基因治疗和细胞治疗为胰岛素抵抗的治疗带来了全新的视角和突破性进展。这些新兴技术旨在从基因层面或细胞层面直接干预病理过程，有望实现持久甚至治愈性的效果。
AAV介导的基因疗法：精准靶向与多器官获益
腺相关病毒（AAV）载体因其较低的免疫原性、较长的基因表达时间和较好的组织特异性，成为基因治疗领域的热门载体。近年来，AAV介导的基因疗法在改善胰岛素抵抗和相关并发症方面展现出巨大潜力。
cBIN1修复心肌横管微结构改善GLUT4转运：
糖尿病心肌病（Diabetic Cardiomyopathy, DCM）是糖尿病的严重并发症之一，表现为心肌收缩功能障碍，并且常伴有胰岛素抵抗和高血糖。研究发现，在2型糖尿病诱导的db/db小鼠中，心肌细胞横管微结构异常重塑，伴随着心脏桥接整合蛋白1（cardiac bridging integrator 1, cBIN1）的下调。cBIN1是一种膜支架蛋白，在维持心肌细胞横管的正常结构和功能中发挥关键作用。横管微结构的完整性对于葡萄糖转运蛋白4（GLUT4）的正常转运和心肌细胞的葡萄糖摄取至关重要。
2023年的一项研究表明，通过AAV9基因疗法在心脏中特异性表达cBIN1，能够恢复db/db糖尿病小鼠心肌细胞的横管微结构。令人惊讶的是，这种干预不仅使钙处理蛋白（对心脏收缩至关重要）的细胞内分布恢复正常，还显著改善了GLUT4的异常分布75。心脏蛋白质组学分析进一步证实，AAV9-cBIN1使钙处理和GLUT4转运机制的组分恢复正常。功能研究显示，AAV9-cBIN1使糖尿病心肌细胞中胰岛素依赖性的葡萄糖摄取恢复正常。从表型上看，AAV9-cBIN1不仅改善了糖尿病小鼠的心脏舒张功能，提高了运动耐受性，还出人意料地减轻了全身高血糖75。这一发现提示，修复心肌细胞横管微结构，即使是在心脏特异性干预下，也能够改善全身血糖控制，为糖尿病心肌病和胰岛素抵抗的治疗提供了新的思路75。肌肉靶向FGF21过表达逆转MASH：
代谢功能障碍相关脂肪性肝炎（MASH，旧称NASH）是一种高度流行的疾病，与肝脏脂肪变性、炎症和肝细胞损伤相关，可进展为肝纤维化、肝细胞癌甚至死亡。目前MASH的治疗选择有限。成纤维细胞生长因子21（FGF21）是一种关键的代谢调节因子，能够改善胰岛素敏感性、减轻肝脏脂肪变性。
2024年的一项研究描述了通过一次性肌肉注射血清型1腺相关病毒载体（AAV1），编码天然FGF21（AAV1-FGF21），在肥胖雄性和雌性小鼠模型中实现了FGF21循环水平的持续升高。这种基因疗法在长期（>1年）内逆转了MASH和肝纤维化，并阻止了肝肿瘤的发生76。AAV1-FGF21治疗还对抗了肥胖、脂肪堆积和胰岛素抵抗，这些都是MASH的重要驱动因素76。为了向临床转化迈进，研究者成功将该方法扩展到大型动物模型（犬），实现了安全有效的骨骼肌生物分布和关键代谢组织中的生物活性。此外，研究还对肥胖、胰岛素抵抗和MASH患者的循环FGF21水平进行了表征76。这些结果强调了肌肉靶向AAV1-FGF21基因疗法治疗MASH的潜力，并支持其临床转化76。PLA2G12A基因疗法抗肥胖和胰岛素抵抗：
分泌型磷脂酶A2（sPLA2s）家族与肥胖、2型糖尿病和心血管疾病的发生发展有关。一项基因组关联研究和基因共表达网络分析表明，sPLA2 XIIA组（PLA2G12A）可能参与肝脏脂质代谢。2024年的一项研究利用携带人PLA2G12A基因的AAV9载体，在小鼠肝脏中异源表达hPLA2G12A。结果显示，hPLA2G12A的过表达显著降低了喂食普通饲料或高脂饮食（HFD）的野生型小鼠的血清脂质水平。更重要的是，hPLA2G12A治疗保护了HFD喂养小鼠免受饮食诱导的肥胖和胰岛素抵抗77。值得注意的是，hPLA2G12A的保护作用与其酶活性无关，而是通过增加身体活动和能量消耗来实现。此外，研究发现hPLA2G12A治疗诱导了载脂蛋白C2（ApoC2）和CD36的上调，以及血管生成素样蛋白8（Angptl8）的下调，从而促进了循环甘油三酯的清除和肝脏对脂肪酸的摄取，而未影响肝脏从头脂肪生成、极低密度脂蛋白分泌或肠道脂质吸收77。这项研究揭示了PLA2G12A基因疗法作为治疗肥胖、胰岛素抵抗和2型糖尿病的潜在新方法77。
脂肪间充质干细胞（ADMSCs）及其外泌体：旁分泌调节胰岛素信号
间充质干细胞（MSCs）因其多能性、免疫调节和旁分泌特性，在代谢综合征和胰岛素抵抗的治疗中受到广泛关注7879。其中，脂肪组织来源的间充质干细胞（ADMSCs）易于获取，并且具有良好的增殖能力和分化潜力。
ADMSCs直接作用：
ADMSCs可以通过分泌多种生物活性分子（如细胞因子、生长因子）来调节胰岛素信号传导。它们能够抑制炎症，改善胰岛素抵抗，调节糖脂代谢，并保护受损器官功能78。在临床前研究中，ADMSCs移植已被证明可以改善糖尿病小鼠模型的血糖控制和胰岛素敏感性。然而，自体MSCs在代谢紊乱的微环境中可能存在功能受损的问题，且不同来源MSCs的特性和疗效差异仍需明确7879。ADMSCs外泌体的旁分泌作用：
ADMSCs的外泌体是ADMSCs旁分泌效应的关键介质。外泌体是细胞分泌的纳米级囊泡，富含蛋白质、脂质、mRNA和microRNA，可作为细胞间通讯的载体，将遗传信息传递给靶细胞，从而调节基因表达80。在胰岛素抵抗的背景下，ADMSCs及其外泌体通过多种机制发挥作用：- 改善炎症：ADMSCs外泌体携带的抗炎microRNA和蛋白，可以调节巨噬细胞的极化，减少促炎细胞因子的释放，从而减轻慢性低级别炎症，进而改善胰岛素敏感性80。
- 调节脂肪生成和棕色化：ADMSCs外泌体可以影响脂肪细胞的分化和功能，促进白色脂肪组织棕色化，增加能量消耗，有助于改善肥胖相关的胰岛素抵抗80。
- 影响胰岛素信号通路：外泌体中的microRNA可以靶向胰岛素信号通路中的关键基因，调节其表达，从而改善细胞对胰岛素的响应。例如，某些microRNA被发现可以提高胰岛素受体底物-1（IRS-1）的表达或磷酸化，进而增强PI3K/Akt信号通路。
- 促进血管生成和组织修复：外泌体还含有血管生成因子，有助于改善微循环，为受损组织提供氧气和营养，间接改善代谢功能。
尽管ADMSCs及其外泌体在改善胰岛素抵抗方面展现出巨大潜力，但其临床转化仍面临挑战，包括细胞来源和制备的标准化、纯化外泌体的量产、体内稳定性、靶向递送效率以及长期安全性和有效性评估7879。未来的研究需要更大规模、设计更严谨的临床试验，以验证其在人类患者中的疗效和安全性，并开发更有效的递送策略和生物标志物来预测治疗反应。
4.2 精准医学模式的应用实践
精准医学的核心理念是根据个体的基因、环境和生活方式的差异，为患者提供定制化的预防和治疗方案。在胰岛素抵抗这一复杂的代谢性疾病管理中，精准医学模式正逐步展现其巨大潜力，特别是在处理具有复杂共病的患者时，能够实现“一人一方”的靶向干预 81。
多组学检测与靶向干预：以阿尔茨海默病为例
尽管阿尔茨海默病（AD）与胰岛素抵抗并非同一疾病，但两者之间存在复杂的关联，AD常被称为“3型糖尿病”，表明胰岛素抵抗在中枢神经系统中的作用。参考文献82讨论了罗格列酮治疗阿尔茨海默病的个性化疗法，这为胰岛素抵抗的精准医学实践提供了重要启示，即针对个体特征进行靶向干预。
胰岛素抵抗的精准干预策略：多维度评估与“一人一方”
借鉴AD精准医学的经验，胰岛素抵抗的精准干预策略应基于以下多维度评估：
炎症状态评估：胰岛素抵抗常常伴随着慢性低级别炎症，特别是脂肪组织炎症。通过检测C反应蛋白（CRP）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）等炎症标志物，以及更精细的脂肪因子谱（如脂联素、抵抗素），可以评估个体炎症负荷。例如，高CRP水平与肥胖和2型糖尿病患者的胰岛素抵抗密切相关 83。基于炎症状态，可选择具有抗炎作用的药物（如噻唑烷二酮类）或非药物干预（如Omega-3脂肪酸补充剂 83）进行靶向治疗。
激素水平分析：胰岛素抵抗受多种内分泌激素的影响。例如，皮质醇、甲状腺激素、性激素（如睾酮、雌激素）的失衡都可能加重胰岛素抵抗。在儿童肥胖中，性激素失调与胰岛素抵抗引起的性别特异性金属元素改变有关 84。精确测定这些激素水平，有助于制定更具针对性的治疗方案，如在绝经后女性中评估激素替代疗法（HRT）的潜力。
营养与代谢组学分析：个体对不同营养素的代谢反应存在显著差异。通过代谢组学分析，可以识别与胰岛素抵抗相关的代谢通路紊乱以及特定的生物标志物。例如，肠道菌群与胰岛素抵抗的相互作用日益受到关注 85。不同营养负荷（如碳水化合物、蛋白质、脂肪）对胰岛素分泌和外周胰岛素抵抗的影响可以通过动态多组学分析进行预测，揭示了不同宏量营养素在介导胰岛素抵抗和胰岛β细胞功能中的分子基础，为精准营养干预提供了依据 86。此外，高糖饮食与高胰岛素血症导致高尿酸血症，而高尿酸又加重胰岛素抵抗。这些发现提示，根据个体的营养代谢特征，可以设计个性化的饮食干预方案，如DASH饮食 87。
遗传背景评估：基因多态性影响个体对胰岛素抵抗的易感性及其对治疗的反应。例如，某些基因变异可能影响药物代谢酶的活性，从而改变药物的疗效和安全性。虽然目前尚未广泛应用于常规临床实践，但基因组学信息有望指导胰岛素抵抗的药物选择，如SGLT2抑制剂或GLP-1受体激动剂在不同糖尿病亚型中的差异化疗效 88。
肠道微生物组分析：肠道菌群在胰岛素抵抗中扮演关键角色。微生物群落的组成和功能失调（菌群失调）可以通过影响宿主能量代谢、炎症反应、短链脂肪酸生成等多个途径，加重胰岛素抵抗 8589。通过宏基因组学、代谢组学等技术，分析个体肠道菌群的特征，可以指导益生菌、益生元或粪菌移植等干预措施，以恢复肠道生态平衡，改善胰岛素敏感性。
“一人一方”在复杂共病中的优势
胰岛素抵抗患者常伴有多种共病，例如2型糖尿病、肥胖、高血压、血脂异常、非酒精性脂肪性肝病、以及抑郁症等 9091。在这些复杂情况下，单一的治疗方案往往难以奏效。精准医学的“一人一方”策略能够：
- 优化治疗选择：例如，对于合并抑郁症的2型糖尿病患者，某些抗抑郁药物可能加重胰岛素抵抗，而另一些则可能改善血糖控制 90。通过精准评估，可以选择对代谢影响最小或有益的药物。
- 降低副作用风险：通过评估个体对药物的反应和代谢能力，避免不必要的或潜在有害的治疗。
- 提升疗效：多维度评估有助于识别驱动疾病的核心机制，从而选择最有效的靶向干预措施，例如，通过改善饮食质量和降低全身免疫炎症指数来介导牙齿脱落与胰岛素抵抗之间的关系 92。
- 改善生活质量：个性化的饮食、运动和生活方式建议更易被患者接受和长期依从，从而带来更持续的健康改善。
总之，精准医学模式为胰岛素抵抗的治疗提供了前所未有的机遇。通过整合多组学数据，对患者进行全面、细致的生物学评估，我们将能够更有效地识别个体差异，制定更具针对性的干预策略，最终实现胰岛素抵抗及其复杂共病的“一人一方”定制化管理。
5. 特殊人群与共病的针对性治疗策略
5.1 女性相关疾病（PCOS、绝经）的管理
女性生命周期中的激素变化，特别是与多囊卵巢综合征（PCOS）和绝经相关的内分泌失调，是胰岛素抵抗发生发展的重要驱动因素。针对这些特殊人群的胰岛素抵抗管理，需要结合其独特的病理生理机制，采取更具针对性的治疗策略。
多囊卵巢综合征（PCOS）中胰岛素抵抗的双向调控
PCOS是育龄期女性最常见的内分泌疾病，其特征包括慢性排卵障碍、高雄激素血症和胰岛素抵抗 93。胰岛素抵抗被认为是PCOS发病机制中的核心环节，它加剧了高雄激素血症，并增加了2型糖尿病、心血管疾病和子宫内膜癌的风险 93949596。PCOS患者即使在没有明显肥胖的情况下，也普遍存在脂肪组织功能障碍，例如储存能力受损、缺氧、脂肪生成受损以及胰岛素信号传导障碍等，这进一步强调了胰岛素抵抗在PCOS中的关键作用。
针对PCOS中的胰岛素抵抗，治疗策略通常采取双向调控，即联合抗雄激素治疗与胰岛素增敏剂：
胰岛素增敏剂：
- 二甲双胍：作为PCOS胰岛素抵抗治疗的一线药物，二甲双胍通过改善胰岛素敏感性，降低胰岛素水平，从而间接减少卵巢雄激素的产生，改善排卵功能和月经周期 9497。然而，二甲双胍常见的胃肠道副作用限制了部分患者的依从性 98。
- 肌醇（Inositol）：近年来，肌醇（尤其是肌醇和D-手性肌醇的组合）作为一种有效的胰岛素增敏剂受到广泛关注。多项研究表明，肌醇在改善PCOS患者的月经周期、BMI、游离睾酮、总睾酮、雄烯二酮以及葡萄糖和胰岛素水平方面显示出非劣效于甚至优于二甲双胍的效果，且副作用更少 9899100。一项系统回顾和Meta分析指出，肌醇是治疗PCOS的一种有效且安全的药物，其在大多数结果方面与金标准治疗二甲双胍相比具有非劣效性 98。另一项研究也证实，肌醇与二甲双胍在改善PCOS女性的体重、胰岛素敏感性和月经周期方面效果相似 97。
- 噻唑烷二酮类（TZDs）：与二甲双胍类似，噻唑烷二酮类药物（如吡格列酮）也能有效改善PCOS患者的胰岛素抵抗，并通过降低HOMA-IR指数来体现，其效果可能优于单一的二甲双胍治疗 100。
抗雄激素与信号通路靶向治疗：
PCOS患者的高雄激素血症不仅是其诊断标准之一，也与胰岛素抵抗互为因果，形成恶性循环 93。因此，通过抗雄激素治疗可以改善PCOS的临床症状。- 信号通路靶向治疗：2023年的研究深入探讨了PCOS的分子机制，并提出基于信号通路（如PI3K/Akt、TGF-β、Wnt/β-catenin和Hippo/YAP）的靶向治疗策略 101。
- PI3K/Akt通路：该通路在胰岛素信号传导中发挥核心作用。PCOS患者中该通路的异常激活或抑制可能导致胰岛素抵抗和雄激素过量生产。靶向调节PI3K/Akt通路有望改善胰岛素敏感性。
- TGF-β通路：转化生长因子-β（TGF-β）及其相关信号通路在卵巢功能、卵泡发育和纤维化中扮演重要角色。PCOS患者卵巢内的TGF-β信号异常可能导致卵泡发育受损 101。靶向TGF-β信号通路有望改善卵巢功能，从而间接缓解胰岛素抵抗。
- 药物组合：在实际临床中，抗雄激素药物（如螺内酯、氟他胺）常与胰岛素增敏剂或口服避孕药联合使用，以更全面地管理PCOS症状，包括高雄激素血症和胰岛素抵抗。例如，替尔泊肽（Tirzepatide）作为GLP-1和GIP双重激动剂，因其在改善肥胖、胰岛素抵抗和生殖功能障碍方面的潜力，被认为可能对肥胖合并代谢综合征的PCOS患者有益 102。
- 信号通路靶向治疗：2023年的研究深入探讨了PCOS的分子机制，并提出基于信号通路（如PI3K/Akt、TGF-β、Wnt/β-catenin和Hippo/YAP）的靶向治疗策略 101。
绝经后雌激素缺乏与胰岛素抵抗
绝经是女性生理过程中的一个重要转折点，其特征是卵巢功能衰退导致雌激素水平急剧下降。雌激素缺乏是导致绝经后女性代谢紊乱和胰岛素抵抗加重的重要因素 103104。
机制：
- 脂肪分布改变：雌激素的减少会引起脂肪重新分布，促使脂肪从皮下组织向内脏区域转移，导致腹部脂肪堆积增加 103105106。内脏脂肪的增多与胰岛素抵抗的发生密切相关，因为它会分泌更多的促炎因子和脂肪因子，干扰胰岛素信号传导。一项研究表明，在绝经后女性中，循环雌二醇水平与两年内内脏脂肪增加呈负相关，提示较高的雌二醇水平可能有助于限制脂肪在腹腔内的沉积 106。
- 炎症和氧化应激：绝经后雌激素水平的下降与炎症和氧化应激有关 103。这两种状态被认为是胰岛素抵抗的重要驱动因素。
- 直接影响胰岛素敏感性：雌激素及其受体在脂肪组织、肌肉和肝脏等胰岛素敏感组织中广泛表达 104107。雌激素可以直接影响胰岛素信号通路，促进葡萄糖摄取和利用。一项研究发现，在绝经后女性中，雌二醇能够抑制人脂肪细胞的葡萄糖利用，并增加雌激素受体2（ESR2）的表达，这提示雌激素对葡萄糖利用的调节在绝经后不同时期可能存在差异 104。然而，也有研究表明，卵巢切除术后给予雌激素治疗可以改善高脂饮食诱导的小鼠胰岛素敏感性，并减少肝脏脂质沉积 107。
激素替代疗法（HRT）的潜在价值：
激素替代疗法通过补充雌激素，旨在缓解绝经症状并改善远期健康结局。在改善绝经后女性胰岛素抵抗方面，HRT显示出一定的潜力：
综上所述，针对PCOS和绝经期女性的胰岛素抵抗管理，需要综合考虑内分泌失调的具体类型、患者的临床症状、代谢状态以及伴随疾病，制定个体化的治疗方案。在药物选择上，应平衡疗效与安全性，并积极探索新型治疗手段，以期达到最佳的治疗效果。
5.2 代谢关联疾病（CKM综合征、NAFLD）的综合干预
胰岛素抵抗是多种代谢关联疾病（Metabolic Associated Diseases, MADs）共同的病理生理基础，其在心血管-肾脏-代谢（Cardiovascular-Kidney-Metabolic, CKM）综合征和代谢功能障碍相关脂肪性肝病（Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD，原称NAFLD）等疾病的发生发展中扮演着核心角色。理解胰岛素抵抗在这些复杂疾病“代谢-炎症-器官损伤”轴中的作用，对于制定综合干预策略至关重要。
CKM综合征中的胰岛素抵抗与“代谢-炎症-器官损伤”轴
CKM综合征是由美国心脏协会（AHA）于近期提出的一个综合性概念，旨在描述肥胖、2型糖尿病、心血管疾病和慢性肾病之间错综复杂的相互关联 109。胰岛素抵抗是CKM综合征中贯穿“代谢-炎症-器官损伤”轴的核心环节：
- 代谢异常：胰岛素抵抗导致高血糖、高胰岛素血症、血脂异常（如高甘油三酯血症）等代谢紊乱。这些代谢异常是CKM综合征的早期表现和主要驱动因素 109。例如，甘油三酯-葡萄糖指数（TyG指数）及其相关指标（如TyG-BMI、TyG-WHtR）作为胰岛素抵抗的替代评估工具，被发现与CKM综合征患者心血管疾病的发生风险呈正相关 110，并与全因死亡率和心血管死亡率密切相关，尤其在CKM综合征的第1和第3阶段患者中这种关联更为显著 111。
- 炎症反应：胰岛素抵抗常伴随慢性低级别炎症，尤其是在肥胖状态下。脂肪组织功能障碍导致促炎细胞因子（如IL-1β, TNF-α）的释放增加，加剧全身炎症。这种炎症反过来又会进一步损害胰岛素信号传导，形成恶性循环 112。CKM综合征的分子机制包含一系列相互关联的因素，包括高血糖、胰岛素抵抗、肾素-血管紧张素-醛固酮系统（RAAS）活性增强、晚期糖基化终产物生成、氧化应激、脂毒性、内质网应激、线粒体功能障碍以及持续的慢性炎症 109。
- 器官损伤：长期存在的代谢异常和慢性炎症最终导致心血管系统（如动脉粥样硬化、心力衰竭）、肾脏（如糖尿病肾病）和肝脏（如MASLD）等靶器官的结构和功能损伤 109。例如，胰岛素抵抗通过氧化应激和炎症干扰胰岛素信号通路，导致葡萄糖代谢受损和器官功能障碍 112。
SGLT2抑制剂在CKM综合征中的多器官获益
钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）是近年来在CKM综合征治疗中取得突破性进展的一类药物。它们通过抑制肾脏近端小管SGLT2，减少葡萄糖重吸收，促进尿糖排泄，从而降低血糖。然而，SGLT2i的多器官保护作用远超其降糖效应，对心肾保护尤其显著，同时也在改善胰岛素敏感性方面发挥作用：
- 改善胰岛素敏感性：SGLT2i通过促进尿糖排泄，导致能量负平衡，从而减少内脏脂肪沉积，改善全身和器官（如肝脏、骨骼肌）的胰岛素抵抗 113114。达格列净（Dapagliflozin）单药治疗能减少白色脂肪组织和骨骼肌脂滴的积累，并改善HOMA-IR 115。SGLT2i诱导的营养剥夺状态也能激活SIRT1，从而增强骨骼肌的胰岛素敏感性 116。
- 心血管保护：SGLT2i能显著降低心血管事件风险，包括心血管死亡和心力衰竭住院率。其机制可能包括：
- 肾脏保护：SGLT2i被证实能延缓慢性肾病进展，降低肾脏终点事件的风险，即使是非糖尿病患者也能获益。其机制包括：
- 肝脏保护：SGLT2i对MASLD也具有潜在益处。它们可以降低肝脏脂肪含量，改善肝酶水平，并通过减少脂毒性、改善胰岛素抵抗和减轻炎症来保护肝脏 114120。一项研究发现，达格列净与有氧运动结合虽未在HOMA-IR上产生额外益处，但在皮下白色脂肪组织和空腹血糖方面有进一步降低 115。
- 其他代谢益处：SGLT2i还具有改善肥胖、高尿酸血症、高血压、高血脂等多种代谢紊乱的作用 120。此外，SGLT2i还能通过交感神经抑制作用，改善高血压和葡萄糖稳态等代谢综合征的特征 121。
MASLD的异质性与分层治疗
MASLD（原称NAFLD）是一种高度异质性的疾病，其进展风险和治疗反应因个体而异。2025年的一项研究强调了MASLD的异质性，并提出基于病理分型的分层治疗策略 122。
- MASLD的分子亚型：2024年的一项综合多组学分析将NAFLD（即MASLD）分为三个不同的分子亚型（NAFLD-mSI、NAFLD-mSII和NAFLD-mSIII）123。
- NAFLD-mSI：表现出CYP1A2和CYP3A4的高表达，这些酶通过介导游离脂肪酸/胆汁酸-mTOR-FXR/PPARα信号传导来减轻肝脂肪变性。
- NAFLD-mSII：显示出肝硬化风险升高，伴随M1和M2巨噬细胞因脂质触发的肝CCL2和CRP生成而增加。
- NAFLD-mSIII：由于EGF-EGFR/CHKA/PI3K-PDK1-AKT级联激活，CEBPB和ERCC3调节的癌基因转录增加，存在肝细胞癌（HCC）的潜在风险。
- 分层治疗策略：鉴于MASLD的高度异质性，未来的治疗将更加注重基于个体病理生理特征的精准分层：
- 针对炎症为主的亚型：对于NAFLD-mSII等炎症显著的亚型，治疗可能需要侧重于抗炎药物（如GLP-1受体激动剂的抗炎作用 124）和巨噬细胞调控剂。
- 针对纤维化进展风险高的亚型：对于存在肝硬化或纤维化风险的患者，可能需要抗纤维化药物（如PPAR激动剂）或更积极的生活方式干预。
- 针对HCC风险高的亚型：对于NAFLD-mSIII等HCC风险高的亚型，除了积极管理基础代谢疾病外，可能需要更密切的监测和针对肿瘤发生通路的靶向治疗。
- 核苷酸类疗法：针对MASLD的基因和代谢因素，如靶向PNPLA3和HSD17B13基因表达的小干扰RNA（siRNA）和反义寡核苷酸（ASO）疗法也正在开发中，以实现更精准的治疗 122。
总体而言，胰岛素抵抗在CKM综合征和MASLD中扮演的核心角色，使得对这些疾病的综合管理必须将改善胰岛素敏感性作为关键目标。SGLT2抑制剂以其多器官保护作用，为CKM综合征的综合干预提供了强大工具。同时，对MASLD异质性的深入理解，正推动向基于病理分型的精准分层治疗发展，以期为患者提供更有效和个性化的治疗方案。
6. 挑战与未来研究方向
6.1 现有治疗的局限性
尽管胰岛素抵抗的治疗在药物和非药物干预方面取得了显著进展，但目前的治疗方案仍面临诸多挑战和未满足的需求。这些局限性主要体现在药物副作用、非药物干预的依从性以及新兴技术的安全性等方面。
药物干预的副作用
二甲双胍的胃肠道反应：二甲双胍是2型糖尿病和胰岛素抵抗的一线治疗药物，但其主要的副作用是胃肠道不适，包括腹泻、恶心、胀气、消化不良、呕吐和腹部不适，其中腹泻和恶心最为常见 125。一项系统回顾和Meta分析显示，二甲双胍使用者中腹泻的患病率为6.9%，腹胀为6.2% 126。这些胃肠道不良反应通常会导致患者依从性下降，甚至停药，使得部分患者无法耐受足够剂量的二甲双胍 125127。虽然起始剂量较低并缓慢滴定，或使用缓释型二甲双胍可以帮助减轻这些副作用 125126，但对于一部分患者来说，这些不适仍然难以克服。
噻唑烷二酮类药物（TZDs）的水钠潴留与骨折风险：噻唑烷二酮类药物（如吡格列酮、罗格列酮）是有效的胰岛素增敏剂，能够改善胰岛素抵抗和NASH。然而，其临床应用受到严重副作用的限制，最主要的是水钠潴留和液体潴留，可能导致外周水肿甚至加重心力衰竭，因此心力衰竭患者禁用 128129130131132。此外，TZDs还会增加骨折的风险，尤其是在女性患者中 128。尽管一些研究表明，通过PPARγ脱乙酰化可能在保留代谢益处的同时减少副作用 133，但目前临床上仍需严格评估其风险效益。此外，体重增加也是TZDs的常见副作用之一 128。
GLP-1受体激动剂的胃肠道副作用：尽管GLP-1受体激动剂在减重和改善胰岛素抵抗方面表现出色，但胃肠道副作用，如恶心、呕吐和腹泻，仍然是其常见的限制因素 127。这些副作用通常是剂量依赖性的，并且在治疗初期更为明显。
非药物干预的长期依从性差
低碳水饮食的质量下降与依从性挑战：低碳水化合物饮食，尤其是生酮饮食（KD），在短期内可以显著改善血糖控制和胰岛素抵抗。然而，其长期依从性是一个普遍存在的问题 134135136。严格限制碳水化合物的摄入可能导致饮食多样性不足、营养不均衡、饱腹感差以及社会生活受限等问题，从而难以长期坚持 135。研究表明，生酮饮食在体重减轻方面效果显著，但长期依从性是影响其持久效果的关键因素 136。
生活方式干预的实施难度：饮食和运动是胰岛素抵抗管理的基础，但改变长期形成的生活习惯极具挑战性。患者往往难以长期坚持规律的体育锻炼和健康的饮食模式，尤其是在缺乏专业指导和支持的情况下。
新兴技术的安全性（基因治疗的脱靶效应）
基因治疗，如AAV介导的基因疗法，为胰岛素抵抗的治疗带来了新的希望。然而，基因治疗的一个主要挑战是安全性问题，特别是“脱靶效应”（off-target effects）。
基因编辑工具的脱靶效应风险：尽管CRISPR-Cas9等基因编辑技术在精确性方面已取得巨大进步，但在某些情况下，编辑工具仍然可能在基因组中非预期的位置进行切割或插入，导致潜在的有害突变或细胞功能改变。例如，在利用LNP-CRISPR-Cas9靶向HAO1基因治疗PH1的动物模型研究中，虽然观察到良好的靶向性和长期安全性，但理论上，任何基因编辑技术在临床应用前都需进行严格的脱靶效应评估 137。
RNAi疗法的脱靶效应：RNA干扰（RNAi）技术（如siRNA和shRNA）通过降解特异性mRNA来抑制基因表达。然而，RNAi分子也可能由于序列同源性而在非预期靶点处发挥作用，导致脱靶效应，影响细胞正常的基因表达和功能 138139。高表达水平的shRNA甚至可能引发非特异性免疫反应或饱和内源性miRNA通路，导致更广泛的副作用 139140。尽管研究人员正在开发更具特异性的RNAi分子和递送策略（如agshRNA和miR-agshRNA）来减轻这些脱靶效应，但安全性问题仍需持续关注和严格验证 139140。
AAV载体的潜在免疫原性和插入突变：尽管AAV载体具有较低的免疫原性，但仍可能引发宿主免疫反应，影响基因表达的持久性。此外，AAV载体DNA偶尔可能整合到宿主基因组中，虽然频率较低，但理论上存在插入突变和致癌的风险。
综上所述，虽然现有治疗方案在改善胰岛素抵抗方面发挥了重要作用，但其局限性提示我们仍需不断探索更安全、更有效、依从性更好的新型治疗策略。未来的研究应致力于克服这些挑战，推动胰岛素抵抗治疗向更精准、更个性化的方向发展。
6.2 未来研究的重点方向
胰岛素抵抗的复杂性及其日益增长的全球负担，驱动着科学界不断探索创新性的研究方向和治疗策略。未来研究的重点将聚焦于更深层次的病理机制理解、更精准的干预手段开发，以及多学科交叉融合的应用。
肠道菌群代谢物（如短链脂肪酸）调控
肠道菌群在宿主能量代谢、炎症反应及胰岛素敏感性调节中扮演着核心角色。未来的研究将更加深入地探索肠道菌群及其代谢产物（特别是短链脂肪酸，SCFAs）在胰岛素抵抗发生发展中的确切机制，并将其作为新的治疗靶点。
- 短链脂肪酸（SCFAs）的作用机制：SCFAs，主要包括乙酸、丙酸和丁酸，是肠道微生物发酵膳食纤维和抗性淀粉的产物 141 142。它们被认为是肠道中最丰富的阴离子，对人体健康具有多方面的影响，包括调节葡萄糖稳态、参与肥胖、胰岛素抵抗和2型糖尿病的发生发展 141。未来研究将进一步阐明SCFAs通过G蛋白偶联受体（如GPR41、GPR43）或抑制组蛋白脱乙酰酶等途径，如何影响胰岛素信号传导、脂肪储存、能量消耗和炎症反应。例如，丁酸被发现能改善胰岛素抵抗，其机制可能涉及增加肠道屏障功能、减少内毒素血症、调节肠道激素分泌以及直接影响肝脏和肌肉的胰岛素敏感性。
- 肠道菌群的精准干预：除了SCFAs，其他肠道菌群代谢物（如胆汁酸、脂多糖、氧化三甲胺等）也与胰岛素抵抗的病理生理学密切相关 143。未来的研究将致力于开发基于肠道菌群的精准干预策略，包括：
- 新型益生菌和益生元：筛选具有特定功能、能够产生有益代谢物的益生菌菌株，或设计能够特异性促进有益菌群生长的益生元制剂。
- 粪菌移植（FMT）：优化FMT的适应症和操作规范，探索其在难治性胰岛素抵抗患者中的长期疗效和安全性。
- 饮食模式与菌群的相互作用：进一步研究饮食如何影响肠道菌群组成和活动，进而影响SCFAs的产生和代谢效应 141。
代谢记忆逆转（如运动诱导的表观遗传修饰）
“代谢记忆”是指在一段时间的高血糖或代谢紊乱后，即使血糖恢复正常，机体细胞仍然“记住”了曾经的不良状态，并持续导致并发症的进展。逆转这种代谢记忆是未来治疗胰岛素抵抗及并发症的关键。表观遗传修饰，如DNA甲基化、组蛋白修饰（如乙酰化、甲基化）和非编码RNA，在代谢记忆的形成中扮演重要角色。
- 运动与表观遗传修饰：运动被认为是改善胰岛素敏感性最有效的方法之一，并且具有调节表观遗传修饰的潜力。研究表明，运动可以调节组蛋白乙酰化水平，影响基因表达，从而改善葡萄糖代谢和炎症反应。例如，跑步机运动可以改善年龄相关的厌恶记忆，并增加海马区组蛋白H4乙酰化水平，这提示运动可以通过表观遗传机制影响大脑功能和炎症状态 144。另一项研究也发现，跑步机运动可以改变厌恶学习情境下大鼠海马区组蛋白H3K14乙酰化水平，提示运动对记忆的调节可能与组蛋白乙酰化有关 145。未来研究将深入探索运动如何通过调节特定基因的表观遗传修饰，来逆转胰岛素抵抗相关的代谢记忆，并开发能够模拟运动效应的表观遗传调控药物。
- 线粒体功能与表观遗传：线粒体功能障碍是胰岛素抵抗和2型糖尿病的关键特征 146。线粒体DNA（mtDNA）的表观遗传修饰（如DNA甲基化）以及对线粒体基因组编码的转录组的表观转录组调控，被认为是2型糖尿病进展中线粒体功能障碍的新机制 146。未来的研究将关注运动或其他干预手段如何通过调节线粒体表观遗传修饰来改善线粒体功能，进而逆转代谢记忆。
AI辅助的个体化治疗方案设计
胰岛素抵抗的高度异质性决定了“一刀切”的治疗方案往往效果不佳。人工智能（AI）和机器学习（ML）技术的发展为实现胰岛素抵抗的精准医学带来了革命性机遇。
- 预测性血糖控制数字孪生技术：2024年的一项研究提出了数字孪生（Digital Twin, DT）技术在2型糖尿病缓解中的应用，该平台通过整合连续血糖监测（CGM）、饮食数据和其他生理输入，为患者提供个性化的饮食建议，以改善胰岛素敏感性、减少高胰岛素血症并支持T2D缓解 147。这种基于ML的平台能够预测和调节餐后血糖反应（PPGRs），这对于胰岛素抵抗患者的个性化饮食干预至关重要。未来研究将进一步完善DT模型的准确性和泛化能力，使其能够整合更多维度的患者数据，实现对胰岛素抵抗的早期预测和干预。
- 多组学数据整合与分析：AI/ML在整合多组学数据（基因组学、表观基因组学、代谢组学、微生物组学等）方面具有独特优势。通过分析这些海量数据，AI可以识别出新的生物标志物、代谢通路和疾病亚型，从而实现对胰岛素抵抗患者的精准分型，并为不同亚型患者设计最合适的治疗方案。例如，2025年的一项研究强调了AI在整合基因组学、表观基因组学、代谢组学和微生物组学数据以深入了解2型糖尿病病理生理学和异质性方面的关键作用，并指出未来研究应探索这些因素的组合效应和相互作用 148。2022年的一项研究也利用机器学习方法识别了代谢综合征的血浆代谢组学生物标志物组，为预测性诊断和靶向预防提供了新策略 149。
- 个性化治疗方案优化：AI可以通过模拟不同治疗方案（药物、饮食、运动等）对个体患者代谢指标的影响，从而预测最佳治疗效果和潜在副作用，为医生提供决策支持。这种“一人一方”的治疗模式将显著提高胰岛素抵抗的治疗效果，并减少不良反应。
多组学整合在靶点发现与疗效预测中的关键作用
多组学技术（包括基因组学、转录组学、蛋白质组学、代谢组学和肠道宏基因组学）能够从不同层面全面解析机体的生物学状态。将这些信息整合起来，将是未来胰岛素抵抗研究的关键：
- 靶点发现：通过多组学分析，可以识别出与胰岛素抵抗发生发展密切相关的新基因、蛋白质、代谢物和微生物，为新药研发提供潜在靶点。例如，代谢组学已用于识别胰岛素抵抗的呼吸生物标志物 150。
- 疗效预测：利用多组学数据，可以构建预测模型，评估患者对不同治疗方案的反应，从而实现精准用药。例如，通过分析患者的基因组特征，可以预测其对二甲双胍或SGLT2抑制剂的敏感性。
- 疾病亚型识别：胰岛素抵抗并非单一疾病，其背后可能存在多种不同的病理生理机制。多组学整合有助于识别这些异质性亚型，并为每种亚型开发特定的治疗策略。
总之，未来胰岛素抵抗的研究将是一个多学科交叉融合的领域。通过深入探索肠道菌群与代谢记忆的分子机制，并结合AI和多组学技术，我们将有望开发出更安全、更有效、更个性化的治疗方案，最终实现对胰岛素抵抗及其并发症的精准管理和治愈。
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参考文献
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Xi Lu, Qingxing Xie, Xiaohui Pan, et al.
Signal Transduct Target Ther. 2024 Oct 2;9(1):262. doi: 10.1038/s41392-024-01951-9.
Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call "diabetic complications" as "MDS-related target organ damage (TOD)", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of "MDS-related TOD".
2VLDL triglyceride accumulation in skeletal muscle and adipose tissue in type 2 diabetes.PubMed
Esben Søndergaard, Søren Nielsen
Curr Opin Lipidol. 2018 Feb;29(1):42-47. doi: 10.1097/MOL.0000000000000471.
PURPOSE OF REVIEW: Insulin resistance is closely linked to accumulation of lipid outside adipose tissue (ectopic fat storage). VLDL particles transport lipids from the liver to peripheral tissues. However, whether abnormalities in VLDL-triglyceride storage in muscle and adipose tissue exist in type 2 diabetes has previously been unknown, primarily because of methodological difficulties. Here, we review recent research on VLDL-triglyceride storage. RECENT FINDINGS: In a recent study, men with type 2 diabetes had increased skeletal muscle VLDL-triglyceride storage compared to weight-matched nondiabetic men, potentially leading to intramyocellular triglyceride accumulation. In contrast, studies of adipose tissue VLDL-triglyceride storage have shown similar storage capacity in men with and without diabetes, both in the postabsorptive and the postprandial period. In the initial submission, studies have failed to show associations between lipoprotein lipase activity, considered the rate-limiting step in storage of lipids from lipoproteins, and VLDL-TG storage in both muscle and adipose tissue. SUMMARY: Differences in muscle VLDL-triglyceride storage may lead to ectopic fat storage and contribute to the development of type 2 diabetes, whereas the ability to store VLDL-triglyceride in adipose tissue is preserved in type 2 diabetes.
3Relation Between Insulin Sensitivity and Metabolic Abnormalities in Japanese Men With BMI of 23-25 kg/m.PubMed
Kageumi Takeno, Yoshifumi Tamura, Minako Kawaguchi, et al.
J Clin Endocrinol Metab. 2016 Oct;101(10):3676-3684. doi: 10.1210/jc.2016-1650. Epub 2016 Jul 6.
CONTEXT: Although metabolic abnormalities are often developed in Asians with body mass index (BMI) of 23-25 kg/m, the characteristics of the nonobese Asians with metabolic abnormality have not been fully understood. OBJECTIVE: The aim of this study was to investigate the clinical significance of insulin sensitivity in Japanese men with BMI of 23-25 kg/m. DESIGN AND PARTICIPANTS: In this study, we defined hypertension, hyperglycemia, and dyslipidemia as cardiometabolic risk factors (CMRFs). We recruited subjects who met the following selection criteria: men with BMI of 21-23 kg/m and no CMRF (n = 24); men with BMI of 23-25 kg/m and no CMRF (n = 28), or one CMRF (n = 28), or at least two CMRFs (n = 14); and overweight men with metabolic syndrome (n = 20). Insulin sensitivity (IS) and ectopic fat content in muscle and liver were measured by two-step hyperinsulinemic-euglycemic clamp and H-magnetic resonance spectroscopy, respectively. RESULTS: Among subjects with BMI of 23-25 kg/m, impaired IS in muscle, but not in liver, was found in those with even one CMRF, whereas impaired IS in both muscle and liver was observed in overweight men with metabolic syndrome. Liver fat accumulation and elevated liver enzymes were associated with impaired IS in both muscle and liver in those subjects. CONCLUSIONS: Among Japanese men with BMI of 23-25 kg/m, muscle insulin resistance was present in those with even one CMRF. In this population, liver fat accumulation and/or elevated liver enzymes could be a good marker for impaired IS in both muscle and liver.
4Ethnic differences in hepatic and systemic insulin sensitivity and their associated determinants in obese black and white South African women.PubMed
Julia H Goedecke, Dheshnie Keswell, Carsten Weinreich, et al.
Diabetologia. 2015 Nov;58(11):2647-52. doi: 10.1007/s00125-015-3720-7. Epub 2015 Aug 1.
AIMS/HYPOTHESIS: There is evidence to suggest that ectopic fat deposition in liver and skeletal muscle may differ between black and white women resulting in organ-specific differences in insulin sensitivity. Accordingly, the aim of the study was to examine ethnic differences in hepatic and peripheral insulin sensitivity, and the association with hepatic and skeletal muscle lipid content, and skeletal muscle gene expression. METHODS: In a cross-sectional study including 30 obese premenopausal black and white women, body composition (dual energy x-ray absorptiometry), liver fat and skeletal muscle (soleus and tibialis anterior) fat accumulation (proton-magnetic resonance spectroscopy), skeletal muscle gene expression, insulin sensitivity (two-step isotope labelled, hyperinsulinaemic-euglycaemic clamp with 10 mU m(-2) min(-1) and 40 mU m(-2) min(-1) insulin infusions), and serum adipokines were measured. RESULTS: We found that, although whole-body insulin sensitivity was not different, obese white women presented with lower hepatic insulin sensitivity than black women (% suppression of endogenous glucose production [% supp EGP], median [interquartile range (IQR)]: 17 [5-51] vs 56 [29-100] %, p = 0.002). While liver fat tended to be lower (p = 0.065) and skeletal muscle fat deposition tended to be higher (p = 0.074) in black compared with white women, associations with insulin sensitivity were only observed in black women (% supp EGP vs liver fat: r = -0.57, p < 0.05 and % supp EGP vs soleus fat: r = -0.56, p < 0.05). CONCLUSIONS/INTERPRETATION: These findings may suggest that black women are more sensitive to the effects of ectopic lipid deposition than white women.
5Updated mechanisms of MASLD pathogenesis.PubMed
Yuxuan Li, Peipei Yang, Jialu Ye, et al.
Lipids Health Dis. 2024 Apr 22;23(1):117. doi: 10.1186/s12944-024-02108-x.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity and is strongly linked to metabolic syndromes. Given that MASLD prevalence is on the rise, there is an urgent need to elucidate its pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity and induces MASLD or progress to metabolic dysfunction-associated steatohepatitis (MASH) by mediating endoplasmic reticulum stress, oxidative stress, organelle dysfunction, and ferroptosis. Recently, significant attention has been directed towards exploring the role of gut microbial dysbiosis in the development of MASLD, offering a novel therapeutic target for MASLD. Considering that there are no recognized pharmacological therapies due to the diversity of mechanisms involved in MASLD and the difficulty associated with undertaking clinical trials, potential targets in MASLD remain elusive. Thus, this article aimed to summarize and evaluate the prominent roles of lipotoxicity, ferroptosis, and gut microbes in the development of MASLD and the mechanisms underlying their effects. Furthermore, existing advances and challenges in the treatment of MASLD were outlined.
6Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation‑mediating treatment options (Review).PubMed
Fani-Niki Varra, Michail Varras, Viktoria-Konstantina Varra, et al.
Mol Med Rep. 2024 Jun;29(6). doi: 10.3892/mmr.2024.13219. Epub 2024 Apr 12.
Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co‑morbidities, including type‑2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular diseases, non‑alcoholic fatty liver disease, kidney diseases, respiratory disorders, sleep apnea, musculoskeletal disorders and osteoarthritis, subfertility, psychosocial problems and certain types of cancers. The underlying inflammatory mechanisms interconnecting obesity with metabolic dysfunction are not completely understood. Increased adiposity promotes pro‑inflammatory polarization of macrophages toward the M1 phenotype, in adipose tissue (AT), with subsequent increased production of pro‑inflammatory cytokines and adipokines, inducing therefore an overall, systemic, low‑grade inflammation, which contributes to metabolic syndrome (MetS), insulin resistance (IR) and T2DM. Targeting inflammatory mediators could be alternative therapies to treat obesity, but their safety and efficacy remains to be studied further and confirmed in future clinical trials. The present review highlights the molecular and pathophysiological mechanisms by which the chronic low‑grade inflammation in AT and the production of reactive oxygen species lead to MetS, IR and T2DM. In addition, focus is given on the role of anti‑inflammatory agents, in the resolution of chronic inflammation, through the blockade of chemotactic factors, such as monocytes chemotractant protein‑1, and/or the blockade of pro‑inflammatory mediators, such as IL‑1β, TNF‑α, visfatin, and plasminogen activator inhibitor‑1, and/or the increased synthesis of adipokines, such as adiponectin and apelin, in obesity‑associated metabolic dysfunction.
7Adipose Tissue Stromal Cells: Rheostats for Adipose Tissue Function and Metabolic Disease Risk.PubMed
Taylor B Scheidl, Jessica L Wager, Jennifer A Thompson
Can J Cardiol. 2025 Sep;41(9):1727-1735. doi: 10.1016/j.cjca.2025.02.025. Epub 2025 Feb 20.
The transition from metabolically healthy obesity to the development of obesity-associated metabolic syndrome and cardiovascular disease is thought to be triggered by a loss in the functional integrity of adipose tissue. Although mature adipocytes are the primary functional units that carry out lipid partitioning in adipose tissue for the promotion of whole-body energy balance, they are supported by a heterogenous collection of nonadipocytes in the stroma. Research over the past couple of decades has expanded perspectives on the homeostatic and pathological roles of the nonadipocyte compartment. Adipose progenitors originate in the embryonic period and drive the developmental adipogenesis that establishes the set point of adiposity. A population of adipocyte progenitors reside in adult depots and serve an important homeostatic role as a reservoir to support adipocyte turnover. Adipocyte hypertrophy in obesity increases the rate of adipocyte death and the ability of progenitors to support this high rate of adipocyte turnover is important for the preservation of the lipid-buffering function of adipose tissue. Some evidence exists to suggest that impaired adipogenesis or a decline in progenitors capable of differentiation is a key event in the development of adipose dysfunction. The efficiency of macrophages to clear the debris and toxic lipids released from dead adipocytes lies at the fulcrum between preservation of adipose function and the progression toward chronic inflammation. Although macrophages in collaboration with other immune cells propagate the inflammation that underlies adipose dysfunction, there is now a greater appreciation for the diverse and unique roles of immune cells within adipose tissue.
8Opposite cross-talk by oleate and palmitate on insulin signaling in hepatocytes through macrophage activation.PubMed
Virginia Pardo, Águeda González-Rodríguez, Carlos Guijas, et al.
J Biol Chem. 2015 May 1;290(18):11663-77. doi: 10.1074/jbc.M115.649483. Epub 2015 Mar 19.
Chronic low grade inflammation in adipose tissue during obesity is associated with an impairment of the insulin signaling cascade. In this study, we have evaluated the impact of palmitate or oleate overload of macrophage/Kupffer cells in triggering stress-mediated signaling pathways, in lipoapoptosis, and in the cross-talk with insulin signaling in hepatocytes. RAW 264.7 macrophages or Kupffer cells were stimulated with oleate or palmitate, and levels of M1/M2 polarization markers and the lipidomic profile of eicosanoids were analyzed. Whereas proinflammatory cytokines and total eicosanoids were elevated in macrophages/Kupffer cells stimulated with palmitate, enhanced arginase 1 and lower leukotriene B4 (LTB4) levels were detected in macrophages stimulated with oleate. When hepatocytes were pretreated with conditioned medium (CM) from RAW 264.7 or Kupffer cells loaded with palmitate (CM-P), phosphorylation of stress kinases and endoplasmic reticulum stress signaling was increased, insulin signaling was impaired, and lipoapoptosis was detected. Conversely, enhanced insulin receptor-mediated signaling and reduced levels of the phosphatases protein tyrosine phosphatase 1B (PTP1B) and phosphatase and tensin homolog (PTEN) were found in hepatocytes treated with CM from macrophages stimulated with oleate (CM-O). Supplementation of CM-O with LTB4 suppressed insulin sensitization and increased PTP1B and PTEN. Furthermore, LTB4 decreased insulin receptor tyrosine phosphorylation in hepatocytes, activated the NFκB pathway, and up-regulated PTP1B and PTEN, these effects being mediated by LTB4 receptor BTL1. In conclusion, oleate and palmitate elicit an opposite cross-talk between macrophages/Kupffer cells and hepatocytes. Whereas CM-P interferes at the early steps of insulin signaling, CM-O increases insulin sensitization, possibly by reducing LTB4.
9Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in mice.PubMed
Ashley M Miller, Darren L Asquith, Axel J Hueber, et al.
Circ Res. 2010 Sep 3;107(5):650-8. doi: 10.1161/CIRCRESAHA.110.218867. Epub 2010 Jul 15.
RATIONALE: Chronic low-grade inflammation involving adipose tissue likely contributes to the metabolic consequences of obesity. The cytokine interleukin (IL)-33 and its receptor ST2 are expressed in adipose tissue, but their role in adipose tissue inflammation during obesity is unclear. OBJECTIVE: To examine the functional role of IL-33 in adipose tissues and investigate the effects on adipose tissue inflammation and obesity in vivo. METHODS AND RESULTS: We demonstrate that treatment of adipose tissue cultures in vitro with IL-33 induced production of Th2 cytokines (IL-5, IL-13, IL-10) and reduced expression of adipogenic and metabolic genes. Administration of recombinant IL-33 to genetically obese diabetic (ob/ob) mice led to reduced adiposity, reduced fasting glucose and improved glucose and insulin tolerance. IL-33 also induced accumulation of Th2 cells in adipose tissue and polarization of adipose tissue macrophages toward an M2 alternatively activated phenotype (CD206(+)), a lineage associated with protection against obesity-related metabolic events. Furthermore, mice lacking endogenous ST2 fed high-fat diet had increased body weight and fat mass and impaired insulin secretion and glucose regulation compared to WT controls fed high-fat diet. CONCLUSIONS: In conclusion, IL-33 may play a protective role in the development of adipose tissue inflammation during obesity.
10Inflammation and Metabolic Complications in HIV.PubMed
Kassem Bourgi, Celestine Wanjalla, John R Koethe
Curr HIV/AIDS Rep. 2018 Oct;15(5):371-381. doi: 10.1007/s11904-018-0411-2.
PURPOSE OF REVIEW: We aim to provide an in-depth review of recent literature highlighting the role of inflammation involving the adipose tissue, liver, skeletal muscles, and gastrointestinal tract in the development of metabolic complications among persons living with HIV (PLWH). RECENT FINDINGS: Recent studies in PLWH have demonstrated a significant association between circulating inflammatory markers and development of insulin resistance and metabolic complications. In adipose tissue, pro-inflammatory cytokine expression inhibits adipocyte insulin signaling, which alters lipid and glucose homeostasis. Increased lipolysis and lipogenesis elevate levels of circulating free fatty acids and promote ectopic fat deposition in liver and skeletal muscles. This leads to lipotoxicity characterized by a pro-inflammatory response with worsening insulin resistance. Finally, HIV is associated with gastrointestinal tract inflammation and changes in the gut microbiome resulting in reduced diversity, which is an additional risk factor for diabetes. Metabolic complications in PLWH are in part due to chronic, multisite tissue inflammation resulting in dysregulation of glucose and lipid trafficking, utilization, and storage.
11Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis.PubMed
Kuei-Chuan Lee, Pei-Shan Wu, Han-Chieh Lin
Clin Mol Hepatol. 2023 Jan;29(1):77-98. doi: 10.3350/cmh.2022.0237. Epub 2022 Oct 13.
The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. The dysfunction of lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes lipid accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress would further contribute to hepatocyte injury and death, leading to inflammation and immune dysfunction in the liver. During the healing process, the accumulation of an excessive amount of fibrosis might occur while healing. During the development of NASH and liver fibrosis, the gut-liver axis, adipose-liver axis, and renin-angiotensin system (RAS) may be dysregulated and impaired. Translocation of bacteria or its end-products entering the liver could activate hepatocytes, Kupffer cells, and hepatic stellate cells, exacerbating hepatic steatosis, inflammation, and fibrosis. Bile acids regulate glucose and lipid metabolism through Farnesoid X receptors in the liver and intestine. Increased adipose tissue-derived non-esterified fatty acids would aggravate hepatic steatosis. Increased leptin also plays a role in hepatic fibrogenesis, and decreased adiponectin may contribute to hepatic insulin resistance. Moreover, dysregulation of peroxisome proliferator-activated receptors in the liver, adipose, and muscle tissues may impair lipid metabolism. In addition, the RAS may contribute to hepatic fatty acid metabolism, inflammation, and fibrosis. The treatment includes lifestyle modification, pharmacological therapy, and non-pharmacological therapy. Currently, weight reduction by lifestyle modification or surgery is the most effective therapy. However, vitamin E, pioglitazone, and obeticholic acid have also been suggested. In this review, we will introduce some new clinical trials and experimental therapies for the treatment of NASH and related fibrosis.
12The gut-brain-metabolic axis: exploring the role of microbiota in insulin resistance and cognitive function.PubMed
Gulshara Zh Abildinova, Valeriy V Benberin, Tamara A Vochshenkova, et al.
Front Microbiol. 2024 Nov 26;15:1463958. doi: 10.3389/fmicb.2024.1463958. eCollection 2024.
The gut-brain-metabolic axis has emerged as a critical area of research, highlighting the intricate connections between the gut microbiome, metabolic processes, and cognitive function. This review article delves into the complex interplay between these interconnected systems, exploring their role in the development of insulin resistance and cognitive decline. The article emphasizes the pivotal influence of the gut microbiota on central nervous system (CNS) function, demonstrating how microbial colonization can program the hypothalamic-pituitary-adrenal (HPA) axis for stress response in mice. It further elucidates the mechanisms by which gut microbial carbohydrate metabolism contributes to insulin resistance, a key factor in the pathogenesis of metabolic disorders and cognitive impairment. Notably, the review highlights the therapeutic potential of targeting the gut-brain-metabolic axis through various interventions, such as dietary modifications, probiotics, prebiotics, and fecal microbiota transplantation (FMT). These approaches have shown promising results in improving insulin sensitivity and cognitive function in both animal models and human studies. The article also emphasizes the need for further research to elucidate the specific microbial species and metabolites involved in modulating the gut-brain axis, as well as the long-term effects and safety of these therapeutic interventions. Advances in metagenomics, metabolomics, and bioinformatics are expected to provide deeper insights into the complex interactions within the gut microbiota and their impact on host health. Overall, this comprehensive review underscores the significance of the gut-brain-metabolic axis in the pathogenesis and treatment of metabolic and cognitive disorders, offering a promising avenue for the development of novel therapeutic strategies targeting this intricate system.
13Gut microbial carbohydrate metabolism contributes to insulin resistance.PubMed
Tadashi Takeuchi, Tetsuya Kubota, Yumiko Nakanishi, et al.
Nature. 2023 Sep;621(7978):389-395. doi: 10.1038/s41586-023-06466-x. Epub 2023 Aug 30.
Insulin resistance is the primary pathophysiology underlying metabolic syndrome and type 2 diabetes. Previous metagenomic studies have described the characteristics of gut microbiota and their roles in metabolizing major nutrients in insulin resistance. In particular, carbohydrate metabolism of commensals has been proposed to contribute up to 10% of the host's overall energy extraction, thereby playing a role in the pathogenesis of obesity and prediabetes. Nevertheless, the underlying mechanism remains unclear. Here we investigate this relationship using a comprehensive multi-omics strategy in humans. We combine unbiased faecal metabolomics with metagenomics, host metabolomics and transcriptomics data to profile the involvement of the microbiome in insulin resistance. These data reveal that faecal carbohydrates, particularly host-accessible monosaccharides, are increased in individuals with insulin resistance and are associated with microbial carbohydrate metabolisms and host inflammatory cytokines. We identify gut bacteria associated with insulin resistance and insulin sensitivity that show a distinct pattern of carbohydrate metabolism, and demonstrate that insulin-sensitivity-associated bacteria ameliorate host phenotypes of insulin resistance in a mouse model. Our study, which provides a comprehensive view of the host-microorganism relationships in insulin resistance, reveals the impact of carbohydrate metabolism by microbiota, suggesting a potential therapeutic target for ameliorating insulin resistance.
14Portal vein-enriched metabolites as intermediate regulators of the gut microbiome in insulin resistance.PubMed
Vitor Rosetto Muñoz, Francois Moreau, Marion Soto, et al.
Cell Metab. 2025 Oct 7;37(10):2048-2065.e6. doi: 10.1016/j.cmet.2025.08.005. Epub 2025 Sep 5.
Diet and obesity contribute to insulin resistance and type 2 diabetes, in part via the gut microbiome. To explore the role of gut-derived metabolites in this process, we assessed portal/peripheral blood metabolites in mice with different risks of obesity/diabetes, challenged with a high-fat diet (HFD) + antibiotics. In diabetes/obesity-prone C57BL/6J mice, 111 metabolites were portally enriched and 74 were peripherally enriched, many of which differed in metabolic-syndrome-resistant 129S1/129S6 mice. Vancomycin treatment of HFD-fed C57BL/6J mice modified the microbiome and the portal/peripheral ratio of many metabolites, including upregulating tricarboxylic acid (TCA) cycle-related metabolites, like mesaconate, in portal blood. Treatment of isolated hepatocytes with mesaconate, itaconate, or citraconate improved insulin signaling and transcriptionally regulated genes involved in gluconeogenesis, fatty acid oxidation, and lipogenesis in vitro and in vivo. In humans, citraconate levels are inversely correlated with plasma glucose. Thus, portal versus peripheral metabolites play important roles in mediating effects of the microbiome on hepatic metabolism and the pathogenesis of HFD-related insulin resistance.
15Unveiling adipose populations linked to metabolic health in obesity.PubMed
Isabel Reinisch, Adhideb Ghosh, Falko Noé, et al.
Cell Metab. 2025 Mar 4;37(3):640-655.e4. doi: 10.1016/j.cmet.2024.11.006. Epub 2024 Dec 17.
Precision medicine is still not considered as a standard of care in obesity treatment, despite a large heterogeneity in the metabolic phenotype of individuals with obesity. One of the strongest factors influencing the variability in metabolic disease risk is adipose tissue (AT) dysfunction; however, there is little understanding of the link between distinct cell populations, cell-type-specific transcriptional programs, and disease severity. Here, we generated a comprehensive cellular map of subcutaneous and visceral AT of individuals with metabolically healthy and unhealthy obesity. By combining single-nucleus RNA-sequencing data with bulk transcriptomics and clinical parameters, we identified that mesothelial cells, adipocytes, and adipocyte-progenitor cells exhibit the strongest correlation with metabolic disease. Furthermore, we uncovered cell-specific transcriptional programs, such as the transitioning of mesothelial cells to a mesenchymal phenotype, that are involved in uncoupling obesity from metabolic disease. Together, these findings provide valuable insights by revealing biological drivers of clinical endpoints.
16Transient Dietary Intervention Induces Healthy Adipose Tissue Expansion and Metabolically Healthy Obesity in Mice.PubMed
Eri Wada, Hirotaka Hosono, Miyako Tanaka, et al.
FASEB J. 2025 Jul 31;39(14):e70847. doi: 10.1096/fj.202501121R.
As obesity progresses, dynamic tissue remodeling of adipose tissue occurs over time, that is, adipocyte hypertrophy, chronic inflammation, and interstitial fibrosis. Some obese individuals exhibit healthy adipose tissue expansion, characterized by modest inflammation and fibrosis despite adipocyte hypertrophy, resulting in "Metabolically Healthy Obesity (MHO)". In this study, we investigated the effects of transient weight loss on adipose tissue remodeling during the development of obesity. Male C57BL6/J mice received various types of transient weight loss treatments during diet-induced obesity. A 2-week weight loss intervention during the inflammatory phase promoted healthy adipose tissue expansion, reduced ectopic lipid accumulation, and improved glucose metabolism. In contrast, protocols with shorter duration and delayed intervention, failed to induce MHO. Since serum concentrations of ketone bodies were elevated during weight loss, we examined the effects of hyperketonemia on obesity-induced adipose tissue remodeling. Transient treatment with 1,3-butanediol (BD), which increased serum ketone body concentrations to levels similar to those observed during weight loss, induced healthy adipose tissue expansion and reduced hepatic steatosis even during continuous high-fat diet (HFD) feeding. Ketone bodies effectively suppressed activation of adipose tissue fibroblasts in vivo and in vitro. This study provides evidence that an appropriate dietary intervention can promote healthy adipose tissue expansion in mice, even after the regaining of weight, thereby leading to MHO. As the underlying mechanism, our data revealed a key role for ketone bodies in suppressing activation of adipose tissue fibroblasts. This study paves the way for nutritional approaches to induce MHO.
17Suppression of adipocyte ABHD6 favors anti-inflammatory and adipogenic programs to preserve adipose tissue fitness in obesity.PubMed
Pegah Poursharifi, Camille Attané, Isabelle Chenier, et al.
Mol Metab. 2025 Nov;101:102241. doi: 10.1016/j.molmet.2025.102241. Epub 2025 Aug 29.
Some individuals exhibit metabolically healthy obesity, characterized by the expansion of white adipose tissue (WAT) without associated complications. The monoacylglycerol (MAG) hydrolase α/β-hydrolase domain-containing 6 (ABHD6) has been implicated in energy metabolism, with its global deletion conferring protection against obesity. However, the immunometabolic roles of adipocyte ABHD6 in WAT remodeling in response to nutri-stress and obesity are not known. Here, we demonstrate that in insulin resistant women, ABHD6 mRNA expression is elevated in visceral fat and positively correlates with obesity and metabolic dysregulation. ABHD6 expression is also elevated in the WATs of diet-induced obese and db/db mice. Although adipocyte-specific ABHD6 knockout (AA-KO) mice become obese under high-fat diet, they show higher plasma adiponectin, reduced circulating insulin and inflammatory markers, improved insulin sensitivity, and lower plasma and liver triglycerides. They also show enhanced insulin action in various tissues, but normal glucose tolerance. In addition, AA-KO mice display healthier and less inflamed expansion of visceral fat, with smaller adipocytes and higher stimulated lipolysis and fatty acid oxidation levels. Similar but less prominent phenotype was found in the subcutaneous and brown fat depots. Thus, adipocyte ABHD6 suppression prevents most of the metabolic and inflammatory complications of obesity, but not obesity per se. Mechanistically, this beneficial process involves a rise in MAG levels in mature adipocytes, and their secretion, resulting in a crosstalk among adipocytes, preadipocytes and macrophages in the adipose microenvironment. Elevated intracellular MAG causes PPARs activation in adipocytes, and MAG secreted from adipocytes curtails the inflammatory polarization of macrophages and promotes preadipocyte differentiation. Hence, adipocyte ABHD6 and MAG hydrolysis contribute to unhealthy WAT remodeling and expansion in obesity, and its suppression represents a candidate strategy to uncouple obesity from many of its immunometabolic complications.
18Adipose Tissue Dysfunction in Polycystic Ovary Syndrome.PubMed
Fernando Bril, Uche Ezeh, Mina Amiri, et al.
J Clin Endocrinol Metab. 2023 Dec 21;109(1):10-24. doi: 10.1210/clinem/dgad356.
PURPOSE: Polycystic ovary syndrome (PCOS) is a complex genetic trait and the most common endocrine disorder of women, clinically evident in 5% to 15% of reproductive-aged women globally, with associated cardiometabolic dysfunction. Adipose tissue (AT) dysfunction appears to play an important role in the pathophysiology of PCOS even in patients who do not have excess adiposity. METHODS: We undertook a systematic review concerning AT dysfunction in PCOS, and prioritized studies that assessed AT function directly. We also explored therapies that targeted AT dysfunction for the treatment of PCOS. RESULTS: Various mechanisms of AT dysfunction in PCOS were identified including dysregulation in storage capacity, hypoxia, and hyperplasia; impaired adipogenesis; impaired insulin signaling and glucose transport; dysregulated lipolysis and nonesterified free fatty acids (NEFAs) kinetics; adipokine and cytokine dysregulation and subacute inflammation; epigenetic dysregulation; and mitochondrial dysfunction and endoplasmic reticulum and oxidative stress. Decreased glucose transporter-4 expression and content in adipocytes, leading to decreased insulin-mediated glucose transport in AT, was a consistent abnormality despite no alterations in insulin binding or in IRS/PI3K/Akt signaling. Adiponectin secretion in response to cytokines/chemokines is affected in PCOS compared to controls. Interestingly, epigenetic modulation via DNA methylation and microRNA regulation appears to be important mechanisms underlying AT dysfunction in PCOS. CONCLUSION: AT dysfunction, more than AT distribution and excess adiposity, contributes to the metabolic and inflammation abnormalities of PCOS. Nonetheless, many studies provided contradictory, unclear, or limited data, highlighting the urgent need for additional research in this important field.
19HMC Ameliorates Hyperglycemia via Acting PI3K/AKT Pathway and Improving FOXO1 Pathway in ob/ob Mice.PubMed
Jeong Yoo, Jae Eun Park, Ji Sook Han
Nutrients. 2023 Apr 22;15(9):2023. doi: 10.3390/nu15092023.
Type 2 diabetes is a disease characterized by hyperglycemia and is a growing health problem worldwide. Since many known diabetes drugs are side effects, it is necessary to develop natural substances with guaranteed safety. HM-chromanone isolated from L. is a homoisoflavonoid compound. We investigated the effects of HM-chromanone on hyperglycemia and its mechanism in C57BL/6J ob/ob mice. C57BL/6J-Jms Slc mice were used as the control group, and C57BL/6J-ob/ob mice were divided into three groups: ob/ob (control), metformin (Met; positive control), and HM-chromanone (HMC). Fasting blood glucose was lower in the HMC group than those in the ob/ob group. Insulin resistance was improved by reducing HbA1c, plasma insulin, and HOMA-IR levels in the HMC group. HMC administration decreased the phosphorylation of IRS-1ser307 and increased the phosphorylation of IRS-1tyr612, PI3K, phosphorylation of AKTser, and PM-GLUT4 in the skeletal muscles of ob/ob mice, indicating improved insulin signaling. HMC administration also increased the phosphorylation of FOXO1 in the liver of ob/ob mice. This inhibited PEPCK and G6pase involved in gluconeogenesis and regulated phosphorylation of glycogen synthase kinase 3β and glycogen synthase involved in glycogen synthesis. In conclusion, HM-chromanone ameliorates hyperglycemia by PI3K/AKT and improves the FOXO1 in ob/ob mice.
20Sirt3 Pharmacologically Promotes Insulin Sensitivity through PI3/AKT/mTOR and Their Downstream Pathway in Adipocytes.PubMed
Alexandra Yatine Lee, Sabrina Marie Christensen, Nhi Duong, et al.
Int J Mol Sci. 2022 Mar 29;23(7):3740. doi: 10.3390/ijms23073740.
Sirtuin-3 (Sirt3) is a major mitochondrial deacetylase enzyme that regulates multiple metabolic pathways, and its expression is decreased in diabetes type 1 and type 2 diabetes. This study aimed to elucidate Sirt3's molecular mechanism in regulating insulin sensitivity in adipocytes that can contribute to the effort of targeting Sirt3 for the treatment of obesity and type 2 diabetes. We found that the Sirt3 activator honokiol (HNK) induced adipogenesis compared to the control, in contrast to Sirt3 inhibitor, 3-TYP. Accordingly, HNK increased expression of adipocyte gene markers, gene-involved lipolysis and glucose transport (GLUT4), while 3-TYP reduced expression of those genes. Interestingly, 3-TYP caused an increase in gene expression of adipocyte-specific cytokines including IL6, resistin, and TNF-α. However, changes in adipocyte-specific cytokines in HNK treated cells were not significant. In addition, HNK stimulated insulin pathway by promoting insulin receptor beta (IRβ) and PI3K/AKT/mTOR pathways, resulting in an increase in phosphorylation of the forkhead family FoxO1/FoxO3a/FoxO4 and glycogen synthase kinase-3 (GSK-3β), opposing 3-TYP. In line with these findings, HNK increased free fatty acid and glucose uptake, contrary to 3-TYP. In conclusion, Sirt3 activator-HNK induced adipogenesis and lipolysis reduced adipocytes specific cytokines. Intriguingly, HNK activated insulin signaling pathway and increased free fatty acid as well as glucose uptake and transport, in sharp contrast to 3-TYP. These results indicate that, via insulin signaling regulation, Sirt3 activation by HNK improves insulin resistance, while Sirt3 inhibition by 3-TYP might precipitate insulin resistance.
21Metformin and Insulin Resistance: A Review of the Underlying Mechanisms behind Changes in GLUT4-Mediated Glucose Transport.PubMed
Rok Herman, Nika Aleksandra Kravos, Mojca Jensterle, et al.
Int J Mol Sci. 2022 Jan 23;23(3):1264. doi: 10.3390/ijms23031264.
Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary syndrome, and obesity. There is a well-documented correlation between glucose transporter 4 (GLUT4) expression and the level of IR. Therefore, the observed increase in peripheral glucose utilization after metformin treatment most likely comes from the induction of GLUT4 expression and its increased translocation to the plasma membrane. However, the mechanisms behind this effect and the critical metformin targets are still largely undefined. The present review explores the evidence for the crucial role of changes in the expression and activation of insulin signaling pathway mediators, AMPK, several GLUT4 translocation mediators, and the effect of posttranscriptional modifications based on previously published preclinical and clinical models of metformin's mode of action in animal and human studies. Our aim is to provide a comprehensive review of the studies in this field in order to shed some light on the complex interactions between metformin action, GLUT4 expression, GLUT4 translocation, and the observed increase in peripheral insulin sensitivity.
22Baicalin against obesity and insulin resistance through activation of AKT/AS160/GLUT4 pathway.PubMed
Penghua Fang, Mei Yu, Lei Zhang, et al.
Mol Cell Endocrinol. 2017 Jun 15;448:77-86. doi: 10.1016/j.mce.2017.03.027. Epub 2017 Mar 27.
Obesity may cause several metabolic complications, including insulin resistance and type 2 diabetes mellitus. Despite great advances in medicine, people still keep exploring novel and effective drugs for treatment of obesity and insulin resistance. The aim of this study was to survey if baicalin might ameliorate obesity-induced insulin resistance and to explore its signal mechanisms in skeletal muscles of mice. Diet-induced obese (DIO) mice were given 50 mg/kg baicalin intraperitoneally (i.p.) once a day for 21 days, and C2C12 myotubes were treated with 100, 200, 400 μM baicalin for 12 h in this study. Then insulin resistance indexes and insulin signal protein levels in skeletal muscles were examined. We discovered that administration of baicalin decreased food intake, body weight, HOMA-IR and NT-PGC-1α levels, but enhanced GLUT4, PGC-1α, pP38MAPK, pAKT and pAS160 contents, as well as GLUT4 mRNA, PGC-1α mRNA, PPARγ mRNA, GLUT1 mRNA expression in skeletal muscles of obese mice and myotubes of C2C12 cells, and reversed high fat diet-induced glucose and insulin intolerance, hyperglycemia and insulin resistance in the mice. These results suggest that baicalin is a powerful and promising agent for treatment of obesity and insulin resistance via Akt/AS160/GLUT4 and P38MAPK/PGC1α/GLUT4 pathway.
23PP1γ regulates neuronal insulin signaling and aggravates insulin resistance leading to AD-like phenotypes.PubMed
Yamini Yadav, Medha Sharma, Chinmoy Sankar Dey
Cell Commun Signal. 2023 Apr 21;21(1):82. doi: 10.1186/s12964-023-01071-x.
BACKGROUND: PP1γ is one of the isoforms of catalytic subunit of a Ser/Thr phosphatase PP1. The role of PP1γ in cellular regulation is largely unknown. The present study investigated the role of PP1γ in regulating neuronal insulin signaling and insulin resistance in neuronal cells. PP1 was inhibited in mouse neuroblastoma cells (N2a) and human neuroblastoma cells (SH-SY5Y). The expression of PP1α and PP1γ was determined in insulin resistant N2a, SH-SY5Y cells and in high-fat-diet-fed-diabetic mice whole-brain-lysates. PP1α and PP1γ were silenced by siRNA in N2a and SH-SY5Y cells and effect was tested on AKT isoforms, AS160 and GSK3 isoforms using western immunoblot, GLUT4 translocation by confocal microscopy and glucose uptake by fluorescence-based assay. RESULTS: Results showed that, in one hand PP1γ, and not PP1α, regulates neuronal insulin signaling and insulin resistance by regulating phosphorylation of AKT2 via AKT2-AS160-GLUT4 axis. On the other hand, PP1γ regulates phosphorylation of GSK3β via AKT2 while phosphorylation of GSK3α via MLK3. Imbalance in this regulation results into AD-like phenotype. CONCLUSION: PP1γ acts as a linker, regulating two pathophysiological conditions, neuronal insulin resistance and AD. Video Abstract.
24What Is Lipotoxicity?PubMed
Ayse Basak Engin
Adv Exp Med Biol. 2017;960:197-220. doi: 10.1007/978-3-319-48382-5_8.
Enlarged fat cells in obese adipose tissue diminish capacity to store fat and are resistant to the anti-lipolytic effect of insulin. Insulin resistance (IR)-associated S-nitrosylation of insulin-signaling proteins increases in obesity. In accordance with the inhibition of insulin-mediated anti-lipolytic action, plasma free fatty acid (FFA) levels increase. Additionally, endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate/Protein kinase A (cAMP/PKA) and extracellular signal-regulated kinase ½ (ERK1/2) signaling in adipocytes. Failure of packaging of excess lipid into lipid droplets causes chronic elevation of circulating fatty acids, which can reach to toxic levels within non-adipose tissues. Deleterious effects of lipid accumulation in non-adipose tissues are known as lipotoxicity. In fact, triglycerides may also serve a storage function for long-chain non-esterified fatty acids and their products such as ceramides and diacylglycerols (DAGs). Thus, excess DAG, ceramide and saturated fatty acids in obesity can induce chronic inflammation and have harmful effect on multiple organs and systems. In this context, chronic adipose tissue inflammation, mitochondrial dysfunction and IR have been discussed within the scope of lipotoxicity.
25Targeting a ceramide double bond improves insulin resistance and hepatic steatosis.PubMed
Bhagirath Chaurasia, Trevor S Tippetts, Rafael Mayoral Monibas, et al.
Science. 2019 Jul 26;365(6451):386-392. doi: 10.1126/science.aav3722. Epub 2019 Jul 4.
Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase 1 (DES1), which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals or tissue-specific deletion in the liver and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders.
26Ceramide-induced FGF13 impairs systemic metabolic health.PubMed
Jamal Naderi, Amanda Kelsey Johnson, Himani Thakkar, et al.
Cell Metab. 2025 May 6;37(5):1206-1222.e8. doi: 10.1016/j.cmet.2025.03.002. Epub 2025 Mar 31.
Ceramide accumulation impairs adipocytes' ability to efficiently store and utilize nutrients, leading to energy and glucose homeostasis deterioration. Using a comparative transcriptomic screen, we identified the non-canonical, non-secreted fibroblast growth factor FGF13 as a ceramide-regulated factor that impairs adipocyte function. Obesity robustly induces FGF13 expression in adipose tissue in mice and humans and is positively associated with glycemic indices of type 2 diabetes. Pharmacological or genetic inhibition of ceramide biosynthesis reduces FGF13 expression. Using mice with loss and gain of function of FGF13, we demonstrate that FGF13 is both necessary and sufficient to impair energy and glucose homeostasis independent of ceramides. Mechanistically, FGF13 exerts these effects by inhibiting mitochondrial content and function, metabolic elasticity, and caveolae formation, which cumulatively impairs glucose utilization and thermogenesis. These studies suggest the therapeutic potential of targeting FGF13 to prevent and treat metabolic diseases.
27Codon-optimized FAM132b gene therapy prevents dietary obesity by blockading adrenergic response and insulin action.PubMed
Zhengtang Qi, Jie Xia, Xiangli Xue, et al.
Int J Obes (Lond). 2022 Nov;46(11):1970-1982. doi: 10.1038/s41366-022-01189-x. Epub 2022 Aug 3.
BACKGROUND: FAM132b (myonectin) has been identified as a muscle-derived myokine with exercise and has hormone activity in circulation to regulate iron homeostasis and lipid metabolism via unknown receptors. Here, we aim to explore the potential of adeno-associated virus to deliver FAM132b in vivo to develop a gene therapy against obesity. METHODS: Adeno-associated virus AAV9 were engineered to induce overexpression of FAM132b with two mutations, A136T and P159A. Then, AAV9 was delivered into high-fat diet mice through tail vein, and glucose homeostasis and obesity development of mice were observed. Methods of structural biology were used to predict the action site or receptor of the FAM132b mutant. RESULTS: Treatment of high-fat diet-fed mice with AAV9 improved glucose intolerance and insulin resistance, and resulted in reductions in body weight, fat depot, and adipocyte size. Codon-optimized FAM132b (coFAM132b) reduced the glycemic response to epinephrine (EPI) in the whole body and increased the lipolytic response to EPI in adipose tissues. However, FAM132b knockdown by shRNA significantly increased the glycemic response to EPI in vivo and reduced adipocyte response to EPI and adipose tissue browning. Structural analysis predicted that the FAM132b mutant with A136T and P159A may form a weak bond with β2 adrenergic receptor (ADRB2) and may have more affinity for insulin and insulin-receptor complexes. CONCLUSIONS: Our study underscores the potential of FAM132b gene therapy with codon optimization to treat obesity by modulating the adrenergic response and insulin action. Both structural biological analysis and in vivo experiments suggest that the adrenergic response and insulin action are most likely blockaded by FAM132b mutants.
28The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review.PubMed
Adrian M Gonzalez-Gil, Leticia Elizondo-Montemayor
Nutrients. 2020 Jun 26;12(6):1899. doi: 10.3390/nu12061899.
Exercise is an effective strategy for preventing and treating obesity and its related cardiometabolic disorders, resulting in significant loss of body fat mass, white adipose tissue browning, redistribution of energy substrates, optimization of global energy expenditure, enhancement of hypothalamic circuits that control appetite-satiety and energy expenditure, and decreased systemic inflammation and insulin resistance. Novel exercise-inducible soluble factors, including myokines, hepatokines, and osteokines, and immune cytokines and adipokines are hypothesized to play an important role in the body's response to exercise. To our knowledge, no review has provided a comprehensive integrative overview of these novel molecular players and the mechanisms involved in the redistribution of metabolic fuel during and after exercise, the loss of weight and fat mass, and reduced inflammation. In this review, we explain the potential role of these exercise-inducible factors, namely myokines, such as irisin, IL-6, IL-15, METRNL, BAIBA, and myostatin, and hepatokines, in particular selenoprotein P, fetuin A, FGF21, ANGPTL4, and follistatin. We also describe the function of osteokines, specifically osteocalcin, and of adipokines such as leptin, adiponectin, and resistin. We also emphasize an integrative overview of the pleiotropic mechanisms, the metabolic pathways, and the inter-organ crosstalk involved in energy expenditure, fat mass loss, reduced inflammation, and healthy weight induced by exercise.
29Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism.PubMed
Tae Hyun Kim, Dong-Gyun Hong, Yoon Mee Yang
Biomedicines. 2021 Dec 14;9(12):1903. doi: 10.3390/biomedicines9121903.
The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. In this review, we describe the hepatokine-driven inter-organ crosstalk in the context of liver pathophysiology, with a particular focus on NAFLD progression. Moreover, we summarize key hepatokines and their molecular mechanisms of metabolic control in non-hepatic tissues, discussing their potential as novel biomarkers and therapeutic targets in the treatment of metabolic diseases.
30Dietary medium-chain fatty acids reduce hepatic fat accumulation via activation of a CREBH-FGF21 axis.PubMed
Ye Cao, Masaya Araki, Yoshimi Nakagawa, et al.
Mol Metab. 2024 Sep;87:101991. doi: 10.1016/j.molmet.2024.101991. Epub 2024 Jul 15.
OBJECTIVE: Dietary medium-chain fatty acids (MCFAs), characterized by chain lengths of 8-12 carbon atoms, have been proposed to have beneficial effects on glucose and lipid metabolism, yet the underlying mechanisms remain elusive. We hypothesized that MCFA intake benefits metabolic health by inducing the release of hormone-like factors. METHODS: The effects of chow diet, high-fat diet rich in long-chain fatty acids (LCFA HFD) fed ad libitum or pair-fed to a high-fat diet rich in MCFA (MCFA HFD) on glycemia, hepatic gene expression, circulating fibroblast growth factor 21 (FGF21), and liver fat content in both wildtype and Fgf21 knockout mice were investigated. The impact of a single oral dose of an MCFA-rich oil on circulating FGF21 and hepatic Fgf21 mRNA expression was assessed. In flag-tagged Crebh knockin mice and liver-specific Crebh knockout mice, fed LCFA HFD or MCFA HFD, active hepatic CREBH and hepatic Fgf21 mRNA abundance were determined, respectively. RESULTS: MCFA HFD improves glucose tolerance, enhances glucose clearance into brown adipose tissue, and prevents high-fat diet-induced hepatic steatosis in wildtype mice. These benefits are associated with increased liver expression of CREBH target genes (Apoa4 and Apoc2), including Fgf21. Both acute and chronic intake of dietary MCFAs elevate circulating FGF21. Augmented hepatic Fgf21 mRNA following MCFA HFD intake is accompanied by higher levels of active hepatic CREBH; and MCFA-induced hepatic Fgf21 expression is blocked in mice lacking Crebh. Notably, while feeding male and female Fgf21 wildtype mice MCFA HFD results in reduced liver triacylglycerol (TG) levels, this liver TG-lowering effect is blunted in Fgf21 knockout mice fed MCFA HFD. The reduction in liver TG levels observed with MCFA HFD was independent of weight loss. CONCLUSIONS: Dietary MCFAs reduce liver fat accumulation via activation of a CREBH-FGF21 signaling axis.
31Hepatocyte-specific GDF15 overexpression improves high-fat diet-induced obesity and hepatic steatosis in mice via hepatic FGF21 induction.PubMed
Kento Takeuchi, Kanji Yamaguchi, Yusuke Takahashi, et al.
Sci Rep. 2024 Oct 14;14(1):23993. doi: 10.1038/s41598-024-75107-8.
GDF15 and FGF21, stress-responsive cytokines primarily secreted from the liver, are promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interaction between GDF15 and FGF21 remains unclear. We examined the effects of hepatocyte-specific GDF15 or FGF21 overexpression in high-fat diet (HFD)-fed mice for 8 weeks. Hydrodynamic injection of GDF15 or FGF21 sustained high circulating levels of GDF15 or FGF21, respectively, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and hepatic steatosis. In addition, GDF15 treatment led to early reduction in body weight despite no change in food intake, indicating the role of GDF15 other than appetite loss. GDF15 treatment increased liver-derived serum FGF21 levels, whereas FGF21 treatment did not affect GDF15 expression. GDF15 promoted eIF2α phosphorylation and XBP1 splicing, leading to FGF21 induction. In murine AML12 hepatocytes treated with free fatty acids (FFAs), GDF15 overexpression upregulated Fgf21 mRNA levels and promoted eIF2α phosphorylation and XBP1 splicing. Overall, continuous exposure to excess FFAs resulted in a gradual increase of β-oxidation-derived reactive oxygen species and endoplasmic reticulum stress, suggesting that GDF15 enhanced this pathway and induced FGF21 expression. GDF15- and FGF21-related crosstalk is an important pathway for the treatment of MASLD.
32Hepatokines and MASLD: The GLP1-Ras-FGF21-Fetuin-A Crosstalk as a Therapeutic Target.PubMed
Ilaria Milani, Michela Codini, Gloria Guarisco, et al.
Int J Mol Sci. 2024 Oct 8;25(19):10795. doi: 10.3390/ijms251910795.
The introduction of the term "Metabolic Steatotic Liver Disease" (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver's increased production of proteins known as "hepatokines" has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD.
33Brown adipose tissue-derived MaR2 contributes to cold-induced resolution of inflammation.PubMed
Satoru Sugimoto, Hebe Agustina Mena, Brian E Sansbury, et al.
Nat Metab. 2022 Jun;4(6):775-790. doi: 10.1038/s42255-022-00590-0. Epub 2022 Jun 27.
Obesity induces chronic inflammation resulting in insulin resistance and metabolic disorders. Cold exposure can improve insulin sensitivity in humans and rodents, but the mechanisms have not been fully elucidated. Here, we find that cold resolves obesity-induced inflammation and insulin resistance and improves glucose tolerance in diet-induced obese mice. The beneficial effects of cold exposure on improving obesity-induced inflammation and insulin resistance depend on brown adipose tissue (BAT) and liver. Using targeted liquid chromatography with tandem mass spectrometry, we discovered that cold and β3-adrenergic stimulation promote BAT to produce maresin 2 (MaR2), a member of the specialized pro-resolving mediators of bioactive lipids that play a role in the resolution of inflammation. Notably, MaR2 reduces inflammation in obesity in part by targeting macrophages in the liver. Thus, BAT-derived MaR2 could contribute to the beneficial effects of BAT activation in resolving obesity-induced inflammation and may inform therapeutic approaches to combat obesity and its complications.
34Brown Adipose Tissue Activation in Humans Increases Plasma Levels of Lipid Mediators.PubMed
Mary E Walker, Sean D Kodani, Hebe Agustina Mena, et al.
J Clin Endocrinol Metab. 2024 Jun 17;109(7):1837-1849. doi: 10.1210/clinem/dgae016.
CONTEXT: Activation of brown adipose tissue (BAT) thermogenesis improves insulin sensitivity and is beneficial in obesity. Emerging evidence indicates that BAT activation increases lipid mediators that play autocrine and endocrine roles to regulate metabolism and inflammation. OBJECTIVE: The goal of the study was to determine the relationship between 2 distinct approaches of BAT activation (cold exposure and mirabegron treatment) with lipid mediators in humans. METHODS: Healthy female subjects (n = 14) were treated with the β3-adrenergic receptor agonist mirabegron (100 mg) daily for 28 days. A subset of female subjects (n = 8) was additionally exposed to cold temperatures (14-16 °C) for 2 hours using a cooling vest prior to initiating mirabegron treatment. A panel of lipid mediators was assessed in plasma using targeted liquid chromatography-tandem mass spectrometry, and their relationship to anthropometric and metabolic parameters was determined. RESULTS: Activation of BAT with cold exposure acutely increased levels of lipoxygenase and cyclooxygenase products, including 12-hydroxyeicosapentaenoic acid, 12-hydroxyeicosatetraenoic acid (HETE), 5-HETE, 14-hydroxydocosahexaenoic acid (HDHA), an isomer of maresin 2 (MaR2), 17-HDHA, protectin D1 (PD1), and prostaglandin E2. Mirabegron treatment similarly increased these products acutely, although levels of some mediators were blunted after chronic mirabegron treatment. Selected lipid mediators, including an MaR2 isomer, 17-HDHA, 5-HETE, and 15-HETE, positively correlated with nonesterified fatty acids and negatively correlated with the respiratory quotient, while PD1, 15-HETE, and 5-HETE positively correlated with adiponectin. CONCLUSION: These results indicate that selected lipid mediators may serve as biomarkers of BAT activation.
35Effect of acupuncture and metformin on insulin sensitivity in women with polycystic ovary syndrome and insulin resistance: a three-armed randomized controlled trial.PubMed
Qidan Wen, Min Hu, Maohua Lai, et al.
Hum Reprod. 2022 Mar 1;37(3):542-552. doi: 10.1093/humrep/deab272.
STUDY QUESTION: Does acupuncture improve insulin sensitivity more effectively than metformin or sham acupuncture in women with polycystic ovary syndrome (PCOS) and insulin resistance (IR)? SUMMARY ANSWER: Among women with PCOS and IR, acupuncture was not more effective than metformin or sham acupuncture in improving insulin sensitivity. WHAT IS KNOWN ALREADY: Uncontrolled trials have shown that acupuncture improved insulin sensitivity with fewer side effects compared with metformin in women with PCOS and IR. However, data from randomized trials between acupuncture and metformin or sham acupuncture are lacking. STUDY DESIGN, SIZE, DURATION: This was a three-armed randomized controlled trial enrolling a total of 342 women with PCOS and IR from three hospitals between November 2015 and February 2018, with a 3-month follow-up until October 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged from 18 to 40 years with PCOS and homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.14 were randomly assigned (n = 114 per group) to receive true acupuncture plus placebo (true acupuncture), metformin plus sham acupuncture (metformin, 0.5 g three times daily) or sham acupuncture plus placebo (sham acupuncture) for 4 months, with an additional 3-month follow-up. True or sham acupuncture was given three times per week, and 0.5 g metformin or placebo was given three times daily. The primary outcome was change in HOMA-IR from baseline to 4 months after baseline visit. Secondary outcomes included changes in the glucose AUC during an oral glucose tolerance test, BMI and side effects at 4 months after baseline visit. MAIN RESULTS AND THE ROLE OF CHANCE: After 4 months of treatment, the changes of HOMA-IR were -0.5 (decreased 14.7%) in the true acupuncture group, -1.0 (decreased 25.0%) in the metformin group and -0.3 (decreased 8.6%) in the sham acupuncture group, when compared with baseline. True acupuncture is not as effective as metformin in improving HOMA-IR at 4 months after baseline visit (difference, 0.6; 95% CI, 0.1-1.1). No significant difference was found in change in HOMA-IR between true and sham acupuncture groups at 4 months after baseline visit (difference, -0.2; 95% CI, -0.7 to 0.3). During the 4 months of treatment, gastrointestinal side effects were more frequent in the metformin group, including diarrhea, nausea, loss of appetite, fatigue, vomiting and stomach discomfort (31.6%, 13.2%, 11.4%, 8.8%, 14.0% and 8.8%, respectively). Bruising was more common in the true acupuncture group (14.9%). LIMITATIONS, REASONS FOR CAUTION: This study might have underestimated the sample size in the true acupuncture group with 4 months of treatment to enable detection of statistically significant changes in HOMA-IR with fixed acupuncture (i.e. a non-personalized protocol). Participants who withdrew because of pregnancy did not have further blood tests and this can introduce bias. WIDER IMPLICATIONS OF THE FINDINGS: True acupuncture did not improve insulin sensitivity as effectively as metformin in women with PCOS and IR, but it is better than metformin in improving glucose metabolism (which might reduce the risk of type 2 diabetes) and has less side effects. Metformin had a higher incidence of gastrointestinal adverse effects than acupuncture groups, and thus acupuncture might be a non-pharmacological treatment with low risk for women with PCOS. Further studies are needed to evaluate the effect of acupuncture combined with metformin on insulin sensitivity in these women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants 2017A020213004 and 2014A020221060 from the Science and Technology Planning Project of Guangdong Province. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov number: NCT02491333. TRIAL REGISTRATION DATE: 8 July 2015. DATE OF FIRST PATIENT’S ENROLLMENT: 11 November 2015.
36Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.PubMed
Lara C Morley, Thomas Tang, Ephia Yasmin, et al.
Cochrane Database Syst Rev. 2017 Nov 29;11(11):CD003053. doi: 10.1002/14651858.CD003053.pub6.
BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. OBJECTIVES: To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction. SEARCH METHODS: We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies. SELECTION CRITERIA: We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I statistic and reported quality of the evidence for primary outcomes using GRADE methodology. MAIN RESULTS: We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatmentThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I = 0%, low-quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I = 61%, moderate-quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I = 43%, moderate-quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I = 58%, moderate-quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I = 54%, low-quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I = 0%, low-quality evidence). Metformin plus clomiphene citrate versus clomiphene citrate alone There was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I = 20%, low-quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I = 47%, moderate-quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I = 33%, moderate-quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I = 64%, moderate-quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I = 0%, low-quality evidence) but this is of uncertain clinical significance due to low-quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I = 0%, low-quality evidence). Metformin versus clomiphene citrateWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I = 86%, very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I = 0%, very low-quality evidence), while data from the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I = 78%, very low-quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I = 0%, very low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I = 0%, low-quality evidence) while among non-obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I = 41%, very low-quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low-quality evidence, I=0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I = 52%, very low-quality evidence). D-chiro-inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatmentWe were unable to draw conclusions regarding other insulin-sensitising drugs as no studies reported primary outcomes. AUTHORS' CONCLUSIONS: Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low. When metformin was compared with clomiphene citrate, data for live birth were inconclusive, and our findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. An improvement in clinical pregnancy and ovulation suggests that clomiphene citrate remains preferable to metformin for ovulation induction in obese women with PCOS.An improved clinical pregnancy and ovulation rate with metformin and clomiphene citrate versus clomiphene citrate alone suggests that combined therapy may be useful although we do not know whether this translates into increased live births. Women taking metformin alone or with combined therapy should be advised that there is no evidence of increased miscarriages, but gastrointestinal side effects are more likely.
37The use of metformin in women with polycystic ovary syndrome: an updated review.PubMed
Adriana Leal Griz Notaro, Filipe Tenorio Lira Neto
J Assist Reprod Genet. 2022 Mar;39(3):573-579. doi: 10.1007/s10815-022-02429-9. Epub 2022 Feb 14.
PURPOSES: Polycystic ovary syndrome (PCOS) is a major cause of female infertility, being present in up to 20% of women of childbearing age. Insulin resistance (IR) plays an important role in the pathophysiology of PCOS; therefore, its treatment may benefit women with the syndrome. The main drug used for IR management is metformin (MT). We aim to review the literature on the use of metformin in women with PCOS. METHODS: Using the terms "metformin" and "polycystic ovary syndrome," we conducted a search the PubMed, EMBASE, and Google Scholar databases. The research was restricted to articles published in English. Initially, only published meta-analyses were included, in the absence of meta-analyzes, RCT and well-designed prospective studies were used. RESULTS: Metformin increases success rates and decreases complication rates when used as an adjunctive medication for ovulation induction during low complexity assisted reproduction treatments and during ovarian stimulation for in vitro fertilization in women with PCOS. Evidence about the effect of metformin on fetal and obstetric complication rates is conflicting. Metformin is associated with high incidence of gastrointestinal symptoms; however, serious adverse effects are rare and there is no evidence of teratogenicity. CONCLUSION: For women with PCOS, metformin is a good adjunctive medication for ovulation induction/stimulation for high and low complexity assisted reproduction therapies. The adverse effects are mostly mild, and there is no risk of teratogenicity, but the risk of long-term complications for the offspring is not yet defined. High heterogeneity of the studies limits extrapolation of findings, and further research is needed to determine which women will benefit most from the medication.
38Efficacy of berberine in patients with type 2 diabetes mellitus.PubMed
Jun Yin, Huili Xing, Jianping Ye
Metabolism. 2008 May;57(5):712-7. doi: 10.1016/j.metabol.2008.01.013.
Berberine has been shown to regulate glucose and lipid metabolism in vitro and in vivo. This pilot study was to determine the efficacy and safety of berberine in the treatment of type 2 diabetes mellitus patients. In study A, 36 adults with newly diagnosed type 2 diabetes mellitus were randomly assigned to treatment with berberine or metformin (0.5 g 3 times a day) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. Significant decreases in hemoglobin A1c (from 9.5%+/-0.5% to 7.5%+/-0.4%, P<.01), fasting blood glucose (from 10.6+/-0.9 mmol/L to 6.9+/-0.5 mmol/L, P<.01), postprandial blood glucose (from 19.8+/-1.7 to 11.1+/-0.9 mmol/L, P<.01), and plasma triglycerides (from 1.13+/-0.13 to 0.89+/-0.03 mmol/L, P<.05) were observed in the berberine group. In study B, 48 adults with poorly controlled type 2 diabetes mellitus were treated supplemented with berberine in a 3-month trial. Berberine acted by lowering fasting blood glucose and postprandial blood glucose from 1 week to the end of the trial. Hemoglobin A1c decreased from 8.1%+/-0.2% to 7.3%+/-0.3% (P<.001). Fasting plasma insulin and homeostasis model assessment of insulin resistance index were reduced by 28.1% and 44.7% (P<.001), respectively. Total cholesterol and low-density lipoprotein cholesterol were decreased significantly as well. During the trial, 20 (34.5%) patients experienced transient gastrointestinal adverse effects. Functional liver or kidney damages were not observed for all patients. In conclusion, this pilot study indicates that berberine is a potent oral hypoglycemic agent with beneficial effects on lipid metabolism.
39Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of nonalcoholic fatty liver disease (NAFLD).PubMed
Yuan-Ye Qiu, Jing Zhang, Fan-Yi Zeng, et al.
Pharmacol Res. 2023 Jun;192:106786. doi: 10.1016/j.phrs.2023.106786. Epub 2023 May 3.
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease phenotypes which start with simple steatosis and lipid accumulation in the hepatocytes - a typical histological lesions characteristic. It may progress to non-alcoholic steatohepatitis (NASH) that is characterized by hepatic inflammation and/or fibrosis and subsequent onset of NAFLD-related cirrhosis and hepatocellular carcinoma (HCC). Due to the central role of the liver in metabolism, NAFLD is regarded as a result of and contribution to the metabolic abnormalities seen in the metabolic syndrome. Peroxisome proliferator-activated receptors (PPARs) has three subtypes, which govern the expression of genes responsible for energy metabolism, cellular development, inflammation, and differentiation. The agonists of PPARα, such as fenofibrate and clofibrate, have been used as lipid-lowering drugs in clinical practice. Thiazolidinediones (TZDs) - ligands of PPARγ, such as rosiglitazone and pioglitazone, are also used in the treatment of type 2 diabetes (T2D) with insulin resistance (IR). Increasing evidence suggests that PPARβ/δ agonists have potential therapeutic effects in improving insulin sensitivity and lipid metabolism disorders. In addition, PPARs ligands have been considered as potential therapeutic drugs for hypertension, atherosclerosis (AS) or diabetic nephropathy. Their crucial biological roles dictate the significance of PPARs-targeting in medical research and drug discovery. Here, it reviews the biological activities, ligand selectivity and biological functions of the PPARs family, and discusses the relationship between PPARs and the pathogenesis of NAFLD and metabolic syndrome. This will open new possibilities for PPARs application in medicine, and provide a new idea for the treatment of fatty liver and related diseases.
40PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets.PubMed
Hao Chen, Huabing Tan, Juan Wan, et al.
Pharmacol Ther. 2023 May;245:108391. doi: 10.1016/j.pharmthera.2023.108391. Epub 2023 Mar 22.
Non-alcoholic fatty liver disease (NAFLD), currently the leading cause of global chronic liver disease, has emerged as a major public health problem, more efficient therapeutics of which are thus urgently needed. Peroxisome proliferator-activated receptor γ (PPAR-γ), ligand-activated transcription factors of the nuclear hormone receptor superfamily, is considered a crucial metabolic regulator of hepatic lipid metabolism and inflammation. The role of PPAR-γ in the pathogenesis of NAFLD is gradually being recognized. Here, we outline the involvement of PPAR-γ in the pathogenesis of NAFLD through adipogenesis, insulin resistance, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In addition, the evidence for PPAR-γ- targeted therapy for NAFLD are summarized. Altogether, PPAR-γ is a promising therapeutic target for NAFLD, and the development of drugs that can balance the beneficial and undesirable effects of PPAR-γ will bring new light to NAFLD patients.
41Non-Alcoholic Fatty Liver Disease and Its Association With Diabetes Mellitus.PubMed
Jaskamal Padda, Khizer Khalid, Anwar Khedr, et al.
Cureus. 2021 Aug 20;13(8):e17321. doi: 10.7759/cureus.17321. eCollection 2021 Aug.
There is a bidirectional relationship between non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). The liver has a vital role in the pathophysiology of both diseases as it leads to the development of insulin resistance (IR), which in turn results in NAFLD and T2DM. It has been shown that T2DM increases the risk of NAFLD progression. Furthermore, the presence of NAFLD raises the probability of T2DM complications, which explains the increased rates of NAFLD screening in patients with T2DM. In addition, there are common management options for the two diseases. Lifestyle changes can play a role in the initial management of both diseases. Medications that are used to treat T2DM are also used in the management of NAFLD, such as metformin, thiazolidinediones (TZD), glucagon-like peptide-1 (GLP-1) analogues, and dipeptidyl peptidase-4 (DPP4) inhibitors. Bariatric surgery is often used as a last resort and has shown promising results. Lifestyle interventions with diet and exercise are important postoperatively to maintain the weight loss. There are many novel treatments that are being investigated for the treatment of NAFLD, targeting multiple pathophysiologic pathways. This review aims to shed some light on the intricate relationship between NAFLD and T2DM and how IR links both diseases. We also try to raise awareness among clinicians about this relationship and how the presence of one disease should raise a high index of suspicion for the existence of the other.
42Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.PubMed
Yoshihisa Takahashi, Keiichiro Sugimoto, Hiroshi Inui, et al.
World J Gastroenterol. 2015 Apr 7;21(13):3777-85. doi: 10.3748/wjg.v21.i13.3777.
Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers (thiazolidinediones) and antioxidants (vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.
43Fatty liver disease in diabetes mellitus.PubMed
Harikrashna B Bhatt, Robert J Smith
Hepatobiliary Surg Nutr. 2015 Apr;4(2):101-8. doi: 10.3978/j.issn.2304-3881.2015.01.03.
Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus (T2DM), likely reflecting the frequent occurrence of obesity and insulin resistance in T2DM. NAFLD also can occur in type 1 DM (T1DM), but must be distinguished from the more common glycogen hepatopathy as a cause of hepatomegaly and liver function abnormalities in T1DM. Weight reduction achieved by diet and exercise is effective in preventing and treating NAFLD in obese diabetic subjects. Bariatric surgery also has been shown to reverse NAFLD in T2DM, and recently approved weight loss medications should be evaluated for their impact on the development and progression of NAFLD. There is limited evidence suggesting that specific drugs used for blood glucose control in T2DM [thiazolidinediones (TZDs), glucagon-like peptide-1 (GLP-1) analogs, and dipeptidyl peptidase-4 (DPP-4) inhibitors] and also statins may have a role in preventing or treating NAFLD in patients with diabetes.
44Comparative effectiveness of multiple different treatment regimens for nonalcoholic fatty liver disease with type 2 diabetes mellitus: a systematic review and Bayesian network meta-analysis of randomised controlled trials.PubMed
Manjun Deng, Yonghao Wen, JingXin Yan, et al.
BMC Med. 2023 Nov 16;21(1):447. doi: 10.1186/s12916-023-03129-6.
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related and mutually contribute to the disease's development. There are many treatment options available to patients. We provide a comprehensive overview of the evidence on the treatment effects of several potential interventions for NAFLD with T2DM. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, Cochrane Library, and Web of Science from inception to June 30, 2023, for randomised controlled trials of treatment of NAFLD with T2DM. We performed Bayesian network meta-analyses to summarise effect estimates of comparisons between interventions. We applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks to rate all comparative outcomes' certainty in effect estimates, categorise interventions, and present the findings. This study was registered with PROSPERO, CRD42022342373. RESULTS: Four thousand three hundred and sixty-nine records were retrieved from the database and other methods, of which 24 records were eligible for studies enrolling 1589 participants. Eight clinical indicators and 14 interventions were finally in focus. Referring to the lower surface under the cumulative ranking curves (SUCRA) and the league matrix table, exenatide and liraglutide, which are also glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed excellent potential to reduce liver fat content, control glycemia, reduce body weight, and improve liver function and insulin resistance. Exenatide was more effective in reducing glycated haemoglobin (HbA) (mean difference (MD) 0.32, 95%CI 0.12 to 0.52), lowering BMI (MD 0.81, 95%CI 0.18 to 1.45), and lowering alanine transaminase (ALT) (MD 10.96, 95%CI 5.27 to 16.66) compared to liraglutide. However, this evidence was assessed as low certainty. Omega-3 was the only intervention that did not have a tendency to lower HbA, with standard-treatment (STA-TRE) as reference (MD - 0.17, 95%CI - 0.42 to 0.07). Glimepiride is the only intervention that causes an increase in ALT levels, with standard-treatment (STA-TRE) as reference (MD - 11.72, 95%CI - 17.82 to - 5.57). Based on the available evidence, the treatment effects of pioglitazone, dapagliflozin, and liraglutide have a high degree of confidence. CONCLUSIONS: The high confidence mandates the confident application of these findings as guides for clinical practice. Dapagliflozin and pioglitazone are used for glycaemic control in patients with NAFLD combined with T2DM, and liraglutide is used for weight loss therapy in patients with abdominal obesity. The available evidence does not demonstrate the credibility of the effectiveness of other interventions in reducing liver fat content, visceral fat area, ALT, and insulin resistance. Future studies should focus on the clinical application of GLP-1Ras and the long-term prognosis of patients.
45Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial.PubMed
Samer Gawrieh, Mazen Noureddin, Nicole Loo, et al.
Hepatology. 2021 Oct;74(4):1809-1824. doi: 10.1002/hep.31843. Epub 2021 Jul 19.
BACKGROUND AND AIMS: NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH. APPROACH AND RESULTS: A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least-squares mean percent change from baseline in ALT at week 16 was -25.5% (5.8), -27.7% (5.9), and -45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27). CONCLUSIONS: Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).
46Antrodan Alleviates High-Fat and High-Fructose Diet-Induced Fatty Liver Disease in C57BL/6 Mice Model via AMPK/Sirt1/SREBP-1c/PPARγ Pathway.PubMed
Charng-Cherng Chyau, Hsueh-Fang Wang, Wen-Juan Zhang, et al.
Int J Mol Sci. 2020 Jan 6;21(1):360. doi: 10.3390/ijms21010360.
Non-alcoholic fatty liver disease (NAFLD) and -steatohepatitis (NASH) imply a state of excessive fat built-up in livers with/or without inflammation and have led to serious medical concerns in recent years. Antrodan (Ant), a purified β-glucan from . has been shown to exhibit tremendous bioactivity, including hepatoprotective, antihyperlipidemic, antiliver cancer, and anti-inflammatory effects. Considering the already well-known alleviating bioactivity of for the alcoholic steatohepatitis (ASH), we propose that Ant can be beneficial to NAFLD, and that the AMPK/Sirt1/PPARγ/SREBP-1c pathways may be involved in such alleviations. To uncover this, we carried out this study with 60 male C57BL/6 mice fed high-fat high-fructose diet (HFD) for 60 days, in order to induce NAFLD/NASH. Mice were then grouped and treated (by oral administration) as: G1: control; G2: HFD (HFD control); G3: Ant, 40 mgkg (Ant control); G4: HFD+Orlistat (10 mg/kg) (as Orlistat control); G5: HFD+Ant L (20 mg/kg); and G6: HFD+Ant H (40 mg/kg) for 45 days. The results indicated Ant at 40 mg/kg effectively suppressed the plasma levels of malondialdehyde, total cholesterol, triglycerides, GOT, GPT, uric acid, glucose, and insulin; upregulated leptin, adiponectin, pAMPK, Sirt1, and down-regulated PPARγ and SREBP-1c. Conclusively, Ant effectively alleviates NAFLD via AMPK/Sirt1/CREBP-1c/PPARγ pathway.
47Effects of semaglutide on metabolism and gut microbiota in high-fat diet-induced obese mice.PubMed
Luyan Sun, Bingqing Shang, Suyuan Lv, et al.
Front Pharmacol. 2025 Jun 2;16:1562896. doi: 10.3389/fphar.2025.1562896. eCollection 2025.
BACKGROUND: The purpose of this study was to explore how semaglutide, a GLP-1RA, regulates serum metabolism and gut microbiota to improve obesity in mice and whether fecal microbiota transplantation (FMT) can transmit the beneficial effects of semaglutide to recipient mice. METHODS: Male C57BL/6J mice were given standard diet (ND), high-fat diet (HFD), or high-fat diet with semaglutide (SHF, 100 μg/kg). Fecal microbiota transplantation was used to transplant the fecal suspension supernatant (MT) and bacteria (FMT) from SHF group mice to antibiotic-induced pseudo-germ-free mice. RESULTS: Results showed that semaglutide significantly reduced the body weight, body fat, FBG, and insulin levels induced by high-fat diet, and improved insulin resistance and sensitivity damage ( < 0.05). This was achieved by regulating the expression of genes related to lipid metabolism such as , and in the liver and adipose tissue, as well as the appetite-related genes and in the hypothalamus. After stopping semaglutide intervention 4 weeks, the body weight of the mice rebounded significantly. Fecal microbiota transplantation could transmit the beneficial effects of semaglutide to recipient mice. Semaglutide and fecal microbiota transplantation affected metabolic pathways such as serum amino acid metabolism and pyrimidine metabolism in obese mice, and reshaped the composition and proportion of fecal gut microbiota in obese mice. CONCLUSION: In summary, semaglutide could inhibit food intake and improve obesity, regulate serum metabolism and the composition of gut microbiota in mice. Bacterial transplantation is key to transmitting the improvement brought about by fecal microbiota transplantation of semaglutide to recipient mice.
48Semaglutide Treatment Effects on Liver Fat Content in Obese Subjects with Metabolic-Associated Steatotic Liver Disease (MASLD).PubMed
Tereza Dusilová, Jan Kovář, Ivana Laňková, et al.
J Clin Med. 2024 Oct 13;13(20):6100. doi: 10.3390/jcm13206100.
: Metabolic-dysfunction-associated steatotic liver disease (MASLD) represents a major clinical complication of obesity. : In this study, we used magnetic resonance (MR) methods to determine the effect of obesity treatment with semaglutide, a GLP-1 receptor agonist, on the liver fat content and selected metabolic variables. We investigated whether treatment would affect the acute response of liver fat to glucose and fructose administration and whether it would affect the fatty acid profile of VLDL-triglycerides. Sixteen obese non-diabetic men underwent a 16-week dietary intervention and 16-week treatment with subcutaneous semaglutide in a crossover design without a washout period. The order of the interventions was randomized. : After treatment, body weight of the subjects decreased by 5% and liver fat by a third, whereas dietary intervention had no impact on these parameters. The decrease in liver fat with semaglutide did not correlate with changes in body weight and other measures of adiposity and was unrelated to improved insulin sensitivity. : The proportion of palmitic and palmitoleic acids in VLDL-triglycerides decreased after treatment, suggesting that the beneficial effects of semaglutide on liver fat are mediated by the suppression of de novo lipogenesis.
49Mechanism of Semaglutide in MASLD Treatment: Where Is the Master Key?PubMed
Devaraj Ezhilarasan
J Gastroenterol Hepatol. 2025 Sep;40(9):2163-2175. doi: 10.1111/jgh.17037. Epub 2025 Jun 19.
BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is used for weight reduction and metabolic improvement. Semaglutide effectively improves MASH but not confers histological fibrosis resolution. The key question remains whether semaglutide exerts direct, independent effects in ameliorating MASH or if its benefits are merely secondary to improvements in weight, insulin resistance, and glycemic control. The exact mechanisms of action through which semaglutide or other GLP-1 RAs offer liver protection are not entirely clear. METHODS: A comprehensive search in PubMed and EMBASE was conducted using the keywords "Semaglutide and NAFLD/MASLD", "glucagon-like peptide-1 receptor agonist and MASLD/NALFD", and "Semaglutide and type II diabetes/obesity and hypertension". Relevant papers published before February, 2025, were included. RESULTS: Semaglutide modulates several lipid-associated molecular pathways through unknown mechanisms. Preclinical and clinical studies suggest that semaglutide acts by (i) reducing appetite and increasing satiety, thereby decreasing dietary intake and subsequent free fatty acid export to the liver; (ii) reducing insulin resistance and improving insulin sensitivity and adipose dysfunction; (iii) reducing de novo lipogenesis by downregulating ChREBP and SREBP-1c signaling, as well as the expression of lipid-synthesizing genes; (iv) reducing the weight of white and brown adipose tissue; and (v) reducing inflammation by decreasing pro-inflammatory markers in GLP-1-expressing macrophages and favorably altering the gut microbiota. CONCLUSION: While this review explores the potential mechanisms of semaglutide action, the lack of GLP-1 receptor expression in the livers of mice and humans suggests that these mechanisms are associated with indirect modulation. Consequently, further mechanistic studies are needed to elucidate these pathways. TRIAL REGISTRATION: NOT APPLICABLE.
50The effect of semaglutide combined with metformin on liver inflammation and pancreatic beta-cell function in patients with type 2 diabetes and non-alcoholic fatty liver disease.PubMed
Rong Ren, Yanxia Pei, Lufei Kong, et al.
J Diabetes Complications. 2025 Feb;39(2):108932. doi: 10.1016/j.jdiacomp.2024.108932. Epub 2024 Dec 9.
BACKGROUND: Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) were often coexistent conditions driven by insulin resistance and systemic inflammation. Effective management strategies that address both metabolic disorders were urgently needed. This study investigates the effect of combining semaglutide, a glucagon-like peptide-1 receptor agonist, with metformin on liver inflammation and pancreatic beta-cell function in patients with T2DM and NAFLD. METHODS: This retrospective study analyzed 261 patients with T2DM and NAFLD treated at our institution from January 2021 to December 2023. Patients were divided into two groups: 127 received metformin alone (M group), and 134 received a combination of semaglutide and metformin (SAM group). Liver inflammation and fibrosis were assessed using alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (γ-GTP), and the FIB-4 index. Pancreatic beta-cell function and insulin sensitivity were evaluated using the Matsuda index, HbA1c, fasting glucose, and the oral disposition index (DIo). RESULTS: Post-treatment, the SAM group showed significantly greater improvements in liver inflammation markers (ALT: 23.59 ± 5.67 U/L in SAM vs. 25.56 ± 5.46 U/L in M; AST: 18.97 ± 3.94 U/L in SAM vs. 20.15 ± 3.95 U/L in M), reduced fibrosis (FIB-4 index: 1.05 ± 0.44 in SAM vs. 1.16 ± 0.51 in M), and enhanced beta-cell function (Matsuda index: 5.18 ± 1.09 in SAM vs. 4.84 ± 1.15 in M; DIo: 0.18 ± 0.06 in SAM vs. 0.16 ± 0.05 in M). Glycemic control, as indicated by reduced HbA1c, was also superior in the SAM group. CONCLUSION: The combination of semaglutide and metformin significantly improves liver inflammation, fibrosis, and beta-cell function in patients with T2DM and NAFLD compared to metformin alone.
51Therapeutic Effects of Semaglutide on Nonalcoholic Fatty Liver Disease with Type 2 Diabetes Mellitus and Obesity: An Open-Label Controlled Trial.PubMed
Ahmed I Gad, Nevin F Ibrahim, Noura Almadani, et al.
Diseases. 2024 Aug 17;12(8):186. doi: 10.3390/diseases12080186.
BACKGROUND: GLP-1 receptor agonists (GLP-1 RAs) have been shown to improve glycemic control and insulin sensitivity and reduce body weight in obese patients with type 2 diabetes mellitus (T2D). This trial sought to evaluate the therapeutic effect of oral and subcutaneous semaglutide in NAFLD and its sequelae in obesity and/or T2D. METHODS: In an open-labelled intervention study, the sample was 180 patients classified into three parallel groups (1:1:1): group I received oral semaglutide, group II patients received injectable semaglutide, and group III received pioglitazone and/or vitamin E. Patients were evaluated at 6 and 12 months. RESULTS: There was a substantial improvement in lipid profile, liver enzymes, and body mass index, especially in group II. As for HDL, only group II showed a consistent increase at both 6 months (51 ± 4.62 mg/dL) and 12 months (50.08 ± 2.45 mg/dL) compared with baseline (45.6 ± 6.37 mg/dL) (-value < 0.001). Despite the non-significant difference in NAFLD fibrosis score (NFS) (-value = 0.45 and 0.63), group II had significantly lower scores of the fibrosis-4 score (FIB-4), liver stiffness measurement (LSM), and controlled attenuation parameter (CAP) at 6 and 12 months (-value < 0.001). Semaglutide improves lipid profile, liver steatosis, and fibrosis parameters and reduces the BMI in T2D and obese patients with NAFLD.
52Effect of semaglutide on fatty liver disease biomarkers in patients with diabetes and obesity.PubMed
Juana Carretero-Gómez, Francisco Javier Carrasco-Sánchez, José María Fernández-Rodríguez, et al.
Rev Clin Esp (Barc). 2023 Mar;223(3):134-143. doi: 10.1016/j.rceng.2022.12.001. Epub 2022 Dec 19.
AIM: This work aims to assess the effect of weekly subcutaneous semaglutide on biomarkers of metabolic-associated fatty liver disease (MAFLD), namely the hepatic steatosis index (HSI) and the fibrosis-4 (FIB-4) index, at 24 weeks in outpatients attended to in internal medicine departments. METHODS: This study analyzed patients in an ongoing, multicenter, prospective, pre-post, uncontrolled cohort registry that enrolls unique, consecutive patients with type 2 diabetes treated with weekly subcutaneous semaglutide. Steatosis/fibrosis were determined by HSI (<30 ruled out, >36 steatosis) and FIB-4 (<1.3 ruled out, >2.67 fibrosis), respectively. RESULTS: The sample included 213 patients (46.9% women) with a median age of 64 (19) years. The median baseline body mass index and weight were 36.1 (8.4) kg/m and 98 (26.9) kg, respectively. A total of 99.9% had HSI values indicating steatosis, with a mean HSI of 47.9 (8.2). Additionally, 10.8% had fibrosis (FIB-4 > 2.67) and 42.72% had values in intermediate ranges (FIB-4 1.3-2.67). At 24 weeks, there was a significant reduction in HSI (-2.36 (95%CI 1.83-2.9) p < 0.00001) and FIB-4 (-0.075 (95%CI 0.015-0.14) p < 0.016), mainly related to declines in body weight, triglyceride levels, insulin resistance (estimated by the triglyceride-glucose index), and liver enzymes. CONCLUSION: These results show that weekly subcutaneous semaglutide had a beneficial effect on liver steatosis that went beyond glucose control. Its effects were mainly related to weight loss, a decline in biomarkers, and improvements in insulin sensitivity. For many patients, early detection is essential for improving MAFLD outcomes and may allow for selecting the most efficient treatment options.
53Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial.PubMed
Tim Heise, Andrea Mari, J Hans DeVries, et al.
Lancet Diabetes Endocrinol. 2022 Jun;10(6):418-429. doi: 10.1016/S2213-8587(22)00085-7. Epub 2022 Apr 22.
BACKGROUND: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, shows a remarkable ability to lower blood glucose, enabling many patients with long-standing type 2 diabetes to achieve normoglycaemia. We aimed to understand the physiological mechanisms underlying the action of tirzepatide in type 2 diabetes. METHODS: This multicentre, randomised, double-blind, parallel-arm, phase 1 study was done at two centres in Germany. Eligible patients were aged 20-74 years, had type 2 diabetes for at least 6 months, and were being treated with lifestyle advice and stable doses of metformin, with or without one additional stable dose of another oral antihyperglycaemic medicine, 3 months before study entry. Via a randomisation table, patients were randomly assigned (3:3:2) to subcutaneously receive either tirzepatide 15 mg, semaglutide 1 mg, or placebo once per week. Endpoint measurements were done at baseline and the last week of therapy (week 28). The primary endpoint was the effect of tirzepatide versus placebo on the change in clamp disposition index (combining measures of insulin secretion and sensitivity) from baseline to week 28 of treatment and was analysed in the pharmacodynamic analysis set, which comprised all randomly assigned participants who received at least one dose of a study drug and had evaluable pharmacodynamic data. Safety was analysed in the safety population, which comprised all randomly assigned participants who received at least one dose of a study drug. Secondary endpoints included the effect of tirzepatide versus semaglutide on the change in clamp disposition index from baseline to week 28 of treatment, glucose control, total insulin secretion rate, M value (insulin sensitivity), and fasting and postprandial glucagon concentrations. Exploratory endpoints included the change in fasting and postprandial insulin concentrations. This study is registered with ClinicalTrials.gov, NCT03951753, and is complete. FINDINGS: Between June 28, 2019, and April 8, 2021, we screened 184 individuals and enrolled 117 participants, all of whom were included in the safety population (45 in the tirzepatide 15 mg group, 44 in the semaglutide 1 mg group, and 28 in the placebo group). Because of discontinuations and exclusions due to missing or unevaluable data, 39 patients in each treatment group and 24 patients in the placebo group comprised the pharmacodynamic analysis set. With tirzepatide, the clamp disposition index increased from a least squares mean of 0·3 pmol m L min kg (SE 0·03) at baseline by 1·9 pmol m L min kg (0·16) to total 2·3 pmol m L min kg (SE 0·16) at week 28 and, with placebo, the clamp disposition index did not change much from baseline (least squares mean at baseline 0·4 pmol m L min kg [SE 0·04]; change from baseline 0·0 pmol m L min kg [0·03]; least squares mean at week 28 0·3 [SE 0·03]; estimated treatment difference [ETD] tirzepatide vs placebo 1·92 [95% CI 1·59-2·24]; p<0·0001). The improvement with tirzepatide in clamp disposition index was significantly greater than with semaglutide (ETD 0·84 pmol m L min kg [95% CI 0·46-1·21]). This result reflected significant improvements in total insulin secretion rate (ETD 102·09 pmol min m [51·84-152·33]) and insulin sensitivity (ETD 1·52 mg min kg [0·53-2·52]) for tirzepatide versus semaglutide. On meal tolerance testing, tirzepatide significantly reduced glucose excursions (lower insulin and glucagon concentrations) compared with placebo, with effects on these variables being greater than with semaglutide. The safety profiles of tirzepatide and semaglutide were similar, with gastrointestinal adverse events being the most common (11 [24%], 13 [30%], and seven [25%] with nausea; nine [20%], 13 [30%], and six [21%] with diarrhoea; and three [7%], five [11%], and one [4%] with vomiting, for tirzepatide, semaglutide, and placebo, respectively). There were no deaths. INTERPRETATION: The glycaemic efficacy of GIP/GLP-1 receptor agonist tirzepatide in type 2 diabetes results from concurrent improvements in key components of diabetes pathophysiology, namely β-cell function, insulin sensitivity, and glucagon secretion. These effects were large and help to explain the remarkable glucose-lowering ability of tirzepatide seen in phase 3 studies. FUNDING: Eli Lilly.
54GLP-1RA Liraglutide and Semaglutide Improves Obesity-Induced Muscle Atrophy via SIRT1 Pathway.PubMed
Jie Xiang, Liyan Qin, Jinling Zhong, et al.
Diabetes Metab Syndr Obes. 2023 Aug 15;16:2433-2446. doi: 10.2147/DMSO.S425642. eCollection 2023.
BACKGROUND: Obesity is related to the loss of skeletal muscle mass and function (sarcopenia). The co-existence of obesity and sarcopenia is called sarcopenic obesity (SO). Glucagon like peptide-1 receptor agonists (GLP-1RA) are widely used in the treatment of diabetes and obesity. However, the protective effects of GLP-1RA on skeletal muscle in obesity and SO are not clear. This study investigated the effects of GLP-1RA liraglutide and semaglutide on obesity-induced muscle atrophy and explored the underlying mechanisms. METHODS: Thirty-six male C57BL/6J mice were randomly divided into two groups and fed a regular diet and a high-fat diet for 18 weeks, respectively. After establishing an obesity model, mice were further divided into six groups: control group, liraglutide (LIRA) group, semaglutide (SEMA) group, high-fat diet (HFD) group, HFD + LIRA group, HFD + SEMA group, and subcutaneous injection for 4 weeks. The body weight, muscle mass, muscle strength, glycolipid metabolism, muscle atrophy markers, myogenic differentiation markers, GLUT4 and SIRT1 were analyzed. C2C12 myotube cells treated with palmitic acid (PA) were divided into four groups: control group, PA group, PA + LIRA group, PA + SEMA group. The changes in glucose uptake, myotube diameter, lipid droplet infiltration, markers of muscle atrophy, myogenic differentiation markers, GLUT4 and SIRT1 were analyzed, and the changes in related indicators were observed after the addition of SIRT1 inhibitor EX527. RESULTS: Liraglutide and semaglutide reduced HFD-induced body weight gain, excessive lipid accumulation and improved muscle atrophy. Liraglutide and semaglutide eliminated the increase of muscle atrophy markers in skeletal muscle and C2C12 myotubes. Liraglutide and semaglutide restored impaired glucose tolerance and insulin resistance. However, these beneficial effects were attenuated by inhibiting SIRT1 expression. CONCLUSION: Liraglutide and semaglutide protects skeletal muscle against obesity-induced muscle atrophy via the SIRT1 pathway.
55Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver.PubMed
Philip N Newsome, Phil Ambery
J Hepatol. 2023 Dec;79(6):1557-1565. doi: 10.1016/j.jhep.2023.07.033. Epub 2023 Aug 9.
The principle pathological drivers of metabolic dysfunction-associated steatohepatitis (MASH) are obesity and associated insulin resistance, rendering them key therapeutic targets. As glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been licensed for the treatment of diabetes and obesity, they were one of the first drug types to be evaluated in patients with MASH, and successful phase IIa and IIb studies have resulted in progression to phase III clinical trials. Alongside GLP-1RAs, newer combinations with glucagon agonists and/or glucose-dependent insulinotropic peptide (GIP) agonists have been explored in related patient groups, with evidence of improvements in weight, insulin resistance and non-invasive liver parameters. Whether GLP-1RAs have direct, independent effects on MASH or whether they impact on pathophysiology through improvements in weight, insulin resistance and glycaemic control remains a matter of debate. Combinations are being explored, although the potential improvement in efficacy will need to be weighed against the cumulative side-effect burden, potential drug-drug interactions and costs. There is also uncertainty regarding the optimal ratio of glucagon and GIP agonism to GLP-1 agonism in combination agents, and as to whether GIP agonism or antagonism is the optimal approach. Finally, there are also multiple hypothetical permutations combining gut hormone agonists with other emerging assets in the field. Given that the likely dominant mode of action of gut hormone agonists is upstream on weight, initial combinations might focus on agents which have been shown to have a more direct effect on fibrosis, which would include FGF21 and pan-PPAR agonists.
56Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes.PubMed
Melissa K Thomas, Amir Nikooienejad, Ross Bray, et al.
J Clin Endocrinol Metab. 2021 Jan 23;106(2):388-396. doi: 10.1210/clinem/dgaa863.
CONTEXT: Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. OBJECTIVE: Explore mechanisms of glucose control by tirzepatide. DESIGN: Post hoc analyses of fasting biomarkers and multiple linear regression analysis. SETTING: Forty-seven sites in 4 countries. PATIENTS OR OTHER PARTICIPANTS: Three hundred and sixteen subjects with type 2 diabetes. INTERVENTIONS: Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. MAIN OUTCOME MEASURES: Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. RESULTS: Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively. CONCLUSIONS: Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.
57Dual GIP and GLP-1 receptor agonist tirzepatide alleviates hepatic steatosis and modulates gut microbiota and bile acid metabolism in diabetic mice.PubMed
Weiting Hu, Wenyu Gong, Fan Yang, et al.
Int Immunopharmacol. 2025 Feb 6;147:113937. doi: 10.1016/j.intimp.2024.113937. Epub 2025 Jan 2.
Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors and is a promising therapeutic option for type 2 diabetes mellitus (T2DM). Nevertheless, its effect and underlying mechanism on hepatic steatosis remain ambiguous. Herein, we explored the impact of tirzepatide on improving hepatic steatosis in diabetic mice, with a particular focus on the gut microbiota and bile acids (BAs) using animal models. The tirzepatide effectively reduced body weight, improved insulin resistance, decreased serum and hepatic lipid levels, and mitigated liver injury. Compared to semaglutide, tirzepatide exhibited superior efficacy in reducing hepatic lipid accumulation. 16S rRNA gene sequencing and targeted metabolomics of BAs revealed that tirzepatide ameliorated gut microbiota dysbiosis and BAs metabolism in diabetic mice. Notably, tirzepatide observably increased the abundance of beneficial genera such as Akkermansia, elevated the ratio of farnesoid X receptor (FXR) antagonists (glycoursodeoxycholic acid: GUDCA, β-muricholic acid: β-MCA, hyodeoxycholic acid: HDCA, ursodeoxycholic acid: UDCA) to natural agonists (cholic acid: CA, lithocholic acid: LCA, chenodeoxycholic acid: CDCA, glycocholic acid: GCA, taurodeoxycholic acid: TDCA), and reduced FXR expression in intestinal tissues. In conclusion, tirzepatide attenuated hepatic steatosis in diabetic mice and regulated the gut microbiota and BAs metabolism, which may help to provide a novel therapeutic approach and therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD).
58Cotadutide effect in liver and adipose tissue in obese mice.PubMed
Ilitch Aquino Marcondes-de-Castro, Thamiris Ferreira Oliveira, Renata Spezani, et al.
J Mol Endocrinol. 2023 Mar 10;70(3). doi: 10.1530/JME-22-0168. Print 2023 Apr 1.
Obesity, adipose tissue inflammation, and nonalcoholic fatty liver disease (NAFLD) are associated with insulin resistance and type 2 diabetes (T2D). Cotadutide is a dual agonist GLP-1/glucagon, currently in a preclinical study phase 2 that presents an anti-obesity effect. Diet-induced obese (DIO) C57BL/6 mice were treated for 4 weeks with cotadutide (30 nm/kg once a day at 14:00 h). The study focused on epididymal white adipose tissue (eWAT), liver (NAFLD), inflammation, lipid metabolism, AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathways, and the endoplasmic reticulum (ER) stress. As a result, cotadutide controlled weight gain, glucose intolerance, and insulin resistance and showed beneficial effects on plasma markers in DIO mice (triacylglycerol, total cholesterol, alanine aminotransferase, and aspartate aminotransferase, leptin, adiponectin, monocyte chemoattractant protein-1, resistin, interleukin-6, tumor necrosis factor-alpha). Also, cotadutide lessened liver fat accumulation, eWAT proinflammatory markers, and ER stress. In addition, cotadutide improved lipid metabolism genes in eWAT, fatty acid synthase, peroxisome proliferator-activated receptor gamma and mitigates adipocyte hypertrophy and apoptosis. Furthermore, the effects of cotadutide were related to liver AMPK/mTOR pathway and ER stress. In conclusion, cotadutide induces weight loss and treats glucose intolerance and insulin resistance in DIO mice. In addition, cotadutide shows beneficial effects on liver lipid metabolism, mitigating steatosis, inflammation, and ER stress. Besides, in adipocytes, cotadutide decreases hypertrophy and reduces apoptosis. These actions rescuing the AMPK and mTOR pathway, improving lipid metabolism, and lessening NAFLD, inflammation, and ER stress in both eWAT and liver of DIO mice indicate cotadutide as a potentially new pharmacological treatment for T2D and associated obesity.
59Glucagon and glucagon-like peptide-1 dual agonist therapy: A possible future towards fatty kidney disease.PubMed
Mehmet Kanbay, Sidar Copur, Mustafa Guldan, et al.
Eur J Clin Invest. 2025 Jan;55(1):e14330. doi: 10.1111/eci.14330. Epub 2024 Oct 13.
BACKGROUND: Obesity is a growing epidemic affecting approximately 40% of the adult population in developed countries with major health consequences and comorbidities, including diabetes mellitus and insulin resistance, metabolically associated fatty liver disease, atherosclerotic cardiovascular and cerebrovascular diseases and chronic kidney disease. Pharmacotherapies targeting significant weight reduction may have beneficial effects on such comorbidities, though such therapeutic options are highly limited. In this narrative review, we aim to evaluate current knowledge regarding dual agonist therapies and potential implications for managing fatty kidney and chronic kidney disease. RESULTS AND CONCLUSION: Glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors are two novel classes of glucose-lowering medications with potential implications and beneficiary effects on renal outcomes, including estimated glomerular filtration rate, albuminuria and chronic kidney disease progression. Recently, dual agonist therapies targeting glucagon-like peptide-1 and glucagon receptors, namely survodutide and cotadutide, have been evaluated in managing metabolically associated fatty liver disease, a well-established example of visceral obesity. Fatty kidney is another novel concept implicated in the pathophysiology of chronic kidney disease among patients with visceral obesity.
60Fibroblast growth factor 21 improves insulin sensitivity and synergizes with insulin in human adipose stem cell-derived (hASC) adipocytes.PubMed
Darwin V Lee, Dongmei Li, Qingyun Yan, et al.
PLoS One. 2014 Nov 3;9(11):e111767. doi: 10.1371/journal.pone.0111767. eCollection 2014.
Fibroblast growth factor 21 (FGF21) has evolved as a major metabolic regulator, the pharmacological administration of which causes weight loss, insulin sensitivity and glucose control in rodents and humans. To understand the molecular mechanisms by which FGF21 exerts its metabolic effects, we developed a human in vitro model of adipocytes to examine crosstalk between FGF21 and insulin signaling. Human adipose stem cell-derived (hASC) adipocytes were acutely treated with FGF21 alone, insulin alone, or in combination. Insulin signaling under these conditions was assessed by measuring tyrosine phosphorylation of insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), and serine 473 phosphorylation of Akt, followed by a functional assay using 14C-2-deoxyglucose [14C]-2DG to measure glucose uptake in these cells. FGF21 alone caused a modest increase of glucose uptake, but treatment with FGF21 in combination with insulin had a synergistic effect on glucose uptake in these cells. The presence of FGF21 also effectively lowered the insulin concentration required to achieve the same level of glucose uptake compared to the absence of FGF21 by 10-fold. This acute effect of FGF21 on insulin signaling was not due to IR, IGF-1R, or IRS-1 activation. Moreover, we observed a substantial increase in basal S473-Akt phosphorylation by FGF21 alone, in contrast to the minimal shift in basal glucose uptake. Taken together, our data demonstrate that acute co-treatment of hASC-adipocytes with FGF21 and insulin can result in a synergistic improvement in glucose uptake. These effects were shown to occur at or downstream of Akt, or separate from the canonical insulin signaling pathway.
61Safety and efficacy of GLP-1/FGF21 dual agonist HEC88473 in MASLD and T2DM: A randomized, double-blind, placebo-controlled study.PubMed
Lin Xiang, Guixia Wang, Yulei Zhuang, et al.
J Hepatol. 2025 Jun;82(6):967-978. doi: 10.1016/j.jhep.2024.12.006. Epub 2024 Dec 19.
BACKGROUND & AIMS: Glucagon-like peptide-1 (GLP-1) and fibroblast growth factor 21 (FGF21) are key regulators of glucose and lipid metabolism. In the present study, we assessed the safety and efficacy of a novel GLP-1/FGF21 dual agonist HEC88473 for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) combined with type 2 diabetes mellitus (T2DM). METHODS: This was a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase Ib/IIa trial. Sixty patients with MASLD and T2DM were randomized (10:2) to receive HEC88473 (5.1, 15.3, 30.6, 45.9, or 68.0 mg) or placebo via weekly subcutaneous injection for 5 weeks. RESULTS: After 5 weeks of treatment with HEC88473, MRI-proton density fat fraction (MRI-PDFF) was reduced in a dose-proportional manner. The largest relative mean change reached -47.21% (p = 0.0143) in the 30.6 mg cohort, compared with -15.05% in the placebo group, with a higher proportion of >30% relative reductions in patients with baseline PDFF >8%. The 5-week treatment with HEC88473 significantly reduced levels of HbA1c (glycated hemoglobin), as well as fasting and postprandial glucose levels. The largest mean change in HbA1c was -1.10% in the 68.0 mg cohort, compared with -0.31% in the placebo group. Improvement was also observed in participants' lipid profiles. Most adverse events were mild to moderate in severity. The most frequently reported adverse events were gastrointestinal disorders (n = 29, 48.3%). CONCLUSIONS: Herein, we report the clinical safety and proof-of-concept data for the GLP-1/FGF21 dual agonist HEC88473. A 5-week treatment with HEC88473 was generally safe and well tolerated, with multiple positive effects observed, including reduced liver fat, and improved glycemic control, insulin resistance and lipid metabolism, together indicating comprehensive improvement in metabolic syndrome. IMPACT AND IMPLICATIONS: In this randomized, double-blind, placebo-controlled phase Ib/IIa study, we assessed clinical safety, pharmacodynamic and pharmacokinetic data of the GLP-1/FGF21 dual agonist HEC88473 in patients with MASLD (metabolic dysfunction-associated steatotic liver disease) and T2DM (type 2 diabetes mellitus). HEC88473 was generally safe and well tolerated. The GLP-1/FGF21 dual agonist significantly reduced the hepatic fat fraction assessed using MRI-proton density fat fraction, and improved glycemic control and lipid profiles with only 5 weeks' treatment, leading to comprehensive improvement in metabolic syndrome. The present results suggest that HEC88473 could be a promising treatment option in this patient population. CLINICAL TRIAL NUMBER: Chinese Drug Trial Identifier (http://www.chinadrugtrials.org.cn/index.html): CTR20211088. CLINICALTRIALS: GOV: NCT05943886.
62GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice.PubMed
Carmelo Quarta, Kerstin Stemmer, Aaron Novikoff, et al.
Nat Metab. 2022 Aug;4(8):1071-1083. doi: 10.1038/s42255-022-00617-6. Epub 2022 Aug 22.
Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography-mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.
63Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data.PubMed
Joshua Z Goldenberg, Andrew Day, Grant D Brinkworth, et al.
BMJ. 2021 Jan 13;372:m4743. doi: 10.1136/bmj.m4743.
OBJECTIVE: To determine the efficacy and safety of low carbohydrate diets (LCDs) and very low carbohydrate diets (VLCDs) for people with type 2 diabetes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Searches of CENTRAL, Medline, Embase, CINAHL, CAB, and grey literature sources from inception to 25 August 2020. STUDY SELECTION: Randomized clinical trials evaluating LCDs (<130 g/day or <26% of a 2000 kcal/day diet) and VLCDs (<10% calories from carbohydrates) for at least 12 weeks in adults with type 2 diabetes were eligible. DATA EXTRACTION: Primary outcomes were remission of diabetes (HbA <6.5% or fasting glucose <7.0 mmol/L, with or without the use of diabetes medication), weight loss, HbA, fasting glucose, and adverse events. Secondary outcomes included health related quality of life and biochemical laboratory data. All articles and outcomes were independently screened, extracted, and assessed for risk of bias and GRADE certainty of evidence at six and 12 month follow-up. Risk estimates and 95% confidence intervals were calculated using random effects meta-analysis. Outcomes were assessed according to a priori determined minimal important differences to determine clinical importance, and heterogeneity was investigated on the basis of risk of bias and seven a priori subgroups. Any subgroup effects with a statistically significant test of interaction were subjected to a five point credibility checklist. RESULTS: Searches identified 14 759 citations yielding 23 trials (1357 participants), and 40.6% of outcomes were judged to be at low risk of bias. At six months, compared with control diets, LCDs achieved higher rates of diabetes remission (defined as HbA <6.5%) (76/133 (57%) 41/131 (31%); risk difference 0.32, 95% confidence interval 0.17 to 0.47; 8 studies, n=264, I=58%). Conversely, smaller, non-significant effect sizes occurred when a remission definition of HbA <6.5% without medication was used. Subgroup assessments determined as meeting credibility criteria indicated that remission with LCDs markedly decreased in studies that included patients using insulin. At 12 months, data on remission were sparse, ranging from a small effect to a trivial increased risk of diabetes. Large clinically important improvements were seen in weight loss, triglycerides, and insulin sensitivity at six months, which diminished at 12 months. On the basis of subgroup assessments deemed credible, VLCDs were less effective than less restrictive LCDs for weight loss at six months. However, this effect was explained by diet adherence. That is, among highly adherent patients on VLCDs, a clinically important reduction in weight was seen compared with studies with less adherent patients on VLCDs. Participants experienced no significant difference in quality of life at six months but did experience clinically important, but not statistically significant, worsening of quality of life and low density lipoprotein cholesterol at 12 months. Otherwise, no significant or clinically important between group differences were found in terms of adverse events or blood lipids at six and 12 months. CONCLUSIONS: On the basis of moderate to low certainty evidence, patients adhering to an LCD for six months may experience remission of diabetes without adverse consequences. Limitations include continued debate around what constitutes remission of diabetes, as well as the efficacy, safety, and dietary satisfaction of longer term LCDs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020161795.
64Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial.PubMed
Cara B Ebbeling, Amy Knapp, Ann Johnson, et al.
Am J Clin Nutr. 2022 Jan 11;115(1):154-162. doi: 10.1093/ajcn/nqab287.
BACKGROUND: Carbohydrate restriction shows promise for diabetes, but concerns regarding high saturated fat content of low-carbohydrate diets limit widespread adoption. OBJECTIVES: This preplanned ancillary study aimed to determine how diets varying widely in carbohydrate and saturated fat affect cardiovascular disease (CVD) risk factors during weight-loss maintenance. METHODS: After 10-14% weight loss on a run-in diet, 164 participants (70% female; BMI = 32.4 ± 4.8 kg/m2) were randomly assigned to 3 weight-loss maintenance diets for 20 wk. The prepared diets contained 20% protein and differed 3-fold in carbohydrate (Carb) and saturated fat as a proportion of energy (Low-Carb: 20% carbohydrate, 21% saturated fat; Moderate-Carb: 40%, 14%; High-Carb: 60%, 7%). Fasting plasma samples were collected prerandomization and at 20 wk. Lipoprotein insulin resistance (LPIR) score was calculated from triglyceride-rich, high-density, and low-density lipoprotein particle (TRL-P, HDL-P, LDL-P) sizes and subfraction concentrations (large/very large TRL-P, large HDL-P, small LDL-P). Other outcomes included lipoprotein(a), triglycerides, HDL cholesterol, LDL cholesterol, adiponectin, and inflammatory markers. Repeated measures ANOVA was used for intention-to-treat analysis. RESULTS: Retention was 90%. Mean change in LPIR (scale 0-100) differed by diet in a dose-dependent fashion: Low-Carb (-5.3; 95% CI: -9.2, -1.5), Moderate-Carb (-0.02; 95% CI: -4.1, 4.1), High-Carb (3.6; 95% CI: -0.6, 7.7), P = 0.009. Low-Carb also favorably affected lipoprotein(a) [-14.7% (95% CI: -19.5, -9.5), -2.1 (95% CI: -8.2, 4.3), and 0.2 (95% CI: -6.0, 6.8), respectively; P = 0.0005], triglycerides, HDL cholesterol, large/very large TRL-P, large HDL-P, and adiponectin. LDL cholesterol, LDL-P, and inflammatory markers did not differ by diet. CONCLUSIONS: A low-carbohydrate diet, high in saturated fat, improved insulin-resistant dyslipoproteinemia and lipoprotein(a), without adverse effect on LDL cholesterol. Carbohydrate restriction might lower CVD risk independently of body weight, a possibility that warrants study in major multicentered trials powered on hard outcomes. The registry is available through ClinicialTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02068885.
65Impact of a low-carbohydrate and high-fiber diet on nonalcoholic fatty liver disease.PubMed
Jie Chen, Yiqin Huang, Hua Xie, et al.
Asia Pac J Clin Nutr. 2020;29(3):483-490. doi: 10.6133/apjcn.202009_29(3).0006.
BACKGROUND AND OBJECTIVES: To study the effects of a low-carbohydrate and high-fiber diet and education on patients with nonalcoholic fatty liver disease. METHODS AND STUDY DESIGN: We randomly divided 44 patients with nonalcoholic fatty liver disease into two groups: low-carbohydrate and high-fiber diet and education (intervention group), and education alone (control group). Liver and kidney function, fasting plasma glucose, insulin resistance index, body composition, and controlled attenuation parameter were detected before and after the intervention. RESULTS: After 2 months, the body fat, body weight, abdominal circumference, and visceral fat area, fasting plasma glucose, insulin resistance index, and levels of serum alanine aminotransferase, aspartate transaminase, uric acid, and insulin of the intervention group were significantly lower than before (p<0.05). In the female intervention group, the insulin resistance index and levels of serum alanine aminotransferase, uric acid, triglyceride, fasting plasma glucose, and C-peptide were lower and the level of serum high-density lipoprotein cholesterol was higher than in the female control group (p<0.05). In the male intervention group, the levels of serum alanine aminotransferase, triglyceride, and fasting plasma glucose were lower and the level of serum high-density lipoprotein cholesterol was higher compared with the male control group (p<0.05). CONCLUSIONS: A low-carbohydrate and high-fiber diet and education can effectively reduce the body weight and body fat of patients with nonalcoholic fatty liver disease and improve metabolic indicators such as liver enzymes, blood glucose, blood lipid, and uric acid. Our female patients showed significantly better improvement in the indicators than our male patients.
66Dietary patterns and management of type 2 diabetes: A systematic review of randomised clinical trials.PubMed
D Papamichou, D B Panagiotakos, C Itsiopoulos
Nutr Metab Cardiovasc Dis. 2019 Jun;29(6):531-543. doi: 10.1016/j.numecd.2019.02.004. Epub 2019 Feb 25.
BACKGROUND AND AIM: The aim of the present review is to examine evidence from published studies on the effectiveness of six or more months of low carbohydrate, macrobiotic, vegan, vegetarian, Mediterranean and intermittent fasting (IF) diets compared to low fat diets on diabetes control and management. METHODS AND RESULTS: In accordance with PRISMA guidelines, Cochrane CENTRAL, PubMed and Scopus databases were systematically searched for relevant studies. Twenty randomised controlled trials (RCTs) > 6 months that investigated the effectiveness of various dietary patterns on type 2 diabetes mellitus (T2DM) were included. Risk of bias was assessed using the Cochrane tool. There were no significant differences in glycemic control, weight and lipids for the majority of low carbohydrate diets (LCDs) compared to low fat diets (LFDs). Four out of fifteen LCD interventions showed better glycemic control while weight loss was greater in one study. The Mediterranean dietary pattern demonstrated greater reduction in body weight and HbA1c levels and delayed requirement for diabetes medications. The vegan and macrobiotic diet demonstrated improved glycemic control, while the vegetarian diet showed greater body weight reduction and insulin sensitivity. CONCLUSIONS: Although more long-term intervention trials are required, mounting evidence supports the view that vegan, vegetarian and Mediterranean dietary patterns should be implemented in public health strategies, in order to better control glycemic markers in individuals with T2DM.
67Obesity, Insulin Resistance, and Hyperandrogenism Mediate the Link between Poor Diet Quality and Ovarian Dysmorphology in Reproductive-Aged Women.PubMed
Maryam Kazemi, Brittany Y Jarrett, Heidi Vanden Brink, et al.
Nutrients. 2020 Jun 30;12(7):1953. doi: 10.3390/nu12071953.
The relationship between diet quality and ovarian morphology has biological plausibility yet remains unclear and was therefore evaluated. In a multicenter cross-sectional analysis, four dietary patterns were scored for 111 consecutive reproductive-aged women (18-45 years) using (1) Healthy Eating Index (HEI-2015); (2) alternative HEI-2010; (3) alternate Mediterranean Diet (aMED); (4) and Dietary Approaches to Stop Hypertension (DASH) indices. Ovarian volume (OV) and follicle number per ovary (FNPO) were evaluated on transvaginal ultrasonography. Relationships between dietary and ovarian morphology indices were evaluated by linear regression and mediation analyses. Associations between aMED and DASH scores and OV/FNPO were completely mediated by obesity, insulin resistance, and hyperandrogenism (All: < 0.05), unlike direct associations (All: ≥ 0.89). Namely, a 1-standard deviation [SD] increase in aMED score was associated with decreases in OV (0.09 SD; 0.4 mL) through reducing waist circumference. Likewise, a 1 SD increase in aMED and DASH score was associated with decreases in OV (0.07 SD; 0.3 mL) by reducing glucose response to a 75 g glucose tolerance test. A 1 SD increase in DASH score was associated with decreased FNPO (0.07 SD; 2 follicles) by reducing free androgen index (All: < 0.05). Adherence to aMED and DASH eating plans was indirectly associated with significant improvements in ovarian form, providing novel mechanistic insights for future interventions about contributions of diet quality on ovarian function.
68Effects of intermittent fasting regimens on glycemic, hepatic, anthropometric, and clinical markers in patients with non-alcoholic fatty liver disease: Systematic review and meta-analysis of randomized controlled trials.PubMed
Saleh A K Saleh, Heitor O Santos, Mihnea-Alexandru Găman, et al.
Clin Nutr ESPEN. 2024 Feb;59:70-80. doi: 10.1016/j.clnesp.2023.11.009. Epub 2023 Nov 28.
OBJECTIVES: Intermittent fasting (IF) regimens have been hypothesized to influence several markers of cardiometabolic and liver function. The objective of our meta-analysis was to investigate the impact of IF regimens on cardiometabolic and liver markers in subjects diagnosed with non-alcoholic fatty liver disease (NAFLD). METHODS: We searched several online databases (PubMed/Medline, Web of Science, Scopus and Embase) in order to identify suitable publications for inclusion in the meta-analysis. Results were expressed as weighted mean differences (WMD). RESULTS: From 12343 articles identified in different databases, a total of 7 RCT arms were entered into the quantitative synthesis. The manuscripts were published between 2019 and 2023. IF regimens (the 5:2 diet, 16/8 time-restricting feeding, and alternate day fasting) varied from 2 months to 3 months. IF regimens reduced steatosis scores (WMD: -33.22 CAP dB/m, 95 % CI: -50.72 to -15.72), anthropometric characteristics of obesity (WMD: -0.77 kg/m, 95 % CI: -1.38 to -0.17 for body mass index; WMD: -3.16 kg, 95 % CI: -4.71 to -1.61 for body weight; WMD: -1.90 kg, 95 % CI: -3.51 to -0.29 for waist circumference), as well as ALT (WMD: -9.10 U/L, 95 % CI: -12.45 to -5.75), triglyceride (WMD: -20.83 mg/dl, 95 % CI: -39.01 to -2.66), total cholesterol (WMD: -7.80 mg/dl, 95 % CI: -15.18), HbA1c (WMD: -0.14 %, 95 % CI: -0.20 to -0.08) and HOMA-IR (WMD: -1.21, 95 % CI: -2.08 to -0.34) levels versus controls. Nevertheless, no between-group differences were detected for other biomarkers, e.g., fasting blood glucose, insulin, AST, HDL-C or LDL-C values, and fibrosis scores. CONCLUSION: IF regimens can improve some markers of cardiometabolic and liver function in patients with NAFLD. However, the available evidence to support the benefits of IF regimens is limited and derived from a small number of studies, thus further research is needed to clarify the impact of IF on the cardiometabolic health of NAFLD patients.
69Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome.PubMed
Michael J Wilkinson, Emily N C Manoogian, Adena Zadourian, et al.
Cell Metab. 2020 Jan 7;31(1):92-104.e5. doi: 10.1016/j.cmet.2019.11.004. Epub 2019 Dec 5.
In animal models, time-restricted feeding (TRF) can prevent and reverse aspects of metabolic diseases. Time-restricted eating (TRE) in human pilot studies reduces the risks of metabolic diseases in otherwise healthy individuals. However, patients with diagnosed metabolic syndrome often undergo pharmacotherapy, and it has never been tested whether TRE can act synergistically with pharmacotherapy in animal models or humans. In a single-arm, paired-sample trial, 19 participants with metabolic syndrome and a baseline mean daily eating window of ≥14 h, the majority of whom were on a statin and/or antihypertensive therapy, underwent 10 h of TRE (all dietary intake within a consistent self-selected 10 h window) for 12 weeks. We found this TRE intervention improves cardiometabolic health for patients with metabolic syndrome receiving standard medical care including high rates of statin and anti-hypertensive use. TRE is a potentially powerful lifestyle intervention that can be added to standard medical practice to treat metabolic syndrome. VIDEO ABSTRACT.
70Intergenerational Metabolic Syndrome and Neuronal Network Hyperexcitability in Autism.PubMed
Aileen Rivell, Mark P Mattson
Trends Neurosci. 2019 Oct;42(10):709-726. doi: 10.1016/j.tins.2019.08.006. Epub 2019 Sep 5.
We review evidence that suggests a role for excessive consumption of energy-dense foods, particularly fructose, and consequent obesity and insulin resistance (metabolic syndrome) in the recent increase in prevalence of autism spectrum disorders (ASD). Maternal insulin resistance, obesity, and diabetes may predispose offspring to ASD by mechanisms involving chronic activation of anabolic cellular pathways and a lack of metabolic switching to ketosis resulting in a deficit in GABAergic signaling and neuronal network hyperexcitability. Metabolic reprogramming by epigenetic DNA and chromatin modifications may contribute to alterations in gene expression that result in ASD. These mechanistic insights suggest that interventions that improve metabolic health such as intermittent fasting and exercise may ameliorate developmental neuronal network abnormalities and consequent behavioral manifestations in ASD.
71Intermittent Fasting and Physical Exercise for Preventing Metabolic Disorders through Interaction with Gut Microbiota: A Review.PubMed
Li Zhang, Yuanshang Wang, Ying Sun, et al.
Nutrients. 2023 May 11;15(10):2277. doi: 10.3390/nu15102277.
Metabolic disorders entail both health risks and economic burdens to our society. A considerable part of the cause of metabolic disorders is mediated by the gut microbiota. The gut microbial structure and function are susceptible to dietary patterns and host physiological activities. A sedentary lifestyle accompanied by unhealthy eating habits propels the release of harmful metabolites, which impair the intestinal barrier, thereby triggering a constant change in the immune system and biochemical signals. Noteworthy, healthy dietary interventions, such as intermittent fasting, coupled with regular physical exercise can improve several metabolic and inflammatory parameters, resulting in stronger beneficial actions for metabolic health. In this review, the current progress on how gut microbiota may link to the mechanistic basis of common metabolic disorders was discussed. We also highlight the independent and synergistic effects of fasting and exercise interventions on metabolic health and provide perspectives for preventing metabolic disorders.
72Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: A randomized controlled trial.PubMed
Mark Ezpeleta, Kelsey Gabel, Sofia Cienfuegos, et al.
Cell Metab. 2023 Jan 3;35(1):56-70.e3. doi: 10.1016/j.cmet.2022.12.001. Epub 2022 Dec 21.
Innovative non-pharmacological lifestyle strategies to treat non-alcoholic fatty liver disease (NAFLD) are critically needed. This study compared the effects of alternate day fasting (ADF) combined with exercise to fasting alone, or exercise alone, on intrahepatic triglyceride (IHTG) content. Adults with obesity and NAFLD (n = 80, 81% female, age: 23-65 years) were randomized to 1 of 4 groups for 3 months: combination of ADF (600 kcal/2,500 kJ "fast day" alternated with an ad libitum intake "feast day") and moderate-intensity aerobic exercise (5 session per week, 60 min/session); ADF alone; exercise alone; or a no-intervention control group. By month 3, IHTG content was significantly reduced in the combination group (-5.48%; 95% CI, -7.77% to -3.18%), compared with the exercise group (-1.30%; 95% CI, -3.80% to 1.20%; p = 0.02) and the control group (-0.17%; 95% CI, -2.17% to 1.83%; p < 0.01) but was not significantly different versus the ADF group (-2.25%; 95% CI, -4.46% to -0.04%; p = 0.05). Body weight, fat mass, waist circumference, and alanine transaminase (ALT) levels significantly decreased, while insulin sensitivity significantly increased in the combination group compared with the control group. Lean mass, aspartate transaminase (AST), HbA1c, blood pressure, plasma lipids, liver fibrosis score, and hepatokines (fetuin-A, FGF-21, and selenoprotein P) did not differ between groups. Combining intermittent fasting with exercise is effective for reducing hepatic steatosis in patients with NAFLD but may offer no additional benefit versus fasting alone.
73Alternate-Day Fasting Combined with Exercise: Effect on Sleep in Adults with Obesity and NAFLD.PubMed
Mark Ezpeleta, Kelsey Gabel, Sofia Cienfuegos, et al.
Nutrients. 2023 Mar 14;15(6):1398. doi: 10.3390/nu15061398.
: This study investigated how alternate-day fasting (ADF) combined with aerobic exercise impacts body weight and sleep in adults with non-alcoholic fatty liver disease (NAFLD). : Adults with obesity and NAFLD (n = 80) were randomized into one of four groups for 3 months: combination of ADF (600 kcal "fast day," alternated with an ad libitum intake "feast day") and moderate-intensity aerobic exercise (five sessions per week, 60 min/session); ADF alone; exercise alone; or a no-intervention control group. : By month 3, body weight and intrahepatic triglyceride content decreased ( < 0.001, group × time interaction) in the combination group versus the exercise group and control group, but not versus the ADF group. Sleep quality, measured by the Pittsburgh Sleep Quality Inventory (PSQI), did not change in the combination group (baseline: 6.0 ± 0.7; month 3: 5.6 ± 0.7), ADF group (baseline: 8.9 ± 1.0; month 3: 7.5 ± 0.8), or exercise group (baseline: 6.4 ± 0.6; month 3: 6.7 ± 0.6), versus controls (baseline: 5.5 ± 0.7; month 3: 4.6 ± 0.5). Wake time, bedtime, sleep duration, and insomnia severity did not change (no group x time interaction) over the course of the study in any group. Risk for obstructive sleep apnea was present in 30% of combination subjects, 75% of ADF subjects, 40% of exercise subjects, and 75% of controls, and did not change in the intervention groups, versus controls, by month 3. No associations were observed between changes in body weight, intrahepatic triglyceride content, and any sleep outcome. : The weight loss induced by ADF combined with exercise does not improve sleep quality, duration, insomnia severity, or risk of obstructive sleep apnea in individuals with NAFLD.
74Synergistic Effects of Time-Restricted Feeding and Resistance Training on Body Composition and Metabolic Health: A Systematic Review and Meta-Analysis.PubMed
Yiling Ho, Xiao Hou, Fenghua Sun, et al.
Nutrients. 2024 Sep 11;16(18):3066. doi: 10.3390/nu16183066.
BACKGROUND: This systematic review and meta-analysis examined the synergistic impact of time-restricted feeding (TRF) combined with resistance training (RT) (TRF + RT) on body composition and metabolic health in adults, contrasting it with habitual eating patterns (CON) and RT (CON + RT). METHODS: Adhering to PRISMA guidelines, five databases were searched up to 28 April 2024. Randomized controlled trials or crossover trials assessing the effects of TRF + RT for at least 4 weeks in adults were selected. Data were pooled as standardized mean differences (SMDs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs). The risk of bias was evaluated using the revised Cochrane risk-of-bias tool. RESULTS: Seven studies with 164 participants were included in the final analysis. TRF + RT significantly reduced body mass (WMD -2.90, 95% CI: -5.30 to -0.51), fat mass (WMD -1.52, 95% CI: -2.30 to -0.75), insulin (SMD -0.72, 95% CI: -1.24 to -0.21), total cholesterol (WMD -9.44, 95% CI: -13.62 to -5.27), low-density lipoprotein cholesterol (LDL-C) (WMD -9.94, 95% CI: -13.47 to -6.41), and energy intake (WMD -174.88, 95% CI: -283.79 to -65.97) compared to CON + RT. No significant changes were observed in muscle mass, strength, or other metabolic markers. CONCLUSIONS: TRF + RT, in contrast to CON + RT, significantly improved body composition, insulin, and cholesterol levels without affecting muscle mass or strength.
75Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose.PubMed
Jing Li, Bradley Richmond, Ahmad A Cluntun, et al.
JCI Insight. 2023 Sep 22;8(18):e166713. doi: 10.1172/jci.insight.166713.
Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes-induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control.
76Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy.PubMed
Veronica Jimenez, Victor Sacristan, Claudia Jambrina, et al.
Mol Ther. 2024 Dec 4;32(12):4285-4302. doi: 10.1016/j.ymthe.2024.10.023. Epub 2024 Oct 28.
The highly prevalent metabolic dysfunction-associated steatohepatitis (MASH) is associated with liver steatosis, inflammation, and hepatocyte injury, which can lead to fibrosis and may progress to hepatocellular carcinoma and death. New treatment modalities such as gene therapy may be transformative for MASH patients. Here, we describe that one-time intramuscular administration of adeno-associated viral vectors of serotype 1 (AAV1) encoding native fibroblast growth factor 21 (FGF21), a key metabolic regulator, resulted in sustained increased circulating levels of the factor, which mediated long-term (>1 year) MASH and hepatic fibrosis reversion and halted development of liver tumors in obese male and female mouse models. AAV1-FGF21 treatment also counteracted obesity, adiposity, and insulin resistance, which are significant drivers of MASH. Scale-up to large animals successfully resulted in safe skeletal muscle biodistribution and biological activity in key metabolic tissues. Moreover, as a step toward the clinic, circulating FGF21 levels were characterized in obese, insulin-resistant and MASH patients. Overall, these results underscore the potential of the muscle-directed AAV1-FGF21 gene therapy to treat MASH and support its clinical translation.
77PLA2G12A protects against diet-induced obesity and insulin resistance by enhancing energy expenditure and clearance of circulating triglycerides.PubMed
Min Wu, Qian Wang, Hengchun Li, et al.
FASEB J. 2024 May 15;38(9):e23643. doi: 10.1096/fj.202302075R.
Secreted phospholipase A2s are involved in the development of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease, which have become serious and growing health concerns worldwide. Integration of genome-wide association study and gene co-expression networks analysis showed that the secreted phospholipase A2 group XIIA (PLA2G12A) may participate in hepatic lipids metabolism. Nevertheless, the role of PLA2G12A in lipid metabolism and its potential mechanism remain elusive. Here, we used AAV9 vector carrying human PLA2G12A gene to exogenously express hPLA2G12A in the liver of mice. We demonstrated that the overexpression of hPLA2G12A resulted in a significant decrease in serum lipid levels in wild-type mice fed with chow diet or high-fat diet (HFD). Moreover, hPLA2G12A treatment protected against diet-induced obesity and insulin resistance in mice fed a HFD. Notably, we found that hPLA2G12A treatment confers protection against obesity and hyperlipidemia independent of its enzymatic activity, but rather by increasing physical activity and energy expenditure. Furthermore, we demonstrated that hPLA2G12A treatment induced upregulation of ApoC2 and Cd36 and downregulation of Angptl8, which contributed to the increase in clearance of circulating triglycerides and hepatic uptake of fatty acids without affecting hepatic de novo lipogenesis, very low-density lipoprotein secretion, or intestinal lipid absorption. Our study highlights the potential of PLA2G12A gene therapy as a promising approach for treating obesity, insulin resistance and T2DM.
78Mesenchymal Stem/Stromal Cells Therapy for Metabolic Syndrome: Potential Clinical Application?PubMed
Xiuyi Huang, Yunchong Liu, Zilun Li, et al.
Stem Cells. 2023 Oct 8;41(10):893-906. doi: 10.1093/stmcls/sxad052.
Mesenchymal stem/stromal cells (MSCs), a class of cells with proliferative, immunomodulatory, and reparative functions, have shown therapeutic potential in a variety of systemic diseases, including metabolic syndrome (MetS). The cluster of morbidities that constitute MetS might be particularly amenable for the application of MSCs, which employ an arsenal of reparative actions to target multiple pathogenic pathways simultaneously. Preclinical studies have shown that MSCs can reverse pathological changes in MetS mainly by inhibiting inflammation, improving insulin resistance, regulating glycolipid metabolism, and protecting organ function. However, several challenges remain to overcome before MSCs can be applied for treating MetS. For example, the merits of autologous versus allogeneic MSCs sources remain unclear, particularly with autologous MSCs obtained from the noxious MetS milieu. The distinct characteristics and relative efficacy of MSCs harvested from different tissue sources also require clarification. Moreover, to improve the therapeutic efficacy of MSCs, investigators have explored several approaches that improved therapeutic efficacy but may involve potential safety concerns. This review summarized the potentially useful MSCs strategy for treating MetS, as well as some hurdles that remain to be overcome. In particular, larger-scale studies are needed to determine the therapeutic efficacy and safety of MSCs for clinical application.
79Mesenchymal stem cell therapy for type 2 diabetes: mechanisms, clinical evidence, and future directions.PubMed
Malek Zarei
Mol Biol Rep. 2025 Oct 21;52(1):1046. doi: 10.1007/s11033-025-11133-7.
Type 2 diabetes mellitus (T2DM) is a global public-health challenge characterized by insulin resistance, progressive β-cell dysfunction, and chronic low-grade inflammation. Conventional therapies often control glycaemia but do not consistently prevent disease progression or complications. Mesenchymal stem cells (MSCs), derived from bone marrow, adipose tissue, and the umbilical cord, have been investigated for T2DM due to their immunomodulatory and paracrine regenerative properties. Preclinical studies and early-phase clinical trials (2000-2025) have reported modest improvements in glycaemic indices, including mean reductions in HbA1c and decreases in exogenous insulin requirements in some cohorts, rather than the uniform 1-2% reduction previously stated. Signals of benefit have also been described in diabetic complications such as nephropathy and wound healing. However, these findings derive largely from small, heterogeneous studies with short follow-up, and should therefore be interpreted cautiously. Recent strategies to enhance MSC efficacy (for example, genetic modification such as OCN-19 overexpression) show preliminary promise but require more rigorous evaluation. Key challenges that currently limit clinical translation include variability in MSC sources and manufacturing, impaired cell function in the diabetic microenvironment, small and underpowered trials, and limited long-term safety and cost-effectiveness data. This review synthesizes mechanistic and clinical evidence for MSC therapy in T2DM, highlights recent technological advances, and outlines priorities for future research, notably standardized GMP-compliant production, robust randomized multicenter trials with long-term follow-up, and the development of predictive biomarkers to identify likely responders and optimize patient selection.
80Adipose Extracellular Vesicles in Intercellular and Inter-Organ Crosstalk in Metabolic Health and Diseases.PubMed
Zhe Huang, Aimin Xu
Front Immunol. 2021 Feb 25;12:608680. doi: 10.3389/fimmu.2021.608680. eCollection 2021.
Adipose tissue (AT) is a highly heterogeneous and dynamic organ that plays important roles in regulating energy metabolism and insulin sensitivity. In addition to its classical roles in nutrient sensing and energy storage/dissipation, AT secretes a large number of bioactive molecules (termed adipokines) participating in immune responses and metabolic regulation through their paracrine and/or endocrine actions. Adipose-derived extracellular vesicles (ADEVs), including exosomes, microvesicles (MVs), and apoptotic bodies, have recently emerged as a novel class of signal messengers, mediating intercellular communications and inter-organ crosstalk. In AT, ADEVs derived from adipocytes, immune cells, mesenchymal stem cells, endothelial cells are actively involved in modulation of immune microenvironment, adipogenesis, browing of white adipose tissue, adipokine release and tissue remodeling. Furthermore, ADEVs exert their metabolic actions in distal organs (such as liver, skeletal muscle, pancreas and brain) by sending genetic information (mainly in the form of microRNAs) to their target cells for regulation of gene expression. Here, we provide an updated summary on the nature and composition of ADEVs, and their pathophysiological functions in regulating immune responses, whole-body insulin sensitivity and metabolism. Furthermore, we highlight the latest clinical evidence supporting aberrant production and/or function of ADEVs as a contributor to obesity-related chronic inflammation and metabolic complications and discuss the opportunities and challenges in developing novel therapies by targeting ADEVs.
81[Role of metaflammation as a systemic manifestation of metabolic diseases].PubMed
Andreas Schäffler
Inn Med (Heidelb). 2023 Apr;64(4):313-322. doi: 10.1007/s00108-022-01416-7. Epub 2022 Nov 8.
Visceral obesity as a component of the metabolic syndrome is characterized by systemic and local inflammation, which can be quantified in organs (metaflammation). This process can be regarded as a chronic, sterile, and low-grade state of inflammation without infection, trauma, tumor or autoimmunity. It is caused by an inflammation of the visceral adipose tissue (adipose inflammation or adipoflammation) due to adipocyte hypertrophy and hyperplasia with increased infiltration by monocytes and macrophages. Important is the presence of proinflammatory, so-called polarized M1 macrophages that are induced by interferon gamma (IFN-γ) and lipopolysaccharides (LPS) with secretion of interleukin (IL)-6, tumor necrosis factor (TNF) and IL‑1. In contrast, the anti-inflammatory, so-called polarized M2 macrophages induced by IL‑4 and IL-13 with secretion of IL‑8 and IL-10 decrease. In addition, the secreted adipokine pattern changes from anti-inflammatory to proinflammatory. Adipocyte necrosis, local hypoxia, dysregulated autophagy, activation of inflammasomes, modulation of toll-like receptors, and epigenetic factors play a complex role. This mechanism results in local insulin resistance and subsequently a systemic insulin resistance of peripheral organs as well as a spillover of local mediators of inflammation into the systemic circulation (measured as obesity C‑reactive protein, CRP). The activation of inflammatory signal transduction cascades leads to inhibitory phosphorylation of the insulin signaling pathway and a weakening of the effect of insulin. In parallel, ectopic lipid accumulation occurs in the liver, musculature, pancreas, pericardium and lungs. Diacylglycerol (DAG) activates specific isoforms of protein kinase C (ε in the liver and τ in the musculature), which in turn lead to inhibition of the insulin signaling pathway. Insulin resistance in obesity and type 2 diabetes mellitus is an inflammatory disease. The aim of future translational approaches is an anti-inflammatory, molecularly individualized (precision medicine) treatment in adipose tissue (targeted therapy) and in organs of insulin resistance.
83Personalized Medicine of Omega-3 Fatty Acids in Depression Treatment in Obese and Metabolically Dysregulated Patients.PubMed
Suet-Kei Wu, Wei-Jen Chen, Jane Pei-Chen Chang, et al.
J Pers Med. 2023 Jun 15;13(6):1003. doi: 10.3390/jpm13061003.
The co-occurrence of depression and obesity has become a significant public health concern worldwide. Recent studies have shown that metabolic dysfunction, which is commonly observed in obese individuals and is characterized by inflammation, insulin resistance, leptin resistance, and hypertension, is a critical risk factor for depression. This dysfunction may induce structural and functional changes in the brain, ultimately contributing to depression's development. Given that obesity and depression mutually increase each other's risk of development by 50-60%, there is a need for effective interventions that address both conditions. The comorbidity of depression with obesity and metabolic dysregulation is thought to be related to chronic low-grade inflammation, characterized by increased circulating levels of pro-inflammatory cytokines and C-reactive protein (CRP). As pharmacotherapy fails in at least 30-40% of cases to adequately treat major depressive disorder, a nutritional approach is emerging as a promising alternative. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are a promising dietary intervention that can reduce inflammatory biomarkers, particularly in patients with high levels of inflammation, including pregnant women with gestational diabetes, patients with type 2 diabetes mellitus, and overweight individuals with major depressive disorder. Further efforts directed at implementing these strategies in clinical practice could contribute to improved outcomes in patients with depression, comorbid obesity, and/or metabolic dysregulation.
84Sexually dimorphic metal alterations in childhood obesity are modulated by a complex interplay between inflammation, insulin, and sex hormones.PubMed
Álvaro González-Domínguez, Jesús Domínguez-Riscart, María Millán-Martínez, et al.
Biofactors. 2023 Jul-Aug;49(4):849-860. doi: 10.1002/biof.1948. Epub 2023 Mar 21.
Although growing evidence points to a pivotal role of perturbed metal homeostasis in childhood obesity, sexual dimorphisms in this association have rarely been investigated. In this study, we applied multi-elemental analysis to plasma and erythrocyte samples from an observational cohort comprising children with obesity, with and without insulin resistance, and healthy control children. Furthermore, a wide number of variables related to carbohydrate and lipid metabolism, inflammation, and sex hormones were also determined. Children with obesity, regardless of sex and insulin resistance status, showed increased plasma copper-to-zinc ratios. More interestingly, obesity-related erythroid alterations were found to be sex-dependent, with increased contents of iron, zinc, and copper being exclusively detected among female subjects. Our findings suggest that a sexually dimorphic hormonal dysregulation in response to a pathological cascade involving inflammatory processes and hyperinsulinemia could be the main trigger of this female-specific intracellular sequestration of trace elements. Therefore, the present study highlights the relevance of genotypic sex as a susceptibility factor influencing the pathogenic events behind childhood obesity, thereby opening the door to develop sex-personalized approaches in the context of precision medicine.
85Exploring the complex interplay: insulin resistance and gut microbiome dysbiosis in multiple sclerosis.PubMed
Fatemeh Nezamzadeh, Azin Masroor, Aylin Esmailkhani, et al.
Neuroscience. 2025 Aug 30;582:134-145. doi: 10.1016/j.neuroscience.2025.07.024. Epub 2025 Jul 22.
Multiple sclerosis (MS) is a progressive, autoimmune demyelinating disorder of the central nervous system (CNS), characterized by neurological impairments driven by complex interactions between genetic, immunological, and environmental factors. While the individual roles of insulin resistance (IR) and gut microbiome dysbiosis in MS have been explored, their synergistic interaction remains under-investigated. In this novel integrative review, we comprehensively examine the bidirectional crosstalk between IR and gut microbiota alterations, highlighting shared inflammatory and metabolic pathways; such as NLRP3 inflammasome activation, Th17/Treg imbalance, and blood-brain barrier disruption; that underpin neuroinflammation in MS. We identify emerging evidence suggesting that concurrent modulation of both IR and microbial composition may offer a more effective therapeutic strategy than targeting each independently. Furthermore, we propose a framework for personalized, microbiota-informed metabolic interventions (e.g., "probiotic-metformin combinatorial strategies"), grounded in recent findings from multi-omics studies and experimental autoimmune encephalomyelitis (EAE) models. This review aims to bridge existing knowledge gaps, provide a unified perspective on metabolic-immune-microbial interplay in MS, and stimulate new research directions toward holistic and precision medicine approaches for disease prevention and management.
86Dynamic multi-omics profiling of islet and gut hormonal secretion and peripheral crosstalk in response to various nutrient loads.PubMed
Jiachen Wang, Ling Liu, Hechun Liu, et al.
Cell Rep Med. 2025 Sep 16;6(9):102327. doi: 10.1016/j.xcrm.2025.102327. Epub 2025 Sep 3.
Postprandial metabolism is a complex and dynamic process involving diverse biomolecules, with islet and gut hormones playing crucial roles. However, how these hormones interact with biomolecules after nutrient intake and coordinate with peripheral insulin resistance (IR) remains elusive. This study characterizes postprandial multi-omics dynamics under mixed meals and four distinct macronutrient loads, investigating hormone secretion patterns, associated responsive molecules, and their relationships with IR. Postprandial multi-omics data significantly elucidate insulin and glucagon secretion, highlighting differences from the fasting state, while glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are exclusively explained postprandially. Hormone secretion and molecular responses exhibit substantial heterogeneity among macronutrients. Postprandial multi-omics better predict IR, particularly with hepatic enrichment. Protein load shows the strongest association with both hepatic and muscular IR, while butter mostly connects with systemic IR. Several identified molecules mediate interactions between IR and islet α and β cell function, providing a molecular basis for advancing precision nutrition therapies in metabolic diseases.
87Effectiveness of DASH Diet versus Other Diet Modalities in Patients with Metabolic Syndrome: A Systematic Review and Meta-Analysis.PubMed
Juan José Valenzuela-Fuenzalida, Vicente Silva Bravo, Laura Moyano Valarezo, et al.
Nutrients. 2024 Sep 10;16(18):3054. doi: 10.3390/nu16183054.
BACKGROUND: Metabolic syndrome refers to the coexistence of several known cardiovascular risk factors, including insulin resistance, obesity, atherogenic dyslipidemia, and hypertension. These conditions are interrelated and share underlying mediators, mechanisms, and pathways. Improvement in dietary habits has been shown to improve metabolic parameters in patients undergoing treatment with different diets. METHODS: A systematic search in different databases was realized using the keywords "Metabolic syndrome", "X syndrome", "Dash dietary" and "Dash diet". Finally, six studies were included in this meta-analysis. RESULTS: All articles comparing the DASH diet vs. other diet modalities reported significant differences in favor of the DASH diet on Systolic blood pressure (SBP) (standardized mean difference [SMD] = -8.06, confidence interval [CI] = -9.89 to -7.32, and < 0.00001), Diastolic blood pressure (SMD = -6.38, CI = -7.62 to -5.14, and < 0.00001), Cholesterol HDL (SMD = 0.70, CI = 0.53 to 0.88, and < 0.00001) and Cholesterol LDL (SMD = -1.29, CI = -1.73 to -0.85, and < 0.00001) scales. CONCLUSIONS: The DASH diet has been shown to be beneficial in altered parameters in patients with MS, and the resulting improvements can significantly affect the daily health of these patients. We therefore recommend that professionals who manage these pathologies promote the use of the DASH diet for the management of specific symptoms.
88Randomized open-label trial of semaglutide and dapagliflozin in patients with type 2 diabetes of different pathophysiology.PubMed
Chinmay Dwibedi, Ola Ekström, Jasmine Brandt, et al.
Nat Metab. 2024 Jan;6(1):50-60. doi: 10.1038/s42255-023-00943-3. Epub 2024 Jan 4.
The limited understanding of the heterogeneity in the treatment response to antidiabetic drugs contributes to metabolic deterioration and cardiovascular complications, stressing the need for more personalized treatment. Although recent attempts have been made to classify diabetes into subgroups, the utility of such stratification in predicting treatment response is unknown. We enrolled participants with type 2 diabetes (n = 239, 74 women and 165 men) and features of severe insulin-deficient diabetes (SIDD) or severe insulin-resistant diabetes (SIRD). Participants were randomly assigned to treatment with the glucagon-like peptide 1 receptor agonist semaglutide or the sodium-glucose cotransporter 2 inhibitor dapagliflozin for 6 months (open label). The primary endpoint was the change in glycated haemoglobin (HbA1c). Semaglutide induced a larger reduction in HbA1c levels than dapagliflozin (mean difference, 8.2 mmol mol; 95% confidence interval, -10.0 to -6.3 mmol mol), with a pronounced effect in those with SIDD. No difference in adverse events was observed between participants with SIDD and those with SIRD. Analysis of secondary endpoints showed greater reductions in fasting and postprandial glucose concentrations in response to semaglutide in participants with SIDD than in those with SIRD and a more pronounced effect on postprandial glucose by dapagliflozin in participants with SIDD than in those with SIRD. However, no significant interaction was found between drug assignment and the SIDD or SIRD subgroup. In contrast, continuous measures of body mass index, blood pressure, insulin secretion and insulin resistance were useful in identifying those likely to have the largest improvements in glycaemic control and cardiovascular risk factors by adding semaglutide or dapagliflozin. Thus, systematic evaluation of continuous pathophysiological variables can guide the prediction of the treatment response to these drugs and provide more information than stratified subgroups ( NCT04451837 ).
89Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease.PubMed
Xin Zhou, Xiaotao Shen, Jethro S Johnson, et al.
Cell Host Microbe. 2024 Apr 10;32(4):506-526.e9. doi: 10.1016/j.chom.2024.02.012. Epub 2024 Mar 12.
To understand the dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune, and clinical markers of microbiomes from four body sites in 86 participants over 6 years. We found that microbiome stability and individuality are body-site specific and heavily influenced by the host. The stool and oral microbiome are more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. We identify individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlate across body sites, suggesting systemic dynamics influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals show altered microbial stability and associations among microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease.
90Insulin resistance: The role in comorbid type 2 diabetes mellitus and depression.PubMed
Jia Yao, Chang-Qing Zhu, Yan Sun, et al.
Neurosci Biobehav Rev. 2025 Aug;175:106218. doi: 10.1016/j.neubiorev.2025.106218. Epub 2025 May 20.
Insulin resistance (IR) plays a significant role in the pathophysiology of comorbid type 2 diabetes mellitus (T2DM) and depression (CDD) through multifaceted mechanisms, including dysregulation of insulin signaling (both central and peripheral), neuroendocrine disturbances (hypothalamic-pituitary-adrenal axis dysfunction and monoaminergic neurotransmission impairment), chronic inflammation, oxidative stress, disruption of the microbiota-gut-brain axis, reduced brain-derived neurotrophic factor levels, and altered synaptic plasticity. These IR-related pathways may predispose individuals to depressive symptoms or exacerbate existing mood disorders. A comprehensive understanding of these mechanisms is critical for developing integrated therapeutic strategies that concurrently target metabolic and psychiatric dysfunction. Antidepressant medications exhibit divergent effects on glucose metabolism. Tricyclic antidepressants, particularly amitriptyline and nortriptyline, worsen metabolic profiles by exacerbating IR, promoting weight gain, and inducing hyperglycemia, thereby increasing diabetes risk with prolonged use. Consequently, tricyclic antidepressants should be avoided in metabolically vulnerable populations unless alternatives are unavailable. Mirtazapine presents a paradoxical profile-while its appetite-stimulating effects often lead to weight gain (a known IR risk factor), some evidence suggests potential β-cell function preservation, necessitating cautious use of mirtazapine in individuals with metabolic syndrome. Among selective serotonin reuptake inhibitors, fluoxetine and escitalopram demonstrate favorable metabolic effects, including improved insulin sensitivity and glycemic control, though hypoglycemia risk (particularly with concomitant sulfonylureas) warrants monitoring. Bupropion, a norepinephrine-dopamine reuptake inhibitor, uniquely promotes weight loss and enhances glycemic control, making it a preferred option for depression comorbid with obesity or T2DM. Agomelatine, with its neutral metabolic profile and circadian rhythm-modulating properties, represents a safer alternative for patients with metabolic concerns. Concurrently, certain antidiabetic agents show promise in managing depression. Metformin and sodium-glucose cotransporter-2 inhibitors may be prioritized for diabetic patients at risk for depression, while glucagon-like peptide-1 receptor agonists appear particularly beneficial for obesity-related mood disturbances. Thiazolidinediones offer value in treatment-resistant cases, whereas insulin secretagogues should be used cautiously in psychiatrically vulnerable individuals. Future research should prioritize three key directions: (1) Mechanistic investigations using advanced neuroimaging to elucidate the contribution of IR to depressive phenotypes and evaluate novel interventions (such as intranasal insulin); (2) Precision medicine approaches incorporating biomarkers, including genetic polymorphisms, inflammatory markers, and gut microbiome signatures, to optimize antidepressant selection and develop personalized treatment algorithms; and (3) Therapeutic innovation, including dual GLP-1/GIP agonists and anti-inflammatory-antidepressant combinations, as well as integrating digital health technologies (e.g., continuous glucose monitoring coupled with mood tracking), will enable real-time, data-driven management. These advances will be instrumental in establishing integrated care paradigms for this comorbidity, which intertwines metabolic and psychiatric conditions.
91Exploring the Therapeutic Potential of SGLT-2 Inhibitors in Managing Metabolic Syndrome: A Narrative Review.PubMed
Sulthan Al Rashid, Monisha Prasad, Inamul Hasan Madar, et al.
Curr Drug Res Rev. 2025 Aug 22. doi: 10.2174/0125899775382225250811111859.
Metabolic syndrome, a cluster of interconnected metabolic risk factors such as central obesity, insulin resistance, hypertension, and dyslipidemia, significantly increases the risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Despite its rising prevalence and serious health consequences, metabolic syndrome remains underdiagnosed and undertreated. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors, initially developed for T2DM management, have demonstrated promising therapeutic potential for addressing multiple components of metabolic syndrome. These drugs lower blood glucose levels by promoting glycosuria and exhibit additional benefits, including weight loss, reduced blood pressure, improved lipid profiles, and cardioprotective effects. The impact of SGLT-2 inhibitors on the five metabolic syndrome criteria listed by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)-central obesity, triglycerides, HDL cholesterol, blood pressure, and fasting glucose levels-is evaluated in this narrative review, which combines results from metaanalyses and clinical trials. Reduced waist circumference, better lipid profiles, lower blood pressure, and improved glycaemic management are some of the main outcomes. Diuresis, natriuresis, enhanced insulin sensitivity, and AMP-activated protein kinase (AMPK) activation are the processes that underlie these effects. Although SGLT-2 inhibitors have a good safety record, they can cause uncommon diabetic ketoacidosis and urinary tract infections, which can be avoided with careful management. The study highlights that more research is necessary to understand long-term effects, optimize dosing regimens, and assess real-world applicability. According to these findings, SGLT-2 inhibitors are essential therapies for managing metabolic syndrome holistically, and they hold great promise for lowering the disease's worldwide burden and related health hazards.
92The Association between Tooth Loss and Insulin Resistance Mediated by Diet Quality and Systemic Immunoinflammatory Index.PubMed
Yaqi Hao, Shaoru Li, Shaojie Dong, et al.
Nutrients. 2023 Dec 4;15(23):5008. doi: 10.3390/nu15235008.
(1) Background: Both tooth loss and diabetes have high global prevalence, and both have a significant influence on patients' general health and quality of life. Previous research has indicated a possible connection between tooth loss and diabetes, but it has been unclear whether tooth loss has an effect on the development of diabetes and how it affects it. We aim to investigate the relationship between insulin resistance (IR) and tooth loss and examine how the systemic immune-inflammation index (SII) level and diet quality mediate it. (2) Methods: The cross-sectional study data were obtained from the National Health and Nutrition Examination Survey (NHANES). After describing and comparing baseline data, we used regression models to evaluate the relationship between IR and tooth loss, diet quality and tooth loss and IR, SII and tooth loss and IR. Furthermore, we applied bootstrapping to test the mediation effect of diet quality and SII between tooth loss and IR. Diet quality is reflected by the HEI (Healthy Eating Index)-2015 score. (3) Results: The total number of subjects included was 8197, with 3861 individuals belonging to the IR group (HOMA-IR ≥ 2.5) and 4336 in the non-IR group (HOMA-IR < 2.5). In the model with all covariates adjusted, tooth loss in the fourth quartile was found to be positively correlated with an increase in HOMA-IR (OR = 1.301; 95% confidence interval (CI) = [1.102, 1.537]; < 0.001) compared to the first quartile; tooth loss in the fourth quartile correlated with the HEI-2015 score compared to the first quantile (β = -0.121, 95% CI = [-4.839, -2.974], < 0.001); and the highest number of tooth loss was found to have a significant effect on SII (β = 0.032; 95%CI = [1.777, 47.448]; < 0.05). Compared to average diet quality, best diet quality acts as a safeguard against elevated HOMA-IR (OR = 0.776; 95% CI = [0.641, 0.939]; < 0.01); inadequate diet quality is a risk factor (OR = 1.267; 95%CI = [1.138, 1.411]; < 0.001) conversely. Meanwhile, it can be seen that compared with the first quantile of SII, the highest score is significantly correlated with the higher incidence of IR (OR = 1.363; 95%CI = [1.179, 1.575]; < 0.001). Diet quality and SII played a partial mediating role in the relationship between HOMA-IR and tooth loss, and the mediating effect ratio for the total effect value was 4.731% and 4.576%, respectively. The mediating effect of SII and diet quality in the association of the relationship between HOMA-IR and tooth loss both was 0.003 (95%CI = [0.001, 0.004]). (4) Conclusions: Our study revealed the relationship between IR and tooth loss, and further explored the mediating role of SII and diet quality between the number of missing teeth and IR, emphasizing that improving diet quality and reducing SII can effectively prevent and treat IR and related diseases. It provides new theoretical support for the study of IR mechanisms and new ideas and approaches to deal with related diseases.
93Insulin resistance in polycystic ovary syndrome across various tissues: an updated review of pathogenesis, evaluation, and treatment.PubMed
Han Zhao, Jiaqi Zhang, Xiangyi Cheng, et al.
J Ovarian Res. 2023 Jan 11;16(1):9. doi: 10.1186/s13048-022-01091-0.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic ovulation dysfunction and overabundance of androgens; it affects 6-20% of women of reproductive age. PCOS involves various pathophysiological factors, and affected women usually have significant insulin resistance (IR), which is a major cause of PCOS. IR and compensatory hyperinsulinaemia have differing pathogeneses in various tissues, and IR varies among different PCOS phenotypes. Genetic and epigenetic changes, hyperandrogenaemia, and obesity aggravate IR. Insulin sensitization drugs are a new treatment modality for PCOS. We searched PubMed, Google Scholar, Elsevier, and UpToDate databases in this review, and focused on the pathogenesis of IR in women with PCOS and the pathophysiology of IR in various tissues. In addition, the review provides a comprehensive overview of the current progress in the efficacy of insulin sensitization therapy in the management of PCOS, providing the latest evidence for the clinical treatment of women with PCOS and IR.
94A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS).PubMed
Sana Siddiqui, Somaiya Mateen, Rizwan Ahmad, et al.
J Assist Reprod Genet. 2022 Nov;39(11):2439-2473. doi: 10.1007/s10815-022-02625-7. Epub 2022 Oct 3.
Polycystic ovarian syndrome (PCOS) is a prevailing endocrine and metabolic disorder occurring in about 6-20% of females in reproductive age. Most symptoms of PCOS arise early during puberty. Since PCOS involves a combination of signs and symptoms, thus it is considered as a heterogeneous disorderliness. The most accepted diagnostic criteria is Rotterdam criteria which involves two of the latter three features: (a) hyperandrogenism, (b) oligo- or an-ovulation, and (c) polycystic ovaries. The persistent hormonal imbalance leads to multiple small antral follicles formation and irregular menstrual cycle, ultimately causing infertility among females. Insulin resistance, cardiovascular diseases, abdominal obesity, psychological disorders, infertility, and cancer are also related to PCOS. These pathophysiologies associated with PCOS are interrelated with each other. Hyperandrogenism causes insulin resistance and hyperglycemia, leading to ROS formation, oxidative stress, and abdominal adiposity. In consequence, inflammation, ROS production, insulin resistance, and hyperandrogenemia also increase. Elevation of AGEs in the body either produced endogenously or consumed from diet exaggerates PCOS symptoms and is also related to ovarian dysfunction. This review summarizes how AGE formation, inflammation, and oxidative stress are significantly essential in PCOS progression. Alterations during prenatal development like exposure to excess AMH, androgens, or toxins (bisphenol-A, endocrine disruptors, etc.) may also be the etiologic mechanism behind PCOS. Although the etiology of this disorder is unclear, environmental and genetic factors are primarily involved. Physical inactivity, as well as unhealthy eating habits, has a vital role in the progression of PCOS. This review outlines a collection of specific genes phenotypically linked with PCOS. Furthermore, beneficial effect of metformin in maintaining endocrine abnormalities and ovarian function is also mentioned. Kisspeptin is a protein which helps in onset of puberty and increases GnRH pulsatile release during ovulation as well as role of KNDy neurons in GnRH pulsatile signal required for reproduction are also elaborated. This review also focuses on the immunology related to PCOS involving chronic low-grade inflammation, and how the alterations within the follicular microenvironment are intricated in the development of infertility in PCOS patients. How PCOS develops following antiepileptic and psychiatric medication is also expanded in this review. Initiation of antiandrogen treatment in early age (≤ 25 years) might be helpful in spontaneous conception in PCOS women. The role of BMP (bone morphogenetic proteins) in folliculogenesis and their expression in oocytes and granulosa cells are also explained. GDF8 and SERPINE1 expression in PCOS is given in detail.
95Polycystic Ovary Syndrome: Etiology, Current Management, and Future Therapeutics.PubMed
Samradhi Singh, Namrata Pal, Swasti Shubham, et al.
J Clin Med. 2023 Feb 11;12(4):1454. doi: 10.3390/jcm12041454.
Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, typically characterized by anovulation, infertility, obesity, insulin resistance, and polycystic ovaries. Lifestyle or diet, environmental pollutants, genetics, gut dysbiosis, neuroendocrine alterations, and obesity are among the risk factors that predispose females to PCOS. These factors might contribute to upsurging metabolic syndrome by causing hyperinsulinemia, oxidative stress, hyperandrogenism, impaired folliculogenesis, and irregular menstrual cycles. Dysbiosis of gut microbiota may play a pathogenic role in the development of PCOS. The restoration of gut microbiota by probiotics, prebiotics, or a fecal microbiota transplant (FMT) might serve as an innovative, efficient, and noninvasive way to prevent and mitigate PCOS. This review deliberates on the variety of risk factors potentially involved in the etiology, prevalence, and modulation of PCOS, in addition to plausible therapeutic interventions, including miRNA therapy and the eubiosis of gut microbiota, that may help treat and manage PCOS.
96Controversies in the Pathogenesis, Diagnosis and Treatment of PCOS: Focus on Insulin Resistance, Inflammation, and Hyperandrogenism.PubMed
Decio Armanini, Marco Boscaro, Luciana Bordin, et al.
Int J Mol Sci. 2022 Apr 8;23(8):4110. doi: 10.3390/ijms23084110.
Polycystic ovary syndrome (PCOS) is a heterogeneous and extremely common disease with symptoms that vary with the age of the patient, typically characterized by hyperandrogenism, chronic oligo-anovulation, and/or several metabolic disorders. The syndrome includes various phenotypes, and the pathogenesis is multifactorial, often involving insulin resistance. This feature is closely related to ovarian dysfunction, inflammation, hyperandrogenism, and metabolic disorders, which characterize and complicate the syndrome. Therapy currently considers both lifestyle improvements and medications, and must be tailored on a case-by-case basis. To date, the published studies have not arrived at a definition of the most suitable therapy for each individual case and many of the drugs used are still off-label. In this review, we discuss some controversial diagnostic and therapeutic aspects of PCOS, such as the role of insulin resistance, inflammation, and hyperandrogenism. We also evaluated the advantages and disadvantages of contraceptive therapy and antiandrogens.
97Comparison of two insulin sensitizers, metformin and myo-inositol, in women with polycystic ovary syndrome (PCOS).PubMed
Franca Fruzzetti, Daria Perini, Marinella Russo, et al.
Gynecol Endocrinol. 2017 Jan;33(1):39-42. doi: 10.1080/09513590.2016.1236078. Epub 2016 Nov 3.
Insulin resistance (IR) plays a pivotal role in PCOS. Insulin-sensitizer agents such as metformin and inositols have been shown to improve the endocrine and metabolic aspects of PCOS. The purpose of this study is to compare their effects on the clinical and metabolic features of the women with PCOS. Fifty PCOS women with IR and/or hyperinsulinemia were randomized to treatment with metformin (1500 mg/day) or myo-inositol (4 g/day). IR was defined as HOMA-IR >2.5, while hyperinsulinemia was defined as a value of AUC for insulin after a glucose load over the cutoff of our laboratory obtained in normal women. The Matsusa Index has been calculated. The women have been evaluated for insulin secretion, BMI, menstrual cycle length, acne and hirsutism, at baseline and after 6 months of therapy. The results obtained in both groups were similar. The insulin sensitivity improved in both treatment groups. The BMI significantly decreased and the menstrual cycle was normalized in about 50% of the women. No significant changes in acne and hirsutism were observed. The two insulin-sensitizers, metformin and myo-inositol, show to be useful in PCOS women in lowering BMI and ameliorating insulin sensitivity, and improving menstrual cycle without significant differences between the two treatments.
98Inositol is an effective and safe treatment in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials.PubMed
Dorina Greff, Anna E Juhász, Szilárd Váncsa, et al.
Reprod Biol Endocrinol. 2023 Jan 26;21(1):10. doi: 10.1186/s12958-023-01055-z.
BACKGROUND: Metformin is the gold standard insulin sensitizer, which is widely used to treat insulin resistance in polycystic ovary syndrome (PCOS). However, metformin may induce gastrointestinal side effects. OBJECTIVE: Inositols have long been debated as a potential alternative for metformin in treating PCOS. Therefore, the present systematic review aimed to evaluate the efficacy and safety of inositols in treating PCOS. METHODS: The present systematic search was performed in CENTRAL, MEDLINE, and Embase from the inception until October 20th, 2021. Eligible randomized controlled trials (RCTs) included women diagnosed with PCOS and compared any inositols with metformin or placebo. Our primary outcome was cycle normalization, whereas secondary outcomes were body mass index (BMI), parameters of carbohydrate metabolism and clinical and laboratory hyperandrogenism. Results are reported as risk ratios or mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: Twenty-six RCTs were identified, including data of 1691 patients (806 inositol, 311 with placebo, and 509 metformin groups). In patients treated with inositols, the risk (CI: 1.13; 2.85) of having a regular menstrual cycle was found by 1.79 higher than in the case of placebo. Moreover, the inositols showed non-inferiority compared to metformin in this outcome. In the case of BMI (MD = -0.45; CI: -0.89; -0.02), free testosterone (MD = -0,41, CI: -0.69; -0.13), total testosterone (MD = -20.39, CI: -40.12; -0.66), androstenedione (MD = -0.69, CI: -1,16; -0.22), glucose (MD = -3.14; CI: -5.75; -0.54) levels and AUC insulin (MD = -2081.05, CI: -2745.32; -1416.78) inositol treatment induced greater decrease compared to placebo. Inositol increased sex-hormone-binding globulin significantly compared to placebo (MD = 32.06, CI:1.27; 62.85). CONCLUSION: Inositol is an effective and safe treatment in PCOS. Moreover, inositols showed non-inferiority in most outcomes compared to the gold standard treatment; metformin. TRIAL REGISTRATION: PROSPERO registration number: CRD42021283275.
99Inositol for Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis to Inform the 2023 Update of the International Evidence-based PCOS Guidelines.PubMed
Victoria Fitz, Sandro Graca, Shruthi Mahalingaiah, et al.
J Clin Endocrinol Metab. 2024 May 17;109(6):1630-1655. doi: 10.1210/clinem/dgad762.
CONTEXT: Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Inositol may have insulin sensitizing effects; however, its efficacy in the management of PCOS remains indeterminate. OBJECTIVE: To inform the 2023 international evidence-based guidelines in PCOS, this systematic review and meta-analysis evaluated the efficacy of inositol, alone or in combination with other therapies, in the management of PCOS. DATA SOURCES: Medline, PsycInfo, EMBASE, All EBM, and CINAHL from inception until August 2022. STUDY SELECTION: Thirty trials (n = 2230; 1093 intervention, 1137 control), with 19 pooled in meta-analyses were included. DATA EXTRACTION: Data were extracted for hormonal, metabolic, lipids, psychological, anthropometric, reproductive outcomes, and adverse effects by 1 reviewer, independently verified by a second. DATA SYNTHESIS: Thirteen comparisons were assessed, with 3 in meta-analyses. Evidence suggests benefits for myo-inositol or D-chiro-inositol (DCI) for some metabolic measures and potential benefits from DCI for ovulation, but inositol may have no effect on other outcomes. Metformin may improve waist-hip ratio and hirsutism compared to inositol, but there is likely no difference for reproductive outcomes, and the evidence is very uncertain for body mass indexI. Myo-inositol likely causes fewer gastrointestinal adverse events compared with metformin; however, these are typically mild and self-limited. CONCLUSION: The evidence supporting the use of inositol in the management of PCOS is limited and inconclusive. Clinicians and their patients should consider the uncertainty of the evidence together with individual values and preferences when engaging in shared decision-making regarding the use of inositol for PCOS.
100Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis.PubMed
Han Zhao, Chuan Xing, Jiaqi Zhang, et al.
Reprod Health. 2021 Aug 18;18(1):171. doi: 10.1186/s12978-021-01207-7.
BACKGROUND: Multiple oral insulin-sensitizing agents, such as metformin, thiazolidinediones, inositols, and berberine, have been proven safe and efficacious in improving the endocrine, metabolic, and reproductive abnormalities seen in polycystic ovary syndrome (PCOS), providing more options for healthcare providers and patients. These oral insulin sensitizers are more convenient, practical, and economic than agents that need to be injected. A comparison of the clinical effectiveness of the four different classes of oral insulin sensitizers in PCOS has not been explored, leading to clinical uncertainty about the optimal treatment pathway. The present study aims to compare the effects of oral insulin sensitizers on endocrine and metabolic profiles in women with PCOS. METHODS: We identified randomized controlled trials for PCOS from a variety of databases, published from January 2005 to October 2020. Outcomes included changes in menstrual frequency, improvements in hyperandrogenism and glucolipid metabolism and adverse side effects. A random-effects network meta-analysis was performed. RESULTS: Twenty-two trials comprising 1079 patients with PCOS were included in this study. Compared with metformin, treatment with myo-inositol + D-chiro-inositol was associated with a greater improvement in menstrual frequency (odds ratio 14.70 [95% confidence interval (CI) 2.31-93.58]). Myo-inositol + D-chiro-inositol and metformin + thiazolidinediones combination therapies were superior to respective monotherapies in reducing total testosterone levels. Thiazolidinediones, metformin + thiazolidinediones, and myo-inositol + D-chiro-inositol were associated with a lower insulin resistance index (HOMA-IR) compared with that in metformin alone (mean differences: - 0.72 [95% CI (- 1.11)-(- 0.34)] to - 0.89 [95% CI (- 1.460)-(- 0.32)]). Metformin + thiazolidinediones treatment was associated with lower triglyceride levels compared with that in metformin and thiazolidinediones monotherapy, while thiazolidinediones was superior to metformin in increasing high-density lipoprotein cholesterol and decreasing fasting plasma glucose, triglycerides, low-density lipoprotein cholesterol, and gastrointestinal adverse events. CONCLUSIONS: Ours is the first study to report that for women with PCOS, myo-inositol combined with D-chiro-inositol and metformin combined with thiazolidinediones appear superior to metformin alone in improving insulin resistance and decreasing total testosterone. Myo-inositol combined with D-chiro-inositol is particularly efficacious in menstrual recovery. Thiazolidinediones and metformin combined with thiazolidinediones improve lipid metabolism better than metformin alone. Trial registration PROSPERO CRD42020211524.
101Signaling pathways and targeted therapeutic strategies for polycystic ovary syndrome.PubMed
Kexin Wang, Yanhua Li
Front Endocrinol (Lausanne). 2023 Oct 19;14:1191759. doi: 10.3389/fendo.2023.1191759. eCollection 2023.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Although promising strides have been made in the field of PCOS over the past decades, the distinct etiologies of this syndrome are not fully elucidated. Prenatal factors, genetic variation, epigenetic mechanisms, unhealthy lifestyles, and environmental toxins all contribute to the development of this intricate and highly heterogeneous metabolic, endocrine, reproductive, and psychological disorder. Moreover, interactions between androgen excess, insulin resistance, disruption to the hypothalamic-pituitary-ovary (HPO) axis, and obesity only make for a more complex picture. In this review, we investigate and summarize the related molecular mechanisms underlying PCOS pathogenesis from the perspective of the level of signaling pathways, including PI3K/Akt, TGF-β/Smads, Wnt/β-catenin, and Hippo/YAP. Additionally, this review provides an overview of prospective therapies, such as exosome therapy, gene therapy, and drugs based on traditional Chinese medicine (TCM) and natural compounds. By targeting these aberrant pathways, these interventions primarily alleviate inflammation, insulin resistance, androgen excess, and ovarian fibrosis, which are typical symptoms of PCOS. Overall, we hope that this paper will pave the way for better understanding and management of PCOS in the future.
102The Potential Utility of Tirzepatide for the Management of Polycystic Ovary Syndrome.PubMed
Alekya Devi Anala, Insiya Sajjad Hussain Saifudeen, Maryam Ibrahim, et al.
J Clin Med. 2023 Jul 10;12(14):4575. doi: 10.3390/jcm12144575.
Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women of reproductive age. The metabolic dysfunction associated with PCOS increases the probability of developing type 2 diabetes (T2D), endometrial cancer, and cardiovascular disease. Research has shown that the metabolic features of PCOS may be improved by weight loss following treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists. Tirzepatide is a dual GLP-GIP (gastric inhibitory polypeptide) receptor agonist that shares a very similar mechanism of action with GLP-1R agonists, and it is hypothesized that it may be a potential contender in the treatment of PCOS. The success of GLP-1R agonists is usually hindered by their adverse gastrointestinal effects, leading to reduced compliance. The mechanism of action of Tirzepatide partly addresses this issue, as its dual receptor affinity may reduce the intensity of gastrointestinal symptoms. Tirzepatide has been licensed for the treatment of type 2 diabetes and given the metabolic issues and obesity that accompanies PCOS, it may be of value in its management for those PCOS patients who are obese with metabolic syndrome, although it may not benefit those who are of normal weight. This study reviews the current therapies for the treatment of PCOS and evaluates the potential use of Tirzepatide to address the symptoms of PCOS, including reproductive dysfunction, obesity, and insulin resistance.
103Metabolic Syndrome and Menopause: Pathophysiology, Clinical and Diagnostic Significance.PubMed
Anna Stefanska, Katarzyna Bergmann, Grazyna Sypniewska
Adv Clin Chem. 2015;72:1-75. doi: 10.1016/bs.acc.2015.07.001. Epub 2015 Aug 21.
Menopause is a risk factor for cardiometabolic diseases, including metabolic syndrome (MetS), type 2 diabetes, and cardiovascular diseases. MetS is a constellation of interdependent factors such as insulin resistance, abdominal obesity, dyslipidemia, and hypertension. The prevalence of MetS in postmenopause is due to loss of the protective role of estrogens and increased circulating androgens resulting in changes to body fat distribution and development of abdominal obesity. Excessive visceral adipose tissue plays an important role due to synthesis and secretion of bioactive substances such as adipocytokines, proinflammatory cytokines, reactive oxygen species, prothrombotic, and vasoconstrictor factors. MetS may also impact risk assessment of breast cancer, osteoporosis and chronic kidney disease, and quality of life during the menopausal transition. Increased MetS has stimulated the exploration of new laboratory tests for early detection and therapies.
104Role of Estrogen and Its Receptors in Adipose Tissue Glucose Metabolism in Pre- and Postmenopausal Women.PubMed
Fozia Ahmed, Prasad G Kamble, Susanne Hetty, et al.
J Clin Endocrinol Metab. 2022 Apr 19;107(5):e1879-e1889. doi: 10.1210/clinem/dgac042.
CONTEXT: Reduced estrogen levels in postmenopausal women predispose them to metabolic side effects, including insulin resistance and type 2 diabetes; however, the cellular mechanisms are not well understood. OBJECTIVE: This work aimed to study the expression of estrogen receptors in adipose tissue from pre- and postmenopausal women and the effects of estradiol (E2) on glucose uptake of adipocytes. METHODS: Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained from pre- and postmenopausal women (19-51 and 46-75 years old, respectively) were used to measure gene expression of ESR1 and ESR2. SAT tissue was incubated with E2, and glucose uptake and estrogen receptor levels were measured. Polymorphisms in ESR1 and ESR2 were addressed in public databases to identify single nucleotide polymorphisms associated with metabolic traits. RESULTS: ESR2 expression was lower in pre- vs postmenopausal women, corresponding to lower ESR1:ESR2 gene expression ratio in postmenopausal women. In premenopausal women, the expression of ESR1 was higher in VAT than in SAT. In both pre- and postmenopausal women, ESR2 expression was lower in VAT than in SAT. In late, but not pre- or early postmenopausal women, E2 reduced glucose uptake and GLUT4 protein and increased expression of ESR2. ESR1 polymorphisms were associated with weight, body fat distribution, and total cholesterol, and ESR2 polymorphisms were associated with total cholesterol and triglyceride levels and with body fat percentage. CONCLUSION: E2 inhibits glucose utilization in human adipocytes in late postmenopausal women. Changes in glucose utilization over time since menopause may be explained by a lower ESR1:ESR2 ratio. This can have clinical implications on the timing of estrogen treatment in postmenopausal women.
105Body composition analysis: A snapshot across the perimenopause.PubMed
Maria Karaflou, Dimitrios G Goulis
Maturitas. 2024 Feb;180:107898. doi: 10.1016/j.maturitas.2023.107898. Epub 2023 Dec 1.
During the perimenopause, estrogen concentrations gradually decrease, and this is associated with changes to women's energy expenditure and intake. These changes result in weight gain and altered body fat distribution, with increased abdominal fat deposition and cardiometabolic risk via insulin resistance. Body composition analysis is a useful clinical tool in outpatient settings, as it is simple, not expensive and provides information on body mass index, skeletal mass, fat mass, fat percentage and basal metabolic rate. This review discusses body composition analysis as part of a health assessment for healthy women during the perimenopause and investigates the associations between body composition and cardiometabolic profile.
106Longitudinal associations of the endocrine environment on fat partitioning in postmenopausal women.PubMed
Amy M Goss, Betty E Darnell, Marian A Brown, et al.
Obesity (Silver Spring). 2012 May;20(5):939-44. doi: 10.1038/oby.2011.362. Epub 2011 Dec 15.
Among postmenopausal women, declining estrogen may facilitate fat partitioning from the periphery to the intra-abdominal space. Furthermore, it has been suggested that excess androgens contribute to a central fat distribution pattern in women. The objective of this longitudinal study was to identify independent associations of the hormone milieu with fat distribution in postmenopausal women. Fifty-three healthy postmenopausal women, either using or not using hormone replacement therapy (HRT) were evaluated at baseline and 2 years. The main outcomes were intra-abdominal adipose tissue (IAAT), subcutaneous abdominal adipose tissue, and total thigh fat analyzed by computed tomography scanning and leg fat and total body fat mass measured by dual-energy X-ray absorptiometry. Serum estradiol, estrone, estrone sulfate, total testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate), sex hormone-binding globulin (SHBG), and cortisol were assessed. On average, in all women combined, IAAT increased by 10% (10.5 cm(2)) over 2 years (P < 0.05). Among HRT users, estradiol was inversely associated with, and estrone was positively associated with, 2-year gain in IAAT. Among HRT nonusers, free testosterone was inversely associated with, and SHBG was positively associated with, 2-year gain in IAAT. These results suggest that in postmenopausal women using HRT, greater circulating estradiol may play an integral role in limiting lipid deposition to the intra-abdominal cavity, a depot associated with metabolically detrimental attributes. However, a high proportion of weak estrogens may promote fat partitioning to the intra-abdominal cavity over time. Furthermore, among postmenopausal women not using HRT, greater circulating free testosterone may limit IAAT accrual.
107Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance.PubMed
Lin Zhu, William C Brown, Qing Cai, et al.
Diabetes. 2013 Feb;62(2):424-34. doi: 10.2337/db11-1718. Epub 2012 Sep 10.
Pathway-selective insulin resistance where insulin fails to suppress hepatic glucose production but promotes liver fat storage may underlie glucose and lipid abnormalities after menopause. We tested the mechanisms by which estrogen treatment may alter the impact of a high-fat diet (HFD) when given at the time of ovariectomy (OVX) in mice. Female C57BL/6J mice underwent sham operation, OVX, or OVX with estradiol (E2) treatment and were fed an HFD. Hyperinsulinemic-euglycemic clamps were used to assess insulin sensitivity, tracer incorporation into hepatic lipids, and liver triglyceride export. OVX mice had increased adiposity that was prevented with E2 at the time of OVX. E2 treatment increased insulin sensitivity with OVX and HFD. In sham and OVX mice, HFD feeding induced fatty liver, and insulin reduced hepatic apoB100 and liver triglyceride export. E2 treatment reduced liver lipid deposition and prevented the decrease in liver triglyceride export during hyperinsulinemia. In mice lacking the liver estrogen receptor α, E2 after OVX limited adiposity but failed to improve insulin sensitivity, to limit liver lipid deposition, and to prevent insulin suppression of liver triglyceride export. In conclusion, estrogen treatment may reverse aspects of pathway-selective insulin resistance by promoting insulin action on glucose metabolism but limiting hepatic lipid deposition.
108Effects of Hormone Replacement Therapy on Insulin Resistance in Postmenopausal Diabetic Women.PubMed
Iskra Bitoska, Branka Krstevska, Tatjana Milenkovic, et al.
Open Access Maced J Med Sci. 2016 Mar 15;4(1):83-8. doi: 10.3889/oamjms.2016.024. Epub 2016 Feb 1.
BACKGROUND: Insulin resistance (IR) is closely associated with diabetes mellitus. On the other hand, increased visceral fat in menopause is also associated with IR, which makes postmenopausal diabetic women in a big risk for cardiovascular diseases. There are conflicting reports about the effects on hormone replacement therapy (HRT) on IR. AIM: The aim of the study was to investigate the effects of HRT on IR. METHODS: A total of 40 postmenopausal women with type 2 diabetes were enrolled and followed for 12 months. Half of them were assigned to take HRT, while the other half made the control group. Fasting plasma glucose (FPG) and insulinemia were measured in both groups at baseline and after 12 months. IR was represented by Homeostatic model assessment for IR (HOMA-IR). RESULTS: HRT was associated with significant decrease in HOMA-IR, FPG and insulinemia in the examined group. There was no significant reduction in FPG and no significant increase in insulinemia levels and HOMA-IR values in control group after 12 months. CONCLUSION: HRT was associated with statistically signifficant increase of insulin sensitivity. Larger clinical trials will be necessary to understand whether HRT may improve insulin resistance and glucose homeostasis in women with diabetes, especially when given shortly after entering menopause.
109Cardiovascular-Kidney-Metabolic (CKM) syndrome: A state-of-the-art review.PubMed
Sneha Annie Sebastian, Inderbir Padda, Gurpreet Johal
Curr Probl Cardiol. 2024 Feb;49(2):102344. doi: 10.1016/j.cpcardiol.2023.102344. Epub 2023 Dec 14.
The correlation between obesity, type 2 diabetes mellitus (DM), cardiovascular disease (CVD), and chronic kidney disease (CKD) is an escalating and widely acknowledged epidemic in industrialized nations. Recently, this complex web of interrelated health conditions has been collectively defined as the Cardiovascular-Kidney-Metabolic (CKM) syndrome by the American Heart Association (AHA). The molecular mechanisms underlying CKM disease contain a spectrum of interconnected factors, including hyperglycemia, insulin resistance, heightened activity of the renin-angiotensin-aldosterone system (RAAS), the generation of advanced glycation end-products, oxidative stress, lipotoxicity, endoplasmic reticulum stress, abnormalities in calcium handling, malfunctioning of mitochondria and impaired energy production, as well as persistent chronic inflammation. Addressing their prevention, management, and treatment is of paramount importance to promote better patient health outcomes. The objective of this review is to provide a comprehensive and critical examination of the current state-of-the-art regarding the recently defined CKM syndrome. This includes an exploration of epidemiological evidence establishing connections between cardio-renal-metabolic diseases, an examination of the underlying pathophysiological mechanisms, and a comprehensive overview of existing treatment modalities.
110Association between the triglyceride glucose-body mass index and future cardiovascular disease risk in a population with Cardiovascular-Kidney-Metabolic syndrome stage 0-3: a nationwide prospective cohort study.PubMed
Weipeng Li, Chaonan Shen, Weiya Kong, et al.
Cardiovasc Diabetol. 2024 Aug 7;23(1):292. doi: 10.1186/s12933-024-02352-6.
BACKGROUND: The American Heart Association (AHA) has recently introduced the concept of Cardiovascular-Kidney-Metabolic (CKM) syndrome, which is the result of an increasing emphasis on the interplay of metabolic, renal and cardiovascular diseases (CVD). Furthermore, there is substantial evidence of a correlation between the triglyceride glucose-body mass index (TyG-BMI ) and CVD as an assessment of insulin resistance (IR). However, it remains unknown whether this correlation exists in population with CKM syndrome. METHODS: All data for this study were obtained from the China Health and Retirement Longitudinal Study (CHARLS). The exposure was the participants' TyG-BMI at baseline, which was calculated using a combination of triglycerides (TG), fasting blood glucose (FBG) and body mass index (BMI). The primary outcome was CVD, which were determined by the use of a standardised questionnaire during follow-up. To examine the relationship between TyG-BMI and CVD incidence in population with CKM syndrome, both Cox regression analyses and restricted cubic spline (RCS) regression analyses were performed. RESULTS: A total of 7376 participants were included in the final analysis. Of these, 1139, 1515, 1839, and 2883 were in CKM syndrome stages 0, 1, 2, and 3, respectively, at baseline. The gender distribution was 52.62% female, and the mean age was 59.17 ± 9.28 (years). The results of the fully adjusted COX regression analyses indicated that there was a 6.5% increase in the risk of developing CVD for each 10-unit increase in TyG-BMI,95% confidence interval (CI):1.041-1.090. The RCS regression analyses demonstrated a positive linear association between TyG-BMI and the incidence of CVD in the CKM syndrome population (P for overall < 0.001, P for nonlinear = 0.355). CONCLUSIONS: This cohort study demonstrated a positive linear association between TyG-BMI index and increased CVD incidence in a population with CKM syndrome stage 0-3. This finding suggests that enhanced assessment of TyG-BMI index may provide a more convenient and effective tool for individuals at risk for CVD in CKM syndrome stage 0-3.
111Association between triglyceride-glucose related indices and all-cause and cardiovascular mortality among the population with cardiovascular-kidney-metabolic syndrome stage 0-3: a cohort study.PubMed
Peng Zhang, Degang Mo, Wenhua Zeng, et al.
Cardiovasc Diabetol. 2025 Feb 28;24(1):92. doi: 10.1186/s12933-025-02642-7.
BACKGROUND: Cardiovascular-Kidney-Metabolic (CKM) syndrome typically commences with the interaction of insulin resistance (IR), excessive or dysfunctional obesity, and the consequent systemic inflammatory response and oxidative stress. The relationship between the triglyceride-glucose (TyG) index and TyG-related indices that may simply assess IR and obesity, as well as the mortality risk in the CKM syndrome population, remains ambiguous. METHODS: This study included 6,383 participants from the National Health and Nutrition Examination Survey (NHANES) 2009-2018. The TyG index, TyG-waist-to-height ratio (TyG-WHtR), TyG-waist circumference (TyG-WC), and TyG-body mass index (TyG-BMI) were developed. Cox proportional hazards models, smooth curve fitting, and two-stage Cox proportional hazards models were employed to examine the association of TyG and TyG-related indices with all-cause and cardiovascular mortality in the CKM syndrome population. Subgroup analyses and interaction tests were conducted to evaluate the risk within various demographics. RESULTS: In survey-weighted multifactorial regression analyses, a significant positive association existed between TyG, TyG-related indices, and both all-cause mortality and cardiovascular mortality, except for the TyG index, which did not demonstrate a significant link with all-cause mortality. Of these indices, the TyG-WC index exhibited the strongest correlation with all-cause mortality, with a hazard ratio (HR) of 1.50 and a 95% confidence interval (CI) of 1.18-1.92, followed by the TyG-WHtR index (HR: 1.45, 95%CI 1.13-1.85). The TyG-WHtR index demonstrated the strongest correlation with cardiovascular mortality (HR: 1.85, 95% CI 1.19-2.86), followed by the TyG-WC index(HR: 1.83, 95%CI 1.21-2.78). An L-shaped association was identified between TyG-WHtR, TyG-BMI, and all-cause mortality in CKM syndrome during the examination of nonlinear relationships (both P for log-likelihood ratio < 0.05). The TyG-WHtR, TyG-WC, and TyG-BMI indices exhibited a more pronounced correlation with all-cause mortality in those with CKM syndrome stages 1 and 3 (P value < 0.05, P for interaction < 0.05). CONCLUSION: Our study emphasizes the association between TyG and TyG-related indices and mortality in individuals with CKM syndrome stages 0-3. Individuals with CKM syndrome stages 1 and 3 should be more vigilant to abnormal alterations in TyG-related indices.
112Overview of oxidative stress and inflammation in diabetes.PubMed
Roni Weinberg Sibony, Omri Segev, Saar Dor, et al.
J Diabetes. 2024 Oct;16(10):e70014. doi: 10.1111/1753-0407.70014.
The global prevalence of diabetes has increased significantly, leading to various complications and a negative impact on quality of life. Hyperglycemia hyperglycemic-induced oxidative stress (OS) and inflammation are closely associated with the development and progression of type 2 diabetes mellitus (T2D) and its complications. This review explores the effect of T2D on target organ damage and potential treatments to minimize this damage. The paper examines the pathophysiology of T2D, focusing on low-grade chronic inflammation and OS and on their impact on insulin resistance. The review discusses the role of inflammation and OS in the development of microvascular and macrovascular complications. The findings highlight the mechanisms by which inflammatory cytokines, stress kinases, and reactive oxygen species (ROS) interfere with insulin signaling pathways, leading to impaired glucose metabolism and organ dysfunction. Lifestyle interventions, including a balanced diet and exercise, can help reduce chronic inflammation and OS, thereby preventing and controlling T2D and its associated complications. Additionally, various antioxidants and anti-inflammatory agents show potential in reducing OS and inflammation. Some anti-diabetic drugs, like pioglitazone, metformin, and glucagon-like peptide-1 (GLP-1) agonists, may also have anti-inflammatory effects. Further research, including randomized controlled trials, is needed to evaluate the efficacy of these interventions.
113SGLT2 inhibitors as metabolic modulators: beyond glycemic control in type 2 diabetes.PubMed
Qian Wu, Jian Zhang, Fuli Zhang, et al.
Front Endocrinol (Lausanne). 2025 Jun 24;16:1601633. doi: 10.3389/fendo.2025.1601633. eCollection 2025.
Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder, and its management has evolved from mere glycemic control to multitarget metabolic regulation. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have demonstrated extensive pleiotropic effects in treating T2DM, and its complications through unique mechanisms. SGLT2is promote urinary glucose excretion, leading to a negative energy balance that triggers lipid metabolic reprogramming and fuel switching in the body. This process significantly reduces visceral fat deposition and improves insulin resistance and the inflammatory status. Additionally, SGLT2is provide a metabolic foundation for cardiovascular, hepatic, and renal protection through multiple pathways, including remodeling cardiac structure, enhancing myocardial metabolism, reducing uric acid levels, and alleviating renal hypoxia. With respect to combination therapy, the pairing of SGLT2is with other hypoglycemic agents and cardiovascular protective drugs has synergistic effects; however, potential adverse reactions should also be considered. Future research should investigate the precise application and long-term safety of SGLT2is as well as develop individualized treatment strategies on the basis of patients' metabolic phenotypes, complications, and drug tolerability to maximize clinical benefits for patients. This review systematically explores the significant roles of SGLT2is in metabolic regulation, cardiovascular protection, and combination therapy, with the aim of providing a comprehensive foundation for optimizing individualized treatment strategies in T2DM management.
114Multi-Organ Protective Effects of Sodium Glucose Cotransporter 2 Inhibitors.PubMed
Hidekatsu Yanai, Mariko Hakoshima, Hiroki Adachi, et al.
Int J Mol Sci. 2021 Apr 23;22(9):4416. doi: 10.3390/ijms22094416.
Sodium glucose cotransporter 2 inhibitors (SGLT2i) block the reabsorption of glucose by inhibiting SGLT2, thus improving glucose control by promoting the renal excretion of glucose, without requiring insulin secretion. This pharmacological property of SGLT2i reduces body weight and improves insulin resistance in diabetic patients. Such beneficial metabolic changes caused by SGLT2i are expected to be useful not only for glucose metabolism, but also for the protection for various organs. Recent randomized controlled trials (RCTs) on cardiovascular diseases (EMPA-REG OUTCOME trial and CANVAS program) showed that SGLT2i prevented cardiovascular death and the development of heart failure. RCTs on renal events (EMPA-REG OUTCOME trial, CANVAS program, and CREDENCE trial) showed that SGLT2i suppressed the progression of kidney disease. Furthermore, SGLT2i effectively lowered the liver fat content, and our study demonstrated that SGLT2i reduced the degree of hepatic fibrosis in patients at high-risk of hepatic fibrosis. Such promising properties of SGLT2i for cardiovascular, renal, and hepatic protection provide us the chance to think about the underlying mechanisms for SGLT2i-induced improvement of multiple organs. SGLT2i have various mechanisms for organ protection beyond glucose-lowering effects, such as an increase in fatty acids utilization for hepatic protection, osmotic diuresis for cardiac protection, an improvement of insulin resistance for anti-atherogenesis, and an improvement of tubuloglomerular feedback for renal protection.
115Effects of dapagliflozin monotherapy and combined aerobic exercise on skeletal muscle mitochondrial quality control and insulin resistance in type 2 diabetes mellitus rats.PubMed
Liangzhi Zhang, Hengjun Lin, Xudong Yang, et al.
Biomed Pharmacother. 2023 Dec 31;169:115852. doi: 10.1016/j.biopha.2023.115852. Epub 2023 Nov 7.
Type 2 diabetes mellitus (T2DM) is a prevalent, chronic metabolic disease. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and aerobic exercise (AE) have shown promise in mitigating insulin resistance (IR) and T2DM. This study investigated the effects of dapagliflozin (Dapa) monotherapy and combined AE on mitochondrial quality control (MQC) in skeletal muscle and IR in T2DM rats. T2DM rats, induced by a high-fat diet/streptozotocin model, were randomly assigned to the following groups: T2DM+vehicle group (DMV), T2DM rats treated with Dapa (DMDa, 10 mg/kg/d), T2DM rats subjected to combined Dapa treatment and AE (DMDa+AE), and the standard control group (CON). Blood and skeletal muscle samples were collected after 6 weeks of intragastric administration and treadmill exercise. The results showed that DMDa monotherapy could reduce the accumulation of white adipose tissue and skeletal muscle lipid droplets and improve HOMA-IR. While the combined AE led to further reductions in subcutaneous white adipose tissue and fasting glucose levels, it did not confer additional benefits in terms of HOMA-IR. Furthermore, Dapa monotherapy enhanced skeletal muscle mitochondrial biogenesis (PGC-1α, NRF1, TFAM, and COX IV), mitochondrial dynamics (OPA1, DRP1, and MFN2), and mitophagy (PGAM5 and PINK1) related protein levels. Nevertheless, the combination of Dapa with AE treatment did not yield an additive effect. In conclusion, this study highlights the potential of SGLT2 inhibitors, specifically Dapa, in ameliorating IR and maintaining MQC in skeletal muscle in rats with T2DM. However, combined AE did not produce an additive effect, indicating the need for further research.
116Dapagliflozin improves skeletal muscle insulin sensitivity through SIRT1 activation induced by nutrient deprivation state.PubMed
Qi Gao, Yingying Jiang, Zhenqiang Song, et al.
Sci Rep. 2024 Jul 23;14(1):16878. doi: 10.1038/s41598-024-67755-7.
Lipid peroxidation and mitochondrial damage impair insulin sensitivity in skeletal muscle. Sirtuin-1 (SIRT1) protects mitochondria and activates under energy restriction. Dapagliflozin (Dapa) is an antihyperglycaemic agent that belongs to the sodium-glucose cotransporter-2 (SGLT2) inhibitors. Evidence shows that Dapa can induce nutrient deprivation effects, providing additional metabolic benefits. This study investigates whether Dapa can trigger nutrient deprivation to activate SIRT1 and enhance insulin sensitivity in skeletal muscle. We treated diet-induced obese (DIO) mice with Dapa and measured metabolic parameters, lipid accumulation, oxidative stress, mitochondrial function, and glucose utilization in skeletal muscle. β-hydroxybutyric acid (β-HB) was intervened in C2C12 myotubes. The role of SIRT1 was verified by RNA interference. We found that Dapa treatment induced nutrient deprivation state and reduced lipid deposition and oxidative stress, improved mitochondrial function and glucose tolerance in skeletal muscle. The same positive effects were observed after β-HB intervening for C2C12 myotubes, and the promoting effects on glucose utilization were diminished by SIRT1 RNA interference. Thus, Dapa promotes a nutrient deprivation state and enhances skeletal muscle insulin sensitivity via SIRT1 activation. In this study, we identified a novel hypoglycemic mechanism of Dapa and the potential mechanistic targets.
117Effect of Dapagliflozin on Myocardial Insulin Sensitivity and Perfusion: Rationale and Design of The DAPAHEART Trial.PubMed
Gian Pio Sorice, Francesca Cinti, Lucia Leccisotti, et al.
Diabetes Ther. 2021 Jul;12(7):2101-2113. doi: 10.1007/s13300-021-01083-1. Epub 2021 May 26.
INTRODUCTION: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been shown to have beneficial effects on various cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) in primary prevention and in those with a high CV risk profile. However, the mechanism(s) responsible for these CV benefits remain elusive and unexplained. The aim of the DAPAHEART study will be to demonstrate that treatment with SGLT-2 inhibitors is associated with greater myocardial insulin sensitivity in patients with T2D, and to determine whether this improvement can be attributed to a decrease in whole-body (and tissue-specific) insulin resistance and to increased myocardial perfusion and/or glucose uptake. We will also determine whether there is an appreciable degree of improvement in myocardial-wall conditions subtended by affected and non-affected coronary vessels, and if this relates to changes in left ventricular function. METHODS: The DAPAHEART trial will be a phase III, single-center, randomized, two-arm, parallel-group, double-blind, placebo-controlled study. A cohort of 52 T2D patients with stable coronary artery disease (without any previous history of myocardial infarction, with or without previous percutaneous coronary intervention), with suboptimal glycemic control (glycated hemoglobin [HbA1c] 7-8.5%) on their current standard of care anti-hyperglycemic regimen, will be randomized in a 1:1 ratio to dapagliflozin or placebo. The primary outcome is to detect changes in myocardial glucose uptake from baseline to 4 weeks after treatment initiation. The main secondary outcome will be changes in myocardial blood flow, as measured by N-ammonia positron emission tomography/computed tomography (PET/CT). Other outcomes include cardiac function, glucose uptake in skeletal muscle, adipose tissue, liver, brain and kidney, as assessed by fluorodeoxyglucose (FDG) PET-CT imaging during hyperinsulinemic-euglycemic clamp; pericardial, subcutaneous and visceral fat, and browning as observed on CT images during FDG PET-CT studies; systemic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp, glycemic control, urinary glucose output; and microbiota modification. DISCUSSION: SGLT-2 inhibitors, in addition to their insulin-independent plasma glucose-lowering effect, are able to directly (substrate availability, fuel utilization, insulin sensitivity) as well as indirectly (cardiac after-load reduction, decreased risk factors for heart failure) affect myocardial functions. Our study will provide novel insights into how these drugs exert CV protection in a diabetic population. TRIAL REGISTRATION: EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.
118Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection.PubMed
Yi-Chou Hou, Cai-Mei Zheng, Tzung-Hai Yen, et al.
Int J Mol Sci. 2020 Oct 22;21(21):7833. doi: 10.3390/ijms21217833.
The development of sodium-glucose transporter 2 inhibitor (SGLT2i) broadens the therapeutic strategies in treating diabetes mellitus. By inhibiting sodium and glucose reabsorption from the proximal tubules, the improvement in insulin resistance and natriuresis improved the cardiovascular mortality in diabetes mellitus (DM) patients. It has been known that SGLT2i also provided renoprotection by lowering the intraglomerular hypertension by modulating the pre- and post- glomerular vascular tone. The application of SGLT2i also provided metabolic and hemodynamic benefits in molecular aspects. The recent DAPA-CKD trial and EMPEROR-Reduced trial provided clinical evidence of renal and cardiac protection, even in non-DM patients. Therefore, the aim of the review is to clarify the hemodynamic and metabolic modulation of SGLT2i from the molecular mechanism.
119SGLT2 inhibition improves coronary flow velocity reserve and contractility: role of glucagon signaling.PubMed
Sven O Göpel, Damilola Adingupu, Jue Wang, et al.
Cardiovasc Diabetol. 2024 Nov 15;23(1):408. doi: 10.1186/s12933-024-02491-w.
BACKGROUND: SGLT2 inhibitors, a T2DM medication to lower blood glucose, markedly improve cardiovascular outcomes but the underlying mechanism(s) are not fully understood. SGLT2i's produce a unique metabolic pattern by lowering blood glucose without increasing insulin while increasing ketone body and glucagon levels and reducing body weight. We tested if glucagon signaling contributes to SGLT2i induced improvement in CV function. METHODS: Cardiac contractility and coronary flow velocity reserve (CFVR) were monitored in ob/ob mice and rhesus monkeys with metabolic syndrome using echocardiography. Metabolic status was characterized by measuring blood ketone levels, glucose tolerance during glucose challenge and Arg and ADMA levels were measured. Baysian models were developed to analyse the data. RESULTS: Dapagliflozin improved CFVR and contractility, co-application of a glucagon receptor inhibitor (GcgRi) blunted the effect on CFVR but not contractility. Dapagliflozin increased the Arg/ADMA ratio and ketone levels and co-treatment with GcgRi blunted only the Dapagliflozin induced increase in Arg/ADMA ratio but not ketone levels. CONCLUSIONS: Since GcgRi co-treatment only reduced the Arg/ADMA increase we hypothesize that dapagliflozin via a glucagon-signaling dependent pathway improves vascular function through the NO-signaling pathway leading to improved vascular function. Increase in ketone levels might be a contributing factor in SGLT2i induced contractility increase and does not require glucagon signaling.
120Multi-dimensional roles of sodium-glucose cotransporter 2 inhibitors: beyond hypoglycemic and cardiorenal protection.PubMed
Siyu Li, Yaqi Wang, Quan Gong
Front Endocrinol (Lausanne). 2025 Sep 29;16:1641699. doi: 10.3389/fendo.2025.1641699. eCollection 2025.
Sodium glucose cotransporter-2 inhibitors (SGLT2i) have been found to have a range of benefits, including improving obesity and insulin resistance, hyperuricemia, hypertension, hyperlipidemia, and other metabolic disorders. Initially used for the hypoglycemic effects, they are now found to benefit atherosclerotic cardiovascular disease and chronic kidney disease. Additionally, SGLT2i has been found to have multiple functions, such as improving liver metabolism, affecting brain function, protecting islet β cell function, anti-tumor, and affecting immune system function. This review provides an overview of the protective effects of SGLT2i on different organs and tissues, as well as the potential mechanisms underlying the functional improvement induced by SGLT2i in recent years.
121Targeting Features of the Metabolic Syndrome Through Sympatholytic Effects of SGLT2 Inhibition.PubMed
Lakshini Y Herat, Jennifer Matthews, Omar Azzam, et al.
Curr Hypertens Rep. 2022 Mar;24(3):67-74. doi: 10.1007/s11906-022-01170-z. Epub 2022 Mar 2.
PURPOSE OF REVIEW: The moderate glucose-lowering effect of sodium glucose co-transporter 2 (SGLT2) inhibitors is unlikely to explain SGLT2 inhibitor-mediated beneficial outcomes, and unravelling the underlying mechanisms is a high priority in the research community. Given the dominant pathophysiologic role of the sympathetic nervous system activation in conditions such as hypertension and perturbed glucose homeostasis, it is pertinent to postulate that SGLT2 inhibitors may exert their beneficial effects at least in part via sympathetic inhibition. RECENT FINDINGS: SGLT2 inhibitors have shown enormous potential to improve cardiovascular outcomes in patients with type 2 diabetes, and their therapeutic potential is currently being investigated in a range of associated comorbidities such as heart failure and chronic kidney disease. Indeed, recent experimental data in relevant animal models highlight a bidirectional interaction between sympathetic nervous system activation and SGLT2 expression, and this facilitates several of the features associated with SGLT2 inhibition observed in clinical trials including improved glucose metabolism, weight loss, increased diuresis, and lowering of blood pressure. Currently available data highlight the various levels of interaction between the sympathetic nervous system and SGLT2 expression and explores the potential for SGLT2 inhibition as a therapeutic strategy in conditions commonly characterised by sympathetic activation.
122Precision medicine and nucleotide-based therapeutics to treat steatotic liver disease.PubMed
Andrea Caddeo, Stefano Romeo
Clin Mol Hepatol. 2025 Feb;31(Suppl):S76-S93. doi: 10.3350/cmh.2024.0438. Epub 2024 Aug 5.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex multifactorial disease and becoming the leading cause of liver-related morbidity and mortality. MASLD spans from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), that may progress to cirrhosis and hepatocellular carcinoma (HCC). Genetic, metabolic, and environmental factors strongly contribute to the heterogeneity of MASLD. Lifestyle intervention and weight loss represent a viable treatment for MASLD. Moreover, Resmetirom, a thyroid hormone beta receptor agonist, has recently been approved for MASLD treatment. However, most individuals treated did not respond to this therapeutic, suggesting the need for a more tailored approach to treat MASLD. Oligonucleotide-based therapies, namely small-interfering RNA (siRNA) and antisense oligonucleotide (ASO), have been recently developed to tackle MASLD by reducing the expression of genes influencing MASH progression, such as PNPLA3 and HSD17B13. Here, we review the latest progress made in the synthesis and development of oligonucleotide-based agents targeting genetic determinants of MASH.
123Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population.PubMed
Jingjing Ding, Huaizheng Liu, Xiaoxun Zhang, et al.
Sci Transl Med. 2024 Nov 6;16(772):eadh9940. doi: 10.1126/scitranslmed.adh9940.
Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid-mTOR-FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.
124Obesity, diabetes, and inflammation: Pathophysiology and clinical implications.PubMed
Marc Y Donath, Daniel J Drucker
Immunity. 2025 Oct 14;58(10):2373-2382. doi: 10.1016/j.immuni.2025.09.011. Epub 2025 Oct 3.
Obesity and its related disorders, including type 2 diabetes and liver, kidney, and cardiovascular diseases, are now recognized as chronic inflammatory conditions. Here, we review the mechanisms underlying inflammation in these settings and how they may contribute to pathology. Nutrient excess triggers immune activation through pattern recognition receptors and the NLRP3 inflammasome, leading to interleukin (IL)-1β production and downstream cytokine cascades. Initially adaptive, this inflammation promotes tissue remodeling and metabolic compensation, but chronic activation contributes to insulin resistance, β cell dysfunction, and end-organ damage. We discuss the current therapeutic options, with a focus on glucagon-like peptide-1 (GLP-1) receptor agonists, which, alone or combined with additional bioactive moieties, exert notable anti-inflammatory effects. Some effects of GLP-1 medicines are independent of glucose control or weight loss, and they are attributed to direct signaling via the immune GLP-1 receptor (GLP-1R) and, indirectly, via central nervous system circuits. Understanding these mechanisms may unlock further therapeutic potential in chronic inflammatory diseases.
125Understanding and overcoming metformin gastrointestinal intolerance.PubMed
Fabrice Bonnet, André Scheen
Diabetes Obes Metab. 2017 Apr;19(4):473-481. doi: 10.1111/dom.12854. Epub 2017 Feb 22.
Metformin is the most widely prescribed drug for patients with type 2 diabetes mellitus and the first-line pharmacological option as supported by multiple international guidelines, yet a rather large proportion of patients cannot tolerate metformin in adequate amounts because of its associated gastrointestinal (GI) adverse events (AEs). GI AEs typically encountered with metformin therapy include diarrhoea, nausea, flatulence, indigestion, vomiting and abdominal discomfort, with diarrhoea and nausea being the most common. Although starting at a low dose and titrating slowly may help prevent some GI AEs associated with metformin, some patients are unable to tolerate metformin at all and it may also be difficult to convince patients to start metformin again after a bout of GI AEs. Despite this clinical importance, the underlying mechanisms of the GI intolerance associated with metformin are poorly known. In the present review, we discuss: the epidemiology of metformin-associated GI intolerance and its underlying mechanisms; genotype variability and associated factors affecting metformin GI intolerance, such as comorbidities, co-medications and bariatric surgery; clinical consequences and therapeutic strategies to overcome metformin GI intolerance. These strategies include appropriate titration of immediate-release metformin, use of extended-release metformin, the promise of delayed-release metformin and gut microbiome modulators, as well as alternative pharmacological therapies when metformin cannot be tolerated at all. Given the available data, all efforts should be made to maintain metformin before considering a shift to another drug therapy.
126Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with meta-regression of observational studies.PubMed
Katarzyna Nabrdalik, Mirela Hendel, Krzysztof Irlik, et al.
BMC Endocr Disord. 2024 Sep 30;24(1):206. doi: 10.1186/s12902-024-01727-w.
INTRODUCTION: Metformin is the most prescribed medication for type 2 diabetes mellitus (T2DM); there is a well-established link with the elevated incidence of gastrointestinal (GI) adverse events (AE) limiting its administration or intensification. OBJECTIVES: The objective of this systematic review and meta-analysis of observational studies was to evaluate the pooled incidence of GI AE related to metformin use in patients with T2DM. MATERIALS AND METHODS: PUB MED/CINAHL/Web of Science/Scopus were searched from database inception until 29.07.2024 for observational studies in English describing the frequency of GI AE in patients with T2DM treated with metformin. Random-effects meta-analyses were used to derive effect sizes: event rates. RESULTS: From 7019 publications, we identified 211 potentially eligible full-text articles. Ultimately, 21 observational studies were included in the meta-analysis. The prevalence of GI AE was as follows: diarrhea 6.9% (95% CI: 0.038-0.123), bloating 6,2% (95% CI: 0.020-0.177), abdominal pain 5,3% (95% CI: 0.003-0.529), vomiting 2.4% (95%: CI 0.007-0.075), constipation 1.1% (95%: CI 0.001-0.100). The incidence of bloating (coefficient -4.46; p < 0.001), diarrhea (coefficient -1.17; p = 0.0951) abdominal pain (coefficient -2.80; p = 0.001), constipation (coefficient -5.78; p = 0.0014) and vomiting (coefficient -2.47; p < 0.001) were lower for extended release (XR) metformin than metformin immediate release (IR) formulation. CONCLUSIONS: This study highlights the prevalence of GI AE in patients receiving metformin, with a diarrhea predominance, followed by bloating, diarrhea, abdominal pain, constipation, and vomiting. The incidence is lower in patients administered with XR metformin. TRIAL REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289975 , identifier CRD42021289975.
127Gastrointestinal adverse effects of old and new antidiabetics: How do we deal with them in real life?PubMed
J R Barrientos-Ávalos, E C Morel-Cerda, F A Félix-Téllez, et al.
Rev Gastroenterol Mex (Engl Ed). 2024 Oct-Dec;89(4):521-532. doi: 10.1016/j.rgmxen.2024.10.008. Epub 2024 Oct 24.
Diabetes is a public health problem with an estimated worldwide prevalence of 10% and a prevalence of 12% in Mexico. The costs resulting from this chronic-degenerative disease are significant. Treatment for diabetes involves different medication groups, some of which can cause significant gastrointestinal adverse effects, such as dyspepsia, nausea, vomiting, bloating, diarrhea, and constipation. The medications most frequently associated with said adverse effects are metformin, acarbose, and GLP-1 agonists. Gastrointestinal adverse effects negatively impact the quality of life and management of patients with diabetes. The factors of visceral neuropathy, acute dysglycemia, dysbiosis, and intestinal bacterial overgrowth contribute to the gastrointestinal symptoms in patients with diabetes, making it necessary to consider multiple etiologic factors in the presence of gastrointestinal symptoms, and not exclusively attribute them to the use of antidiabetics. Personalized treatment, considering gastrointestinal comorbidity and the type of drug utilized, is essential for mitigating the adverse effects and improving the quality of life in patients with diabetes. The aim of the present narrative review was to describe the gastrointestinal adverse effects of the antidiabetic drugs, their pathophysiologic mechanisms, and the corresponding therapeutic measures.
128Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes.PubMed
Ralph A DeFronzo, Silvio Inzucchi, Muhammad Abdul-Ghani, et al.
Diab Vasc Dis Res. 2019 Mar;16(2):133-143. doi: 10.1177/1479164118825376. Epub 2019 Feb 1.
Type 2 diabetes individuals are at high risk for macrovascular complications: myocardial infarction, stroke and cardiovascular mortality. Recent cardiovascular outcome trials have demonstrated that agents in two antidiabetic classes (SGLT2 inhibitors and GLP-1 receptor agonists) reduce major adverse cardiovascular events. However, there is strong evidence that an older and now generically available medication, the thiazolidinedione, pioglitazone, can retard the atherosclerotic process (PERISCOPE and Chicago) and reduce cardiovascular events in large randomized prospective cardiovascular outcome trials (IRIS and PROactive). Pioglitazone is a potent insulin sensitizer, preserves beta-cell function, causes durable reduction in HbA1c, corrects multiple components of metabolic syndrome and improves nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Adverse effects (weight gain, fluid retention, fractures) must be considered, but are diminished with lower doses and are arguably outweighed by these multiple benefits. With healthcare expenses attributable to diabetes increasing rapidly, this cost-effective drug requires reconsideration in the therapeutic armamentarium for the disease.
129Rosiglitazone.PubMed
B H Wolffenbuttel, J P Sels, M S Huijberts
Expert Opin Pharmacother. 2001 Mar;2(3):467-78. doi: 10.1517/14656566.2.3.467.
Type 2 diabetes mellitus is characterised by impaired insulin secretion, diminished peripheral insulin action and increased hepatic glucose production. Clinical trials have indicated that near-normal glucose control may reduce the risk for microvascular and - to a lesser extent - macrovascular complications in Type 2 diabetic patients. Thiazolidinediones improve insulin action by activating a nuclear receptor, PPARgamma. Therefore, these drugs are often referred to as 'insulin sensitisers'. Rosiglitazone is the second compound of this group. Clinical studies with rosiglitazone have shown that it is effective in lowering blood glucose levels in Type 2 diabetic patients treated with either diet alone, sulphonylurea or metformin. Preliminary studies suggest that rosiglitazone also improves glycaemic control in insulin-treated patients while even slightly decreasing insulin dose. The magnitude of the effects is, however, moderate. In diet-treated patients, the reduction of HbA1c levels amounted on average 0.5 - 1.5% and addition to existing sulphonylurea therapy decreased HbA1c by 1.0 - 1.2%. The clinical relevance of additional beneficial effects, i.e., on blood pressure and microalbuminuria, needs to be determined further. Rosiglitazone does not cause hypoglycaemia or gastrointestinal side effects. There is however some concern related to fluid retention, which seems to be an effect of all PPARgamma agonists. In patients treated with rosiglitazone, no severe hepatotoxic side effects have been noticed until now. In the treatment of our patients with Type 2 diabetes, drugs like rosiglitazone which directly reduce insulin resistance are very welcome but more data on its combined use with insulin are needed. Additional studies will also explore its long-term effects in sparing beta-cell function and reducing diabetes-related complications and atherosclerosis.
132Does Thiazolidinedione therapy exacerbate fluid retention in congestive heart failure?PubMed
Ilia Goltsman, Emad E Khoury, Joseph Winaver, et al.
Pharmacol Ther. 2016 Dec;168:75-97. doi: 10.1016/j.pharmthera.2016.09.007. Epub 2016 Sep 4.
The ever-growing global burden of congestive heart failure (CHF) and type 2 diabetes mellitus (T2DM) as well as their co-existence necessitate that anti-diabetic pharmacotherapy will modulate the cardiovascular risk inherent to T2DM while complying with the accompanying restrictions imposed by CHF. The thiazolidinedione (TZD) family of peroxisome proliferator-activated receptor γ (PPARγ) agonists initially provided a promising therapeutic option in T2DM owing to anti-diabetic efficacy combined with pleiotropic beneficial cardiovascular effects. However, the utility of TZDs in T2DM has declined in the past decade, largely due to concomitant adverse effects of fluid retention and edema formation attributed to salt-retaining effects of PPARγ activation on the nephron. Presumably, the latter effects are potentially deleterious in the context of pre-existing fluid retention in CHF. However, despite a considerable body of evidence on mechanisms responsible for TZD-induced fluid retention suggesting that this class of drugs is rightfully prohibited from use in CHF patients, there is a paucity of experimental and clinical studies that investigate the effects of TZDs on salt and water homeostasis in the CHF setting. In an attempt to elucidate whether TZDs actually exacerbate the pre-existing fluid retention in CHF, our review summarizes the pathophysiology of fluid retention in CHF. Moreover, we thoroughly review the available data on TZD-induced fluid retention and proposed mechanisms in animals and patients. Finally, we will present recent studies challenging the common notion that TZDs worsen renal salt and water retention in CHF.
133PPARγ deacetylation dissociates thiazolidinedione's metabolic benefits from its adverse effects.PubMed
Michael J Kraakman, Qiongming Liu, Jorge Postigo-Fernandez, et al.
J Clin Invest. 2018 Jun 1;128(6):2600-2612. doi: 10.1172/JCI98709. Epub 2018 May 14.
Thiazolidinediones (TZDs) are PPARγ agonists with potent insulin-sensitizing effects. However, their use has been curtailed by substantial adverse effects on weight, bone, heart, and hemodynamic balance. TZDs induce the deacetylation of PPARγ on K268 and K293 to cause the browning of white adipocytes. Here, we show that targeted PPARγ mutations resulting in constitutive deacetylation (K268R/K293R, 2KR) increased energy expenditure and protected from visceral adiposity and diet-induced obesity by augmenting brown remodeling of white adipose tissues. Strikingly, when 2KR mice were treated with rosiglitazone, they maintained the insulin-sensitizing, glucose-lowering response to TZDs, while displaying little, if any, adverse effects on fat deposition, bone density, fluid retention, and cardiac hypertrophy. Thus, deacetylation appears to fulfill the goal of dissociating the metabolic benefits of PPARγ activation from its adverse effects. Strategies to leverage PPARγ deacetylation may lead to the design of safer, more effective agonists of this nuclear receptor in the treatment of metabolic diseases.
134Long-Term Efficacy and Safety of Nutritional and Pharmacological Strategies for Obesity.PubMed
Luigi Barrea, Mara Boschetti, Elena Gangitano, et al.
Curr Obes Rep. 2025 Jan 3;14(1):1. doi: 10.1007/s13679-024-00602-y.
PURPOSE OF REVIEW: This review examines the long-term efficacy and safety of various nutritional and pharmacological strategies for managing obesity. The focus is on the Mediterranean diet (MedDiet), very low-energy ketogenic therapy (VLEKT), and pharmacological interventions such as naltrexone/bupropion and liraglutide. Given the chronic nature of obesity, understanding the sustainability and impact of these treatments over time is critical. RECENT FINDINGS: The MedDiet has shown significant benefits for cardiovascular health and moderate long-term weight loss, though it does not always outperform other diets in terms of weight reduction. VLEKT is highly effective for rapid weight loss, but concerns remain about its long-term sustainability. Pharmacological treatments, including naltrexone/bupropion and liraglutide, have shown promise in promoting significant weight loss and improving metabolic markers. However, issues related to long-term adherence and potential side effects need further exploration. Both nutritional and pharmacological strategies offer valuable tools in obesity management. While treatments like VLEKT and pharmacological options provide significant short-term benefits, the MedDiet remains a sustainable long-term approach. The long-term efficacy and safety of naltrexone/bupropion and liraglutide require more investigation to address challenges in weight maintenance and side effects. Further studies are needed to establish the optimal duration and combination of these therapies for sustained obesity management.
135Investigating the experiences of low-carbohydrate diets for people living with Type 2 Diabetes: A thematic analysis.PubMed
Lisa Newson, Francesca Helen Parody
PLoS One. 2022 Aug 22;17(8):e0273422. doi: 10.1371/journal.pone.0273422. eCollection 2022.
Low-Carbohydrate Diets (LCDs) are becoming increasingly popular to manage Type 2 diabetes mellitus (T2DM). However, there is a need to identify people with T2DM's understanding of LCDs, their reasons for engaging in such a diet, how they sustain it and any challenges they face. This study aimed to assess the experience of adhering to a LCD within a sample of individuals with T2DM. Ten participants with T2DM were recruited using a self-selecting sampling method from an online diabetes community that promotes LCDs. Participants completed one-to-one digitally recorded semi-structured interviews, which were later transcribed verbatim and data subjected to Thematic Analysis. Five core themes and twelve subthemes were developed during the analysis: (1) Lack of professional guidance; (2) Fear of complications & long-term medication use; (3) Dietary control as motivation; (4) Positive health outcomes; and (5) Social support. The findings are discussed with reference to a psychological model of behaviour, COM-B. Participants reported gaining knowledge and skills to increase their Capability to engage in LCDs, Motivation to manage diabetes outcomes influenced adherence. However, challenges were reported with the Opportunity to engage in behaviour, mainly influenced by social support. Health professionals and significant others may benefit from resources to help build knowledge and understanding and assist with maintaining a LCD long-term.
136Ketogenic Diet Intervention for Obesity Weight-Loss- A Narrative Review, Challenges, and Open Questions.PubMed
Adina Bachar, Ruth Birk
Curr Nutr Rep. 2025 Mar 8;14(1):43. doi: 10.1007/s13668-025-00634-3.
PURPOSE OF REVIEW: The ketogenic diet (KD) has gained clinical attention for its potential benefits in weight loss and metabolic syndrome. By mimicking fasting through carbohydrate (CHO) restriction, KD shifts energy utilization to ketone bodies (KB) instead of glucose. Despite promising results, the effects on different weight loss indicators remain controversial, with challenges in monitoring adherence standards, optimal macronutrient composition, potential risks, and long-term sustainability. This article aims to review the different weight-loss outcomes of KD interventions for obesity, monitored by KB (adherence indication). RECENT FINDINGS: Current literature on KD interventions for obesity weight loss monitored by KB show reduction in different outcomes, including body weight, body mass index, waist circumference, visceral adipose tissue, fat mass, and body fat percentage. Minor decreases in lean body mass and skeletal muscle mass were noted without resistance training. Variability existed in adherence (KB markers), CHO intake (7-27% of daily energy), diet duration (28 days to 12 months), and follow-up frequency (weekly to biannual). KD, particularly accompanied by exercise, positively influenced appetite regulation. KD interventions improves weight-related outcomes in participants with obesity but presents challenges in lean body mass reduction without resistance training and adherence variability. Standardizing methodologies, refining interventions and suitability to sub-populations, setting KB markers, and defining clinical relevance are essential for optimizing KD effectiveness.
137Efficient and safe in vivo treatment of primary hyperoxaluria type 1 via LNP-CRISPR-Cas9-mediated glycolate oxidase disruption.PubMed
Yanhong Jiang, Shuanghong Chen, Shenlin Hsiao, et al.
Mol Ther. 2025 Jan 8;33(1):104-118. doi: 10.1016/j.ymthe.2024.10.003. Epub 2024 Oct 9.
Primary hyperoxaluria type 1 (PH1) is a severe genetic metabolic disorder caused by mutations in the AGXT gene, leading to defects in enzymes crucial for glyoxylate metabolism. PH1 is characterized by severe, potentially life-threatening manifestations due to excessive oxalate accumulation, which leads to calcium oxalate crystal deposits in the kidneys and, ultimately, renal failure and systemic oxalosis. Existing substrate reduction therapies, such as inhibition of liver-specific glycolate oxidase (GO) encoded by HAO1 using siRNA or CRISPR-Cas9 delivered by adeno-associated virus, either require repeated dosing or have raised safety concerns. To address these limitations, our study employed lipid nanoparticles (LNPs) for CRISPR-Cas9 delivery to rapidly generate a PH1 mouse model and validate the therapeutic efficacy of LNP-CRISPR-Cas9 targeting the Hao1 gene. The LNP-CRISPR-Cas9 system exhibited efficient editing of the Hao1 gene, significantly reducing GO expression and lowering urinary oxalate levels in treated PH1 mice. Notably, these effects persisted for 12 months with no significant off-target effects, liver-induced toxicity, or substantial immune responses, highlighting the approach's safety and specificity. Furthermore, the developed humanized mouse model validated the efficacy of our therapeutic strategy. These findings support LNP-CRISPR-Cas9 targeting HAO1 as a promising and safer alternative for PH1 treatment with a single administration.
138RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies.PubMed
Gavin M Traber, Ai-Ming Yu
J Pharmacol Exp Ther. 2023 Jan;384(1):133-154. doi: 10.1124/jpet.122.001234. Epub 2022 Jun 9.
RNA interference (RNAi) provides researchers with a versatile means to modulate target gene expression. The major forms of RNAi molecules, genome-derived microRNAs (miRNAs) and exogenous small interfering RNAs (siRNAs), converge into RNA-induced silencing complexes to achieve posttranscriptional gene regulation. RNAi has proven to be an adaptable and powerful therapeutic strategy where advancements in chemistry and pharmaceutics continue to bring RNAi-based drugs into the clinic. With four siRNA medications already approved by the US Food and Drug Administration (FDA), several RNAi-based therapeutics continue to advance to clinical trials with functions that closely resemble their endogenous counterparts. Although intended to enhance stability and improve efficacy, chemical modifications may increase risk of off-target effects by altering RNA structure, folding, and biologic activity away from their natural equivalents. Novel technologies in development today seek to use intact cells to yield true biologic RNAi agents that better represent the structures, stabilities, activities, and safety profiles of natural RNA molecules. In this review, we provide an examination of the mechanisms of action of endogenous miRNAs and exogenous siRNAs, the physiologic and pharmacokinetic barriers to therapeutic RNA delivery, and a summary of the chemical modifications and delivery platforms in use. We overview the pharmacology of the four FDA-approved siRNA medications (patisiran, givosiran, lumasiran, and inclisiran) as well as five siRNAs and several miRNA-based therapeutics currently in clinical trials. Furthermore, we discuss the direct expression and stable carrier-based, in vivo production of novel biologic RNAi agents for research and development. SIGNIFICANCE STATEMENT: In our review, we summarize the major concepts of RNA interference (RNAi), molecular mechanisms, and current state and challenges of RNAi drug development. We focus our discussion on the pharmacology of US Food and Drug Administration-approved RNAi medications and those siRNAs and miRNA-based therapeutics that entered the clinical investigations. Novel approaches to producing new true biological RNAi molecules for research and development are highlighted.
139-targeting miR-agshRNAs combine efficacy with specificity and safety for retinal gene therapy.PubMed
Sidsel Alsing, Thomas Koed Doktor, Anne Louise Askou, et al.
Mol Ther Nucleic Acids. 2022 Feb 28;28:58-76. doi: 10.1016/j.omtn.2022.02.019. eCollection 2022 Jun 14.
Retinal gene therapy using RNA interference (RNAi) to silence targeted genes requires both efficacy and safety. Short hairpin RNAs (shRNAs) are useful for RNAi, but high expression levels and activity from the co-delivered passenger strand may cause undesirable cellular responses. Ago2-dependent shRNAs (agshRNAs) produce no passenger strand activity. To enhance efficacy and to investigate improvements in safety, we have generated -targeting agshRNAs and microRNA (miRNA)-embedded agshRNAs (miR-agshRNAs) and inserted these RNAi effectors in Pol II/III-driven expression cassettes and lentiviral vectors (LVs). Compared with corresponding shRNAs, agshRNAs and miR-agshRNAs increased specificity and safety, while retaining a high knockdown efficacy and abolishing passenger strand activity. The agshRNAs also caused significantly smaller reductions in cell viability and reduced competition with the processing of endogenous miR21 compared with their shRNA counterparts. RNA sequencing (RNA-seq) analysis of LV-transduced ARPE19 cells revealed that expression of shRNAs in general leads to more changes in gene expression levels compared with their agshRNA counterparts and activation of immune-related pathways. In mice, subretinal delivery of LVs encoding tissue-specific miR-agshRNAs resulted in retinal pigment epithelium (RPE)-restricted expression and significant knockdown of in transduced RPE cells. Collectively, our data suggest that agshRNAs and miR-agshRNA possess important advantages over shRNAs, thereby posing a clinically relevant approach with respect to efficacy, specificity, and safety.
140Alleviation of off-target effects from vector-encoded shRNAs via codelivered RNA decoys.PubMed
Stefan Mockenhaupt, Stefanie Grosse, Daniel Rupp, et al.
Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):E4007-16. doi: 10.1073/pnas.1510476112. Epub 2015 Jul 13.
Exogenous RNAi triggers such as shRNAs ideally exert their activities exclusively via the antisense strand that binds and silences designated target mRNAs. However, in principle, the sense strand also possesses silencing capacity that may contribute to adverse RNAi side effects including off-target gene regulation. Here, we address this concern with a novel strategy that reduces sense strand activity of vector-encoded shRNAs via codelivery of inhibitory tough decoy (TuD) RNAs. Using various shRNAs for proof of concept, we validate that coexpression of TuDs can sequester and inactivate shRNA sense strands in human cells selectively without affecting desired antisense activities from the same shRNAs. Moreover, we show how coexpressed TuDs can alleviate shRNA-mediated perturbation of global gene expression by specifically de-repressing off-target transcripts carrying seed matches to the shRNA sense strand. Our combination of shRNA and TuD in a single bicistronic gene transfer vector derived from Adeno-associated virus (AAV) enables a wide range of applications, including gene therapies. To this end, we engineered our constructs in a modular fashion and identified simple hairpin design rules permitting adaptation to preexisting or new shRNAs. Finally, we demonstrate the power of our vectors for combinatorial RNAi strategies by showing robust suppression of hepatitis C virus (HCV) with an AAV expressing a bifunctional TuD against an anti-HCV shRNA sense strand and an HCV-related cellular miRNA. The data and tools reported here represent an important step toward the next generation of RNAi triggers with increased specificity and thus ultimately safety in humans.
141Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis.PubMed
Piero Portincasa, Leonilde Bonfrate, Mirco Vacca, et al.
Int J Mol Sci. 2022 Jan 20;23(3):1105. doi: 10.3390/ijms23031105.
Gut microbiota encompasses a wide variety of commensal microorganisms consisting of trillions of bacteria, fungi, and viruses. This microbial population coexists in symbiosis with the host, and related metabolites have profound effects on human health. In this respect, gut microbiota plays a pivotal role in the regulation of metabolic, endocrine, and immune functions. Bacterial metabolites include the short chain fatty acids (SCFAs) acetate (C2), propionate (C3), and butyrate (C4), which are the most abundant SCFAs in the human body and the most abundant anions in the colon. SCFAs are made from fermentation of dietary fiber and resistant starch in the gut. They modulate several metabolic pathways and are involved in obesity, insulin resistance, and type 2 diabetes. Thus, diet might influence gut microbiota composition and activity, SCFAs production, and metabolic effects. In this narrative review, we discuss the relevant research focusing on the relationship between gut microbiota, SCFAs, and glucose metabolism.
142Gut microbial metabolites in obesity, NAFLD and T2DM.PubMed
Emanuel E Canfora, Ruth C R Meex, Koen Venema, et al.
Nat Rev Endocrinol. 2019 May;15(5):261-273. doi: 10.1038/s41574-019-0156-z.
Evidence is accumulating that the gut microbiome is involved in the aetiology of obesity and obesity-related complications such as nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes mellitus (T2DM). The gut microbiota is able to ferment indigestible carbohydrates (for example, dietary fibre), thereby yielding important metabolites such as short-chain fatty acids and succinate. Numerous animal studies and a handful of human studies suggest a beneficial role of these metabolites in the prevention and treatment of obesity and its comorbidities. Interestingly, the more distal colonic microbiota primarily ferments peptides and proteins, as availability of fermentable fibre, the major energy source for the microbiota, is limited here. This proteolytic fermentation yields mainly harmful products such as ammonia, phenols and branched-chain fatty acids, which might be detrimental for host gut and metabolic health. Therefore, a switch from proteolytic to saccharolytic fermentation could be of major interest for the prevention and/or treatment of metabolic diseases. This Review focuses on the role of products derived from microbial carbohydrate and protein fermentation in relation to obesity and obesity-associated insulin resistance, T2DM and NAFLD, and discusses the mechanisms involved.
143Targeting the gut microbiota and its metabolites for type 2 diabetes mellitus.PubMed
Jiaqiang Wu, Kangping Yang, Hancheng Fan, et al.
Front Endocrinol (Lausanne). 2023 May 9;14:1114424. doi: 10.3389/fendo.2023.1114424. eCollection 2023.
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance. The incidence of T2DM is increasing globally, and a growing body of evidence suggests that gut microbiota dysbiosis may contribute to the development of this disease. Gut microbiota-derived metabolites, including bile acids, lipopolysaccharide, trimethylamine-N-oxide, tryptophan and indole derivatives, and short-chain fatty acids, have been shown to be involved in the pathogenesis of T2DM, playing a key role in the host-microbe crosstalk. This review aims to summarize the molecular links between gut microbiota-derived metabolites and the pathogenesis of T2DM. Additionally, we review the potential therapy and treatments for T2DM using probiotics, prebiotics, fecal microbiota transplantation and other methods to modulate gut microbiota and its metabolites. Clinical trials investigating the role of gut microbiota and its metabolites have been critically discussed. This review highlights that targeting the gut microbiota and its metabolites could be a potential therapeutic strategy for the prevention and treatment of T2DM.
144Treadmill exercise induces age-related changes in aversive memory, neuroinflammatory and epigenetic processes in the rat hippocampus.PubMed
Gisele Agustini Lovatel, Viviane Rostirola Elsner, Karine Bertoldi, et al.
Neurobiol Learn Mem. 2013 Mar;101:94-102. doi: 10.1016/j.nlm.2013.01.007. Epub 2013 Jan 26.
It has been described that exercise can modulate both inflammatory response and epigenetic modifications, although the effect of exercise on these parameters during the normal brain aging process yet remains poorly understood. Here, we investigated the effect of aging and treadmill exercise on inflammatory and epigenetic parameters specifically pro and anti-inflammatory cytokines levels, activation of NF-kB and histone H4 acetylation levels in hippocampus from Wistar rats. Additionally, we evaluated aversive memory through inhibitory avoidance task. Rats of 3 and 20 months of age were assigned to non-exercised (sedentary) and exercised (running daily for 20 min for 2 weeks) groups. The effect of daily forced exercise in the treadmill was assessed. The levels of inflammatory and epigenetic parameters were determined 1h, 18 h, 3 days or 7 days after the last training session of exercise. It was observed an age-related decline on aversive memory, as well as aged rats showed increased hippocampal levels of inflammatory markers, such as TNFα, IL1-β and NF-kB and decreased IL-4 levels, an anti-inflammatory cytokine. Moreover, lower levels of global histone H4 acetylation were also observed in hippocampi from aged rats. Interestingly, there was a significant correlation between the biochemical markers and the inhibitory avoidance test performance. The forced exercise protocol ameliorated aging-related memory decline, decreased pro-inflammatory markers and increased histone H4 acetylation levels in hippocampi 20-months-old rats, while increased acutely IL-4 levels in hippocampi from young adult rats. Together, these results suggest that an imbalance of inflammatory markers might be involved to the aging-related aversive memory impairment. Additionally, our exercise protocol may reverse aging-related memory decline through improving cytokine profile.
145Treadmill exercise alters histone acetylation differently in rats exposed or not exposed to aversive learning context.PubMed
Louisiana Carolina Ferreira de Meireles, Karine Bertoldi, Viviane Rostirola Elsner, et al.
Neurobiol Learn Mem. 2014 Dec;116:193-6. doi: 10.1016/j.nlm.2014.10.008. Epub 2014 Nov 1.
Epigenetic modifications have been linked to memory formation after learning context exposure and to exercise effects on memory performance. The aim of this study was to investigate the effect of treadmill exercise (20 min/day during 2 weeks) on H3K14 acetylation and H3S10 phosphorylation levels in the hippocampi of 3-month-old Wistar rats exposed and not exposed to aversive learning context. Male Wistar rats aged 2-3 months were assigned to non-exercised (sedentary) and exercised (running daily for 20 min for 2 weeks) groups. Single-trial step-down inhibitory avoidance (IA) conditioning was employed as an aversive memory model. Epigenetic parameters were determined 30 min after the IA test. A decrease in the H3K14 acetylation in the hippocampus 24 h after IA training (30 min after test session) was observed. Exercise reversed the IA effect, and no effect was observed in the non-IA exposed group. Our data support the hypothesis that modulation of H3K14 acetylation levels in the hippocampus might be related, at least in part, to exercise effects on aversive memory.
146Mitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis.PubMed
Mark V Pinti, Garrett K Fink, Quincy A Hathaway, et al.
Am J Physiol Endocrinol Metab. 2019 Feb 1;316(2):E268-E285. doi: 10.1152/ajpendo.00314.2018. Epub 2019 Jan 2.
Type 2 diabetes mellitus (T2DM) is a systemic disease characterized by hyperglycemia, hyperlipidemia, and organismic insulin resistance. This pathological shift in both circulating fuel levels and energy substrate utilization by central and peripheral tissues contributes to mitochondrial dysfunction across organ systems. The mitochondrion lies at the intersection of critical cellular pathways such as energy substrate metabolism, reactive oxygen species (ROS) generation, and apoptosis. It is the disequilibrium of these processes in T2DM that results in downstream deficits in vital functions, including hepatocyte metabolism, cardiac output, skeletal muscle contraction, β-cell insulin production, and neuronal health. Although mitochondria are known to be susceptible to a variety of genetic and environmental insults, the accumulation of mitochondrial DNA (mtDNA) mutations and mtDNA copy number depletion is helping to explain the prevalence of mitochondrial-related diseases such as T2DM. Recent work has uncovered novel mitochondrial biology implicated in disease progressions such as mtDNA heteroplasmy, noncoding RNA (ncRNA), epigenetic modification of the mitochondrial genome, and epitranscriptomic regulation of the mtDNA-encoded mitochondrial transcriptome. The goal of this review is to highlight mitochondrial dysfunction observed throughout major organ systems in the context of T2DM and to present new ideas for future research directions based on novel experimental and technological innovations in mitochondrial biology. Finally, the field of mitochondria-targeted therapeutics is discussed, with an emphasis on novel therapeutic strategies to restore mitochondrial homeostasis in the setting of T2DM.
147Personalized nutrition in type 2 diabetes remission: application of digital twin technology for predictive glycemic control.PubMed
Paramesh Shamanna, Shashank Joshi, Mohamed Thajudeen, et al.
Front Endocrinol (Lausanne). 2024 Nov 20;15:1485464. doi: 10.3389/fendo.2024.1485464. eCollection 2024.
BACKGROUND: Type 2 Diabetes (T2D) is a complex condition marked by insulin resistance and beta-cell dysfunction. Traditional dietary interventions, such as low-calorie or low-carbohydrate diets, typically overlook individual variability in postprandial glycemic responses (PPGRs), which can lead to suboptimal management of the disease. Recent advancements suggest that personalized nutrition, tailored to individual metabolic profiles, may enhance the effectiveness of T2D management. OBJECTIVE: This study aims to present the development and application of a Digital Twin (DT) technology-a machine learning (ML)-powered platform designed to predict and modulate PPGRs in T2D patients. By integrating continuous glucose monitoring (CGM), dietary data, and other physiological inputs, the DT provides individualized dietary recommendations to improve insulin sensitivity, reduce hyperinsulinemia, and support the remission of T2D. METHODS: We developed a sophisticated DT platform that synthesizes real-time data from CGM, dietary logs, and other biometric inputs to create personalized metabolic models for T2D patients. The intervention is delivered via a mobile application, which dynamically adjusts dietary recommendations based on predicted PPGRs. This methodology is validated through a randomized controlled trial (RCT) assessing its impact on various metabolic markers, including HbA1c, metabolic-associated fatty liver disease (MAFLD), blood pressure, body weight, ASCVD risk, albuminuria, and diabetic retinopathy. RESULTS: Preliminary data from the ongoing RCT and real-world study demonstrate the DT's capacity to generate significant improvements in glycemic control and metabolic health. The DT-driven personalized nutrition plan has been associated with reductions in HbA1c, enhanced beta-cell function, and normalization of hyperinsulinemia, supporting sustained T2D remission. Additionally, the DT's predictions have contributed to improvements in MAFLD markers, blood pressure, and cardiovascular risk factors, highlighting its potential as a comprehensive management tool. CONCLUSION: The DT technology represents a novel and scalable approach to personalized nutrition in T2D management. By addressing individual variability in PPGRs, this method offers a promising alternative to conventional dietary interventions, with the potential to improve long-term outcomes and reduce the global burden of T2D.
148The research progress and future directions in the pathophysiological mechanisms of type 2 diabetes mellitus from the perspective of precision medicine.PubMed
Xinyi Tian, Liuqing Wang, Liuting Zhong, et al.
Front Med (Lausanne). 2025 Mar 5;12:1555077. doi: 10.3389/fmed.2025.1555077. eCollection 2025.
Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by pathophysiological mechanisms such as insulin resistance and -cell dysfunction. Recent advancements in T2DM research have unveiled intricate multi-level regulatory networks and contributing factors underlying this disease. The emergence of precision medicine has introduced new perspectives and methodologies for understanding T2DM pathophysiology. A recent study found that personalized treatment based on genetic, metabolic, and microbiome data can improve the management of T2DM by more than 30%. This perspective aims to summarize the progress in T2DM pathophysiological research from the past 5 years and to outline potential directions for future studies within the framework of precision medicine. T2DM develops through the interplay of factors such as gut microbiota, genetic and epigenetic modifications, metabolic processes, mitophagy, NK cell activity, and environmental influences. Future research should focus on understanding insulin resistance, -cell dysfunction, interactions between gut microbiota and their metabolites, and the regulatory roles of miRNA and genes. By leveraging artificial intelligence and integrating data from genomics, epigenomics, metabolomics, and microbiomics, researchers can gain deeper insights into the pathophysiological mechanisms and heterogeneity of T2DM. Additionally, exploring the combined effects and interactions of these factors may pave the way for more effective prevention strategies and personalized treatments for T2DM.
149Machine learning of plasma metabolome identifies biomarker panels for metabolic syndrome: findings from the China Suboptimal Health Cohort.PubMed
Hao Wang, Youxin Wang, Xingang Li, et al.
Cardiovasc Diabetol. 2022 Dec 23;21(1):288. doi: 10.1186/s12933-022-01716-0.
BACKGROUND: Metabolic syndrome (MetS) has been proposed as a clinically identifiable high-risk state for the prediction and prevention of cardiovascular diseases and type 2 diabetes mellitus. As a promising "omics" technology, metabolomics provides an innovative strategy to gain a deeper understanding of the pathophysiology of MetS. The study aimed to systematically investigate the metabolic alterations in MetS and identify biomarker panels for the identification of MetS using machine learning methods. METHODS: Nuclear magnetic resonance-based untargeted metabolomics analysis was performed on 1011 plasma samples (205 MetS patients and 806 healthy controls). Univariate and multivariate analyses were applied to identify metabolic biomarkers for MetS. Metabolic pathway enrichment analysis was performed to reveal the disturbed metabolic pathways related to MetS. Four machine learning algorithms, including support vector machine (SVM), random forest (RF), k-nearest neighbor (KNN), and logistic regression were used to build diagnostic models for MetS. RESULTS: Thirteen significantly differential metabolites were identified and pathway enrichment revealed that arginine, proline, and glutathione metabolism are disturbed metabolic pathways related to MetS. The protein-metabolite-disease interaction network identified 38 proteins and 23 diseases are associated with 10 MetS-related metabolites. The areas under the receiver operating characteristic curve of the SVM, RF, KNN, and logistic regression models based on metabolic biomarkers were 0.887, 0.993, 0.914, and 0.755, respectively. CONCLUSIONS: The plasma metabolome provides a promising resource of biomarkers for the predictive diagnosis and targeted prevention of MetS. Alterations in amino acid metabolism play significant roles in the pathophysiology of MetS. The biomarker panels and metabolic pathways could be used as preventive targets in dealing with cardiometabolic diseases related to MetS.
150Breath biomarkers of insulin resistance in pre-diabetic Hispanic adolescents with obesity.PubMed
Mohammad S Khan, Suzanne Cuda, Genesio M Karere, et al.
Sci Rep. 2022 Jan 10;12(1):339. doi: 10.1038/s41598-021-04072-3.
Insulin resistance (IR) affects a quarter of the world's adult population and is a major factor in the pathogenesis of cardio-metabolic disease. In this pilot study, we implemented a non-invasive breathomics approach, combined with random forest machine learning, to investigate metabolic markers from obese pre-diabetic Hispanic adolescents as indicators of abnormal metabolic regulation. Using the ReCIVA breathalyzer device for breath collection, we have identified a signature of 10 breath metabolites (breath-IR model), which correlates with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (R = 0.95, p < 0.001). A strong correlation was also observed between the breath-IR model and the blood glycemic profile (fasting insulin R = 0.91, p < 0.001 and fasting glucose R = 0.80, p < 0.001). Among tentatively identified metabolites, limonene, undecane, and 2,7-dimethyl-undecane, significantly cluster individuals based on HOMA-IR (p = 0.003, p = 0.002, and p < 0.001, respectively). Our breath-IR model differentiates between adolescents with and without IR with an AUC-ROC curve of 0.87, after cross-validation. Identification of a breath signature indicative of IR shows utility of exhaled breath metabolomics for assessing systemic metabolic dysregulation. A simple and non-invasive breath-based test has potential as a diagnostic tool for monitoring IR progression, allowing for earlier detection of IR and implementation of early interventions to prevent onset of type 2 diabetes mellitus.