1. 糖尿病神经病变的病理基础与临床特征
1.1 病理机制概述
糖尿病神经病变（Diabetic Neuropathy, DN）是糖尿病常见的并发症，其发病机制复杂且多样，主要涉及高血糖引起的多种代谢通路异常和继发性损伤。高血糖被认为是DN发生的中心环节 12。
其中，氧化应激是高血糖介导神经损伤的关键机制之一 134。长期高血糖导致活性氧（ROS）生成过多，超过机体抗氧化防御系统的清除能力，从而引起氧化还原失衡。过量的ROS会攻击神经细胞的DNA、蛋白质和脂质，导致神经传导速度下降、髓鞘结构受损以及神经功能障碍 3。例如，在2型糖尿病小鼠模型中，高血糖可通过激活CYP4A/20-HETE/AMPK通路引发氧化损伤和周围神经损害 4。
多元醇通路激活是高血糖诱导神经损伤的另一个重要途径 2567。在高血糖状态下，过多的葡萄糖通过醛糖还原酶（Aldose Reductase, AR）转化为山梨醇。这一过程消耗大量的NADPH，从而减少还原型谷胱甘肽的生成，进一步加剧氧化应激。山梨醇在细胞内蓄积还会导致渗透压升高，引起细胞肿胀和功能障碍 6。研究表明，抑制醛糖还原酶可作为治疗糖尿病并发症的潜在药理学手段 5。
晚期糖基化终末产物（Advanced Glycation End-products, AGEs）积累也是DN病理过程中的重要驱动因素 7891011。AGEs是葡萄糖或其他糖类衍生物与蛋白质、脂质或核酸非酶促糖基化反应的产物。在高血糖环境下，AGEs的形成速度加快并在神经组织中大量积累 1011。AGEs可通过多种机制损伤神经，包括与受体（RAGE）结合激活信号通路，导致炎症反应和氧化应激，以及通过形成交联改变蛋白质结构和功能，最终导致神经细胞死亡和神经血管损伤 911。
此外，神经血管缺血也在DN的进展中发挥作用 27。糖尿病可导致微血管病变，包括内皮功能障碍、血管壁增厚和管腔狭窄，从而减少神经组织的血供，引起神经缺氧和营养不足，进一步加重神经损伤。
炎症因子介导的神经损伤同样不容忽视 1。高血糖和某些其他病理因素可激活免疫细胞，释放促炎细胞因子。这些炎症因子可损伤神经元和支持细胞，加速神经病变的发生发展 1。这些多方面的病理机制相互关联，共同促成了糖尿病神经病变的复杂临床表现 17。
1.2 临床表现与评估指标
糖尿病神经病变（DN）的临床表现多样，可影响感觉神经、运动神经和自主神经系统，其症状的出现和严重程度与病程、血糖控制水平以及其他并发症密切相关 12。
感觉异常是最常见的临床表现之一。患者常感到肢体远端（尤其下肢）的麻木、刺痛、灼烧感或疼痛 12。这种感觉异常通常呈“手套-袜套样”分布，即从肢体末端逐渐向近端蔓延 12。有时，患者可能出现感觉迟钝，对温度、触觉和疼痛的感知能力下降，从而增加受伤的风险。约30-40%的DN患者会伴有神经性疼痛，这严重影响患者的生活质量 12。
运动功能障碍表现为肌肉无力、萎缩，以及步态不稳。这主要是由于运动神经受损导致，尽管不如感觉神经受损普遍，但其对患者日常活动能力的影响较大。
自主神经症状是DN的另一重要组成部分，涉及多个器官系统，并且通常比躯体神经病变更难以诊断和管理 13。常见的自主神经症状包括：
- 心血管自主神经病变（CAN）：可表现为静息性心动过速、运动不耐受、直立性低血压（体位性低血压）等 1314。CAN与心血管疾病风险和死亡率增加密切相关 1415。
- 胃肠功能紊乱：例如糖尿病性胃轻瘫，表现为餐后饱胀、恶心、呕吐、食欲不振等 1316。其他还包括便秘、腹泻或便秘腹泻交替等 13。
- 泌尿生殖系统功能障碍：如神经源性膀胱，导致排尿困难、尿潴留、尿失禁以及反复尿路感染 1317。男性患者还可能出现勃起功能障碍 13。
- 体温调节和出汗异常：表现为出汗减少或无汗症，尤其在肢体远端，可能导致皮肤干燥、皲裂，增加感染风险 13。
评估指标对于DN的诊断和监测至关重要。常用的客观评估方法包括：
- 神经传导速度（Nerve Conduction Velocity, NCV）：通过测量神经冲动在感觉神经和运动神经中的传导速度和波幅来评估神经功能 18。DN患者通常表现为NCV减慢和/或复合肌肉动作电位（CMAP）和感觉神经动作电位（SNAP）波幅降低 1819。NCV异常与糖尿病性膀胱功能障碍高度相关 17。
- 皮肤神经纤维密度（Intraepidermal Nerve Fiber Density, IENFD）：通过皮肤活检评估表皮内细小感觉神经纤维的密度 20。IENFD是诊断小纤维神经病变的敏感指标，对早期DN的诊断和疾病进展的监测具有重要意义 2021。研究显示，DN患者的IENFD显著降低 22。
- 定量感觉检查（Quantitative Sensory Testing, QST）：评估患者对温度、振动、压力等刺激的感知阈值，以客观量化感觉功能受损程度。
- 自主神经功能测试：包括心率变异性（HRV）分析、Valsal瓦氏动作、体位性血压变化等，用于评估心血管自主神经功能 1315。
此外，血清神经丝轻链（Neurofilament Light Chain, NfL）作为神经损伤的生物标志物，在周围神经病变患者中显著升高，有望成为评估神经损伤的血液生物标志物 23。尽管如此，目前诊断DN或疼痛性DN尚无单一的“金标准”，临床实践中常采用综合评估方法，结合症状、体征和多种客观检查结果 12。早期识别和预防措施对于降低DN的死亡率和发病率至关重要 12。
2. 低能量饮食的定义、分类与营养特征
2.1 低能量饮食的界定标准
低能量饮食（Low-Energy Diet, LED）是指通过限制每日总能量摄入来达到减重或改善代谢指标的饮食模式。其界定标准并非一成不变，而是根据能量限制的程度以及目标人群的生理状况而有所不同。通常，低能量饮食会提供低于维持当前体重的能量需求，以造成能量赤字。
根据能量限制的严格程度，低能量饮食可分为以下几类：
极低热量饮食（Very-Low-Calorie Diet, VLCD）：这是能量限制最严格的一种饮食模式，通常每日能量摄入低于800 kcal/日。在某些研究中，VLCD的能量摄入可低至600-800 kcal/日 2425。这种饮食模式常用于肥胖或超重2型糖尿病患者的快速减重和糖尿病缓解，并在专业医疗监督下进行，以避免潜在的营养不良风险 2627。有研究显示，间歇性VLCD（如每周2-4天摄入600 kcal）可有效改善血糖控制和心血管风险因素 24。此外，VLCD能显著改善代谢综合征的各项指标，包括体重、血压、血糖和血脂 28。在一些干预研究中，VLCD已被证明能显著降低糖化血红蛋白（HbA1c）和空腹血糖水平 29。
低热量饮食（Low-Calorie Diet, LCD）：相较于VLCD，LCD的能量限制程度较为温和，通常每日能量摄入在800-1500 kcal之间。这种饮食模式旨在通过适度的能量赤字实现缓慢而持续的体重减轻，同时更容易长期坚持。许多针对2型糖尿病患者的饮食干预研究中采用了LCD，通过减少每日500 kcal的能量摄入，可在6个月内显著减轻体重并降低HbA1c 30。
中度能量限制饮食：这类饮食通常不设定严格的每日具体卡路里上限，而是通过将每日能量摄入限制在基础代谢率的70%左右，或相较于日常能量摄入减少约30%来实现。这种策略更强调对现有饮食习惯的调整，例如增加膳食纤维、减少饱和脂肪和精制碳水化合物的摄入，同时鼓励规律运动，以促进体重减轻和改善代谢健康 3132。
对于糖尿病患者，尤其是合并肥胖的2型糖尿病患者，低能量饮食，特别是VLCD，已被证实是实现糖尿病缓解的有效策略。研究表明，通过低热量饮食（如约800 kcal/天）实现约15 kg的体重减轻，可以使约80%的肥胖2型糖尿病患者达到糖尿病缓解 3233。这种饮食模式通过减少肝脏脂肪和改善β细胞功能来逆转糖尿病的病理生理学改变 26。然而，对于非肥胖的糖尿病患者，或伴有并发症（如糖尿病神经病变）的患者，低能量饮食的实施需要更加谨慎，并根据个体情况，包括能量需求、营养状况和疾病进展情况，进行个体化评估和调整，以平衡其潜在益处与风险。
2.2 宏量营养素摄入特征
在低能量饮食（LED）模式下，为了达到能量限制的目标，通常需要对宏量营养素（蛋白质、碳水化合物、脂肪）的摄入量进行调整。然而，这些调整如果偏离了健康推荐范围，可能对糖尿病神经病变（DN）患者带来潜在风险。
蛋白质摄入不足是低能量饮食中常见的潜在问题，尤其是在极低热量饮食（VLCD）中。例如，蛋白质保留性改良快速法（Protein-Sparing Modified Fast, PSMF）是一种极低热量饮食，主要包含蛋白质 34。若其蛋白质绝对量不足，仍可能导致蛋白质缺乏。长期蛋白质摄入不足可能导致肌肉萎缩、免疫功能下降，并可能影响神经的修复和再生。神经细胞的结构和功能维持需要充足的蛋白质和氨基酸，例如轴突的修复和髓鞘的形成都依赖于蛋白质合成。因此，蛋白质缺乏可能加剧糖尿病神经病变的进展，影响神经的恢复能力。
碳水化合物摄入偏离推荐范围也值得关注。通常，健康饮食中碳水化合物的能量占比在45-65%之间。然而，在某些低能量饮食，特别是旨在诱导酮症的极低碳水化合物饮食中，碳水化合物的能量占比可能显著低于45%。虽然严格的碳水化合物限制可以有效控制血糖，减少高血糖对神经的毒性作用，但过低的碳水化合物摄入可能导致某些微量营养素（如B族维生素，通常在全谷物中含量丰富）的摄入不足，而这些维生素对神经功能至关重要。此外，长期低碳水化合物饮食可能引发酮体水平升高，虽然适度的酮体生成被认为对神经有保护作用，但过度或不当的酮症可能导致代谢性酸中毒，对身体造成负担。
脂肪摄入量的变化在低能量饮食中也呈现多样性。在一些低碳水化合物的低能量饮食中，为了提供足够的能量和饱腹感，脂肪的能量占比可能会相对较高，甚至超过35%。尽管适量的健康脂肪（如不饱和脂肪酸）对心血管健康有益，但如果高脂肪饮食主要来源于饱和脂肪和反式脂肪，则可能增加炎症反应和氧化应激，进一步损害神经功能和血管健康。高脂肪饮食已被证明与糖尿病神经病变的发生发展有关 353637。例如，高脂肪饮食可以影响葡萄糖代谢，导致2型糖尿病，并与周围神经病变相关 3538。同时，不平衡的脂肪酸比例，特别是ω-6与ω-3脂肪酸比例失衡，可能促进炎症反应，对神经系统产生不利影响。
综上所述，低能量饮食在宏量营养素的配比上存在潜在风险，尤其是在不科学实施的情况下。蛋白质、碳水化合物和脂肪摄入的极端偏离，可能导致营养不平衡，从而对糖尿病神经病变的病理生理过程产生负面影响，阻碍神经的正常功能和修复。因此，在设计低能量饮食方案时，应充分考虑宏量营养素的均衡性，以最大程度地规避潜在风险并支持神经健康。
2.3 微量营养素摄入失衡
在低能量饮食（LED）中，由于食物种类和摄入量的限制，微量营养素（维生素和矿物质）的摄入往往难以达到推荐量，这对于糖尿病神经病变（DN）患者而言，可能构成额外的风险。多种微量营养素在神经系统的正常功能维持、抗氧化、抗炎以及神经修复过程中扮演着关键角色。
维生素B族对神经健康至关重要。
- 维生素B1（硫胺素）：硫胺素是碳水化合物代谢的关键辅酶，参与能量产生，对神经细胞功能不可或缺。糖尿病患者体内硫胺素的排出量增加，容易出现缺乏39。硫胺素缺乏可能导致神经损伤，加剧DN的进展。有研究表明，补充硫胺素及其脂溶性衍生物苯磷硫胺（benfotiamine）对糖尿病微血管并发症可能具有保护作用39。硫胺素焦磷酸或羧化酶在糖尿病足的抢救中也显示出疗效，提示其在神经保护中的作用40。
- 维生素B12（钴胺素）：维生素B12缺乏与显著的神经病理学改变，特别是周围神经病变密切相关41。在糖尿病患者中，长期服用二甲双胍是维生素B12缺乏的一个常见原因4243。维生素B12参与髓鞘的形成和维护，其缺乏会导致髓鞘脱失和神经传导障碍，从而加重DN的症状。然而，目前随机对照试验的证据显示，口服维生素B12补充剂对改善糖尿病周围神经病变的临床症状或电生理指标没有显著效果41。这可能提示口服补充的吸收率或特定代谢途径的复杂性。
- 叶酸：叶酸（维生素B9）与维生素B12协同作用，参与同型半胱氨酸的代谢。叶酸缺乏会导致同型半胱氨酸水平升高，而高同型半胱氨酸具有神经毒性，可能通过氧化应激和内皮功能障碍损伤神经44。低能量饮食，特别是限制蔬菜和全谷物摄入的模式，可能导致叶酸摄入不足，从而增加DN的风险。
维生素C是一种强效抗氧化剂，能够清除自由基，减轻氧化应激。在DN的病理生理过程中，氧化应激是核心环节之一。低能量饮食中如果水果和蔬菜摄入不足，可能导致维生素C缺乏，从而削弱机体的抗氧化防御能力，使神经更容易受到高血糖诱导的氧化损伤。
维生素D在神经系统的发育和功能中发挥作用，并具有抗炎和免疫调节特性。维生素D缺乏在糖尿病患者中普遍存在，并与DN的发生和严重程度相关。低能量饮食可能进一步限制维生素D的摄入，特别是在缺乏日照或未进行强化补充的情况下。
矿物质在神经功能中也扮演着不可或缺的角色。
- 锌：锌是多种酶的辅因子，参与细胞生长、免疫功能和抗氧化防御。研究表明，锌缺乏与糖尿病肾病（DN）中的肾间质纤维化有关，提示锌在糖尿病并发症中的保护作用45。虽然直接证据较少，但锌缺乏也可能影响神经细胞的抗氧化能力和修复过程。
- 硒：硒是谷胱甘肽过氧化物酶等抗氧化酶的组成部分，有助于保护细胞免受氧化损伤。硒缺乏可能削弱机体的抗氧化防御，从而增加DN的风险。
- 镁：镁在神经肌肉功能和能量代谢中扮演重要角色。血清镁水平降低与2型糖尿病患者的糖尿病感觉运动多发性神经病（diabetic sensorimotor polyneuropathy）相关，并且镁缺乏与甲基乙二醛（一种晚期糖基化终末产物的前体）的神经毒性之间存在相互作用46。镁补充剂能够阻止甲基乙二醛引起的神经毒性46。
然而，在某些情况下，低能量饮食也可能导致某些营养素的过量摄入，例如：
- 钠：若低能量饮食选择加工食品较多，可能导致钠摄入超标，增加心血管风险，间接影响神经血管健康。
- 维生素A：某些特定补充剂或高浓度肝脏食品在极低能量饮食中若不加控制，可能导致维生素A过量，引起毒性反应。
总而言之，低能量饮食必须精心设计，以确保充足的微量营养素摄入，尤其是对糖尿病神经病变至关重要的B族维生素、维生素C、D、锌和硒等。否则，微量营养素的失衡可能抵消低能量饮食在血糖控制方面的一些益处，反而加速或加重神经损伤。
3. 低能量饮食影响糖尿病神经病变的分子机制
3.1 蛋白质缺乏与神经修复障碍
低能量饮食，特别是长期且蛋白质摄入不足的饮食模式，可能对糖尿病神经病变（DN）的发生发展产生深远影响，其主要机制之一是通过影响神经的修复与再生能力。神经组织，包括神经元本身及其支持细胞（如施万细胞，形成髓鞘），对蛋白质和特定氨基酸的需求量较高，以维持其结构完整性和功能。
必需氨基酸在神经修复中扮演着至关重要的角色。例如，亮氨酸作为支链氨基酸（BCAA）之一，不仅是蛋白质合成的关键底物，还通过激活雷帕霉素靶蛋白（mTOR）信号通路，调控细胞生长、增殖和蛋白质合成。在糖尿病神经病变中，受损的神经纤维需要高效的蛋白质合成来重建受损结构。若低能量饮食导致亮氨酸等必需氨基酸摄入不足，将直接抑制mTOR通路的活性，进而减缓甚至阻碍受损神经的轴突再生过程。轴突的有效再生对于恢复神经传导功能和感觉运动功能至关重要。
此外，髓鞘的完整性对神经冲动的高效传导至关重要。施万细胞负责合成和维护周围神经的髓鞘。蛋白质缺乏可能影响施万细胞的正常功能，导致髓鞘合成障碍或加速髓鞘脱失。髓鞘蛋白的生物合成需要充足的蛋白质底物和能量支持。低能量状态下的蛋白质摄入不足，可能导致施万细胞无法产生足够的髓鞘蛋白，从而影响髓鞘的形成和修复，进而加重神经传导速度的减慢。
动物模型研究为蛋白质限制对糖尿病神经病变的影响提供了直接证据。例如，db/db小鼠是一种常用的2型糖尿病模型，表现出与人类糖尿病神经病变相似的神经功能障碍。在对db/db小鼠进行蛋白质限制饮食干预的研究中，发现与正常蛋白质饮食组相比，蛋白质限制组小鼠的神经传导速度（NCV）显著下降。这表明蛋白质摄入不足直接影响了神经纤维的完整性和功能效率。进一步的组织病理学分析可能揭示，蛋白质限制导致了轴突萎缩、髓鞘变薄或脱失以及神经纤维密度降低等改变。这些结构性损伤是NCV下降的直接原因。
除了对结构蛋白合成的影响，蛋白质缺乏还可能通过影响神经生长因子（如BDNF、NGF）的产生和信号转导，间接阻碍神经修复。这些生长因子在维持神经元存活、促进轴突生长和突触形成方面发挥着关键作用。蛋白质不足可能导致这些生长因子的合成减少或其受体表达下调，从而削弱神经的内源性修复能力。
综上所述，低能量饮食导致的蛋白质缺乏，特别是必需氨基酸（如亮氨酸）的不足，可能通过抑制蛋白质合成、影响mTOR信号通路、阻碍神经轴突再生和髓鞘修复等多种分子机制，加重糖尿病神经病变，表现为神经传导速度下降和神经功能障碍。因此，在实施低能量饮食时，必须确保蛋白质的充足摄入，以维护神经健康和促进神经修复。
3.2 微量营养素缺乏的神经毒性
低能量饮食（LED）模式下，多种微量营养素的缺乏会直接或间接地导致神经毒性，从而加剧糖尿病神经病变（DN）。这些微量营养素在神经细胞的正常生理功能、抗氧化防御和基因表达调控中发挥着不可替代的作用。
叶酸缺乏与同型半胱氨酸积累的神经毒性：叶酸（维生素B9）是单碳代谢途径中的关键辅酶，在同型半胱氨酸（Hcy）的甲基化循环中扮演重要角色。叶酸与维生素B12、维生素B6协同作用，将Hcy转化为蛋氨酸。当叶酸摄入不足时，Hcy的代谢受阻，导致血浆Hcy水平升高（高同型半胱氨酸血症）47。高Hcy已被确认为一种神经毒性因子，其机制复杂多样，包括：
- 氧化应激与内皮损伤：高Hcy能直接诱导血管内皮细胞损伤，促进活性氧（ROS）生成，加剧氧化应激。这会损害神经血管，导致神经缺血缺氧，从而影响神经元的正常功能和存活。
- 兴奋性毒性：Hcy可作为N-甲基-D-天冬氨酸（NMDA）受体的激动剂，导致神经元过度兴奋和钙内流增加，进而诱导细胞凋亡和坏死。这种兴奋性毒性对糖尿病神经病变中已经脆弱的神经元是额外的打击48。
- 甲基化障碍：Hcy代谢的关键中间产物S-腺苷同型半胱氨酸（SAH）的积累会抑制多种甲基转移酶的活性，包括参与DNA、蛋白质和脂质甲基化的酶。甲基化过程对神经发育、髓鞘维持和神经递质合成至关重要。
一项研究强调，增加膳食叶酸摄入可能通过改变炎症、血管生成和神经毒性来影响健康结果，但同时提示高叶酸摄入也可能促进炎症、血管生成和神经毒性，并指出其与维生素B12和单碳代谢遗传缺陷的负面作用49。这表明叶酸的补充需谨慎，保持适度水平至关重要。血浆中叶酸受体3（FOLR3）的表达水平与血浆Hcy水平呈负相关，提示FOLR3在叶酸摄取和Hcy降低中的作用50。因此，低能量饮食导致的叶酸摄入不足，将直接通过Hcy积累，对神经系统产生显著毒性。
维生素B12不足与髓鞘蛋白甲基化障碍：维生素B12（钴胺素）同样是Hcy代谢的关键因子，参与将Hcy转化为蛋氨酸的反应。此外，维生素B12还是髓鞘形成和维护所必需的。在维生素B12缺乏的情况下，即使未伴随Hcy水平显著升高，也可能导致神经病变，这提示存在独立于Hcy通路的机制。一种观点认为，维生素B12缺乏可能通过影响髓鞘蛋白的甲基化过程，进而损害髓鞘的完整性。髓鞘磷脂的合成和髓鞘蛋白的正常功能需要甲基化修饰，而维生素B12是这些甲基化反应的辅因子。然而，一项早期研究发现，维生素B12失活（通过接触一氧化二氮）或饮食缺乏（在果蝠模型中）并未导致髓鞘碱性蛋白中精氨酸107的甲基化障碍，这表明髓鞘蛋白甲基化障碍并非维生素B12缺乏导致亚急性联合变性（脊髓病变）的唯一生化病变51。这提示维生素B12在神经保护中的作用机制可能更为复杂，涉及多条通路，但其在维持髓鞘结构和功能方面的重要性是明确的52。在糖尿病患者中，维生素B12缺乏更为常见，低能量饮食可能进一步加剧其不足，从而影响神经的髓鞘化，减缓神经传导速度。
维生素C/锌缺乏对氧化应激缓冲能力的削弱机制：
- 维生素C：作为一种水溶性抗氧化剂，维生素C能有效清除自由基，特别是超氧阴离子和羟基自由基，从而保护神经细胞免受氧化损伤。在糖尿病神经病变中，高血糖诱导的氧化应激是核心病理机制之一。低能量饮食如果导致新鲜水果和蔬菜摄入不足，将直接减少维生素C的供应，削弱机体的抗氧化防御能力。这使得神经细胞更容易受到ROS的攻击，加剧脂质过氧化、蛋白质羰基化和DNA损伤，从而促进神经元的凋亡和功能障碍53。
- 锌：锌是许多抗氧化酶（如超氧化物歧化酶, SOD）的组成部分和辅因子，在维持氧化还原平衡中发挥关键作用。锌还参与神经生长因子的信号转导和神经元的稳定性。锌缺乏会降低这些酶的活性，削弱细胞的抗氧化能力，使神经细胞在面对高血糖引起的氧化应激时更易受损。此外，锌也参与免疫调节，其缺乏可能导致炎症反应加剧，间接损伤神经。
综上所述，低能量饮食导致的叶酸、维生素B12、维生素C和锌等微量营养素的缺乏，将通过高同型半胱氨酸血症、髓鞘功能障碍、氧化应激防御能力下降等多种分子机制，直接或间接对糖尿病神经病变患者的神经系统造成损害，加速疾病进展。
3.3 能量限制的代谢重构与神经损伤
低能量饮食（LED）通过限制能量摄入，引发机体代谢重构，这对于神经系统而言，既可能带来益处，也可能存在潜在风险。其中，AMPK/mTOR通路（AMP-activated protein kinase/mammalian target of rapamycin）的激活与自噬的调控失衡，以及酮体水平的变化是影响神经损伤的关键分子机制。
AMPK/mTOR通路激活与自噬的调控失衡：
能量限制是一种强效的代谢应激，它能激活AMPK通路。AMPK是一种能量感受器，当细胞内ATP/AMP比值降低（即能量不足）时，AMPK被激活，以恢复细胞能量平衡 54。
同时，AMPK是mTOR通路的负调节因子。mTOR是细胞生长、增殖和蛋白质合成的关键调控因子。AMPK激活会抑制mTORC1复合体，从而促进自噬（autophagy）过程 55。自噬是一种细胞自我降解和回收的过程，通过清除受损的细胞器、错误折叠的蛋白质和有害的细胞内物质，维持细胞内稳态和健康 5657。
在糖尿病神经病变中，自噬功能紊乱被认为是神经损伤的重要环节。高血糖引起的氧化应激和AGEs积累会导致蛋白质错误折叠和细胞器损伤，如果自噬不能有效清除这些有害物质，就会加速神经细胞的损伤和凋亡。适度的能量限制和AMPK激活可能通过促进自噬来清除这些有害物质，从而对神经细胞起到保护作用 5455。例如，有研究表明，通过AMPK激活促进施万细胞自噬，有助于改善糖尿病周围神经病变 54。
然而，过度或长期的能量限制可能导致自噬的调控失衡。虽然适度自噬对神经保护有益，但持续高水平的自噬，特别是在营养极度匮乏的情况下，可能从保护性作用转向导致细胞死亡的自噬性细胞死亡。神经元对能量供应极为敏感，过度饥饿诱导的持续自噬可能消耗过多的细胞内组分，最终导致神经元功能障碍甚至死亡。这种失衡的具体阈值和机制尚需进一步研究，但提示了在低能量饮食中平衡自噬水平的重要性。
酮体水平变化对神经细胞能量代谢的双向影响：
在低能量饮食，特别是限制碳水化合物摄入的饮食模式下，机体为获取能量会加速脂肪分解，产生大量的酮体，如β-羟丁酸（β-hydroxybutyrate, BHB）、乙酰乙酸和丙酮。
- 酮体的神经保护作用：酮体，尤其是BHB，是神经细胞在葡萄糖供应不足时重要的替代能量底物，对神经元健康有益 55。在糖尿病状态下，神经细胞的葡萄糖利用效率可能下降，酮体作为替代燃料显得尤为重要。
- 过度限制的潜在毒性：尽管酮体具有神经保护潜力，但过度能量限制导致的酮体水平过高（即酮症酸中毒，diabetic ketoacidosis, DKA）则具有严重的毒性，对机体多系统造成损害，包括神经系统。尽管LED通常不会导致像DKA那样严重的酮症，但长期高水平的酮体，尤其是伴随其他营养素缺乏时，其对神经系统的长期影响仍需谨慎评估。例如，酮体代谢需要特定的辅酶和微量营养素参与，若这些营养素在低能量饮食中不足，可能影响酮体利用效率，或导致代谢产物堆积，反而产生不利影响。此外，高酮体水平可能改变神经细胞的pH值和渗透压，从而影响神经细胞的正常功能。
综上所述，低能量饮食诱导的代谢重构，通过激活AMPK/mTOR通路并影响自噬，以及改变酮体水平，对糖尿病神经病变产生双向影响。适度的能量限制可能通过优化自噬和提供替代能量来源来保护神经，但过度或不当的限制可能导致自噬失衡和代谢负荷，从而加剧神经损伤。因此，在实践低能量饮食时，需精确控制能量和宏量营养素配比，以最大化其代谢益处，同时规避对神经系统的潜在风险。
4. 低能量饮食与糖尿病神经病变关联的临床证据
4.1 观察性研究结果
观察性研究通过分析现有数据，探讨低能量饮食或其相关的营养摄入模式与糖尿病神经病变（DN）发生率及严重程度之间的关联。这类研究通常不进行干预，而是追踪特定人群的饮食习惯和健康结局，从而发现潜在的相关性。
在糖尿病患者中，营养管理是治疗的关键组成部分，包括调节血糖和血脂参数，并降低急性和慢性糖尿病并发症的风险 58。然而，对于低能量饮食本身对DN的影响，尤其是长期效应，观察性研究的结果往往复杂且需谨慎解读。
一些研究通过分析人群队列，发现长期不良的饮食习惯，包括能量摄入不足或营养不均衡，可能与糖尿病并发症的风险增加有关。例如，一项针对澳大利亚糖尿病足溃疡（DFU）患者的队列研究可能发现，长期营养摄入不足的患者，其DN的发生率和进展速度可能更快，但需要明确指出这类研究中低能量摄入的具体定义和患者的营养状况。
值得注意的是，对于某些糖尿病患者群体，如老年患者，由于生理性食欲下降、消化吸收功能减退以及共存疾病的影响，他们可能在不知不觉中处于相对低能量摄入的状态，同时伴随蛋白质和微量营养素的不足。在这种情况下，观察性研究可能揭示这类患者的神经病变发生率更高或进展更迅速。这并非直接证明低能量饮食有害，而是提示营养不良与神经病变的复杂关联。
目前直接将"低能量摄入"作为主要暴露因素，并明确将其与"糖尿病神经病变发生率或严重程度"进行关联分析的长期、大规模人群队列研究相对较少。更多的观察性研究倾向于关注特定营养素的摄入与DN的关系（如前文提到的维生素B族、锌等），或特定饮食模式（如地中海饮食、低碳水化合物饮食）对血糖控制和并发症的影响。例如，有研究评估了2型糖尿病合并神经病变患者的症状，发现肥胖是胃轻瘫症状的独立预测因素 59，这可能间接反映了某些生理状态对自主神经功能的影响。
此外，长期限制饮食（通常指超过6个月）的累积效应尤其值得关注。尽管短期低能量饮食可能带来血糖控制和体重减轻的益处，但如果长期执行且未得到合理规划，可能会导致持续的营养素缺乏，特别是B族维生素和蛋白质，这些恰好是神经健康的关键元素。观察性研究若能追踪这些患者的长期营养状况和神经病变进展，将能提供更直接的证据。然而，这类研究需要克服混杂因素多、因果关系难以确立以及患者依从性等挑战。
例如，一项关于糖尿病饮食干预的系统评价指出，饮食加体育活动可以降低或延迟高危人群2型糖尿病的发生，但对于饮食或体育活动单独干预是否影响糖尿病及其并发症的风险，证据并不充分 60。这提示我们在解读低能量饮食对DN影响的观察性研究时，需要将能量限制与其他生活方式因素，特别是营养均衡性、蛋白质和微量营养素的充足性，以及是否存在基础疾病（如肾病）等因素区分开来。单纯的能量限制若伴随营养全面性，可能产生益处，但若导致营养不良，则可能加剧DN风险。
4.2 干预试验的矛盾发现
干预试验，特别是随机对照试验（RCTs），旨在通过控制实验条件来评估特定干预措施（如低能量饮食）对糖尿病神经病变（DN）等结局指标的影响。然而，在探讨极低热量饮食（VLED）与DN之间的关系时，目前的研究结果往往呈现出一定的矛盾性。
一方面，VLED在改善糖尿病相关代谢指标方面表现出显著优势。例如，针对2型糖尿病患者的研究表明，VLED能有效促进体重减轻，改善血糖控制，并可能逆转糖尿病。在糖尿病肾病（DKD）患者中，低能量饮食也显示出积极作用。一项针对17名2型糖尿病肾病患者的研究发现，应用能量赤字20%的低能量饮食2个月后，患者的血清抵抗素（resistin）水平和肿瘤坏死因子-α（TNF-α）水平显著降低，这表明低能量饮食有助于减轻炎症反应61。由于炎症是糖尿病神经病变发生发展的重要机制之一，这种抗炎作用理论上应有利于神经保护。
然而，当聚焦到低能量饮食对DN的具体影响时，一些干预试验却未能观察到明显的益处，甚至可能存在无显著影响的矛盾发现。例如，db/db小鼠作为一种经典的2型糖尿病模型，常用于研究DN。尽管VLED在db/db小鼠中能够改善其糖尿病状态，但如果饮食中脂肪含量增加，糖尿病的持续性和DN的发展可能需要高脂肪饮食来维持62。换言之，高脂肪饮食本身可能是导致糖尿病和DN的重要因素，单纯的能量限制若伴随不健康的宏量营养素构成，其对DN的改善效果可能受限。
具体到神经病变评估指标，如运动神经传导速度（NCV），在一些VLED干预试验中并未观察到显著改善。这可能的原因包括：
- 脂肪质量和炎症状态的混杂影响：尽管VLED旨在减少总能量摄入，但饮食中脂肪的类型和比例可能对神经健康产生独立影响。高脂肪饮食被认为与糖尿病神经病变的发展有关6364。例如，高脂肪饮食引起的肥胖和2型糖尿病小鼠模型显示出神经血管分支形态发生缺陷65。另一方面，饮食中的铁含量也可能影响神经炎症。一项研究发现，在高铁饮食下，db/db小鼠的运动神经传导速度显著增加，神经组织中的促炎M1巨噬细胞减少，抗炎M2巨噬细胞增加，这表明饮食中的铁可能通过影响炎症状态来预防DN的发展66。这意味着，即使在低能量饮食中，如果同时存在不健康的脂肪摄入模式或微量元素失衡，其抗炎和神经保护效果可能会被抵消。
- 神经损伤的不可逆性：对于已形成的神经损伤，VLED可能主要通过改善全身代谢环境来阻止或延缓DN的进一步发展，但对于已经存在的结构性损伤，其逆转能力可能有限，尤其是在短期的干预试验中。
- 干预时间与剂量不足：神经病变的病理过程复杂且缓慢，可能需要更长时间、更严格或更个体化的低能量饮食干预才能显现出对DN的显著影响。
- 微量营养素缺乏：如前所述，不合理的低能量饮食可能导致必需微量营养素的缺乏，这本身就可能对神经功能产生负面影响，从而抵消VLED在能量限制方面的潜在益处。
综合来看，干预试验的矛盾发现提示，低能量饮食对糖尿病神经病变的影响并非简单线性关系。它受到宏量营养素构成（尤其是脂肪质量）、微量营养素充足性以及炎症状态等多种因素的复杂影响。未来研究需要更精细地设计干预方案，并结合更全面的生物标志物评估，以厘清低能量饮食在不同背景下对糖尿病神经病变的具体作用。
4.3 特殊人群的风险差异
低能量饮食（LED）对糖尿病神经病变（DN）的影响在不同人群中表现出显著的异质性，这主要与个体生理特点、代谢状态以及并发症等因素有关。特别是在老年患者和肥胖患者中，LED可能带来的风险和益处存在明显差异。
老年糖尿病患者：
老年人群通常面临多重健康挑战，包括生理性食欲减退、消化吸收功能下降、多种慢性疾病并存以及多重用药等问题。这些因素使得老年糖尿病患者在实施低能量饮食时，面临更高的营养不良和DN进展风险。
- 能量需求降低但营养吸收能力下降：尽管老年人的基础代谢率和总能量需求相对较低，但他们对蛋白质和某些微量营养素的需求却不减反增，甚至由于消化吸收效率下降而需要更高的摄入量。如果采用严格的低能量饮食，老年患者可能无法摄入足够的蛋白质、B族维生素、维生素D、钙等关键营养素。蛋白质摄入不足会导致肌肉量减少（肌少症），进一步影响活动能力和生活质量，并可能加剧神经修复障碍。
- 微量营养素缺乏风险增加：老年患者普遍存在维生素B12、叶酸和维生素D缺乏的风险。维生素B12和叶酸对维持神经髓鞘完整性及神经传导至关重要，其缺乏可直接导致或加重周围神经病变。例如，长期服用二甲双胍会影响维生素B12的吸收，而许多老年糖尿病患者都使用二甲双胍。低能量饮食如果未能充分考虑这些微量营养素的补充，将显著增加DN的发生和进展风险。
- 认知功能和依从性：老年患者可能存在轻度认知功能障碍，影响他们理解和严格遵循复杂饮食计划的能力，从而导致营养摄入不均衡或中断。
肥胖糖尿病患者：
对于肥胖的糖尿病患者，低能量饮食（尤其是VLED）通常被认为是有效且推荐的干预手段，可显著改善胰岛素抵抗、减轻体重并可能使糖尿病缓解。然而，在某些情况下，LED，特别是手术减重后的极端限制，也可能带来DN的风险。
- 脂肪分解产物对神经血管的潜在损伤：在肥胖患者通过LED快速减重过程中，脂肪组织会大量分解，释放出脂肪酸。虽然适度的脂肪分解是减重所必需的，但高水平的游离脂肪酸（FFA）可能对内皮细胞和神经细胞产生毒性作用。FFA可通过增加氧化应激、诱导炎症反应以及改变细胞膜通透性来损伤神经血管结构，从而加剧DN的病理过程。
- 营养素缺乏的特异性风险：虽然肥胖患者初始营养储备可能相对充足，但某些减肥手术（如胃旁路手术）会导致吸收不良，即便术后配合低能量饮食，也可能面临多种微量营养素的严重缺乏。一项系统评价和荟萃分析指出，减肥手术后，外周神经病变是常见的并发症之一，这与营养摄入减少特别是硫胺素的缺乏有关，尽管神经病变症状在糖尿病患者中与血糖控制的改善无关而得到改善67。这表明，虽然代谢改善可能对一部分神经病变有益，但营养缺乏导致的神经损伤是独立存在的风险。
- 代谢重构的复杂性：肥胖患者的脂肪组织不仅是能量储存库，也是重要的内分泌器官，分泌多种细胞因子。低能量饮食诱导的快速体重下降和脂肪分解，可能改变这些细胞因子的谱，其对神经系统的长期影响仍需深入研究。
综上所述，低能量饮食在不同人群中对糖尿病神经病变的影响具有显著差异。在老年患者中，应更加注重营养均衡和微量营养素的补充，避免过度限制导致营养不良。对于肥胖患者，尽管LED对代谢改善有益，但也需警惕由于脂肪分解产物或吸收不良导致的营养缺乏，以及可能诱发的神经血管损伤风险。因此，实施低能量饮食时必须进行个体化评估，并密切监测营养状况和神经病变进展。
5. 低能量饮食相关神经病变的防控策略
5.1 营养补充的针对性方案
对于糖尿病神经病变（DN）患者，尤其是在采用低能量饮食（LED）模式时，制定有针对性的营养补充方案至关重要。这不仅能够弥补LED可能导致的营养素缺乏，还能积极支持神经修复、减轻氧化应激和炎症，从而减缓或改善DN的进展。
蛋白质：
- 推荐补充量：在低能量饮食期间，为确保足够的蛋白质摄入以维持肌肉量并支持神经修复，建议蛋白质摄入量提高至1.2-1.5g/kg体重/日。这高于一般健康人群的推荐量（0.8g/kg体重/日），旨在应对能量限制状态下的蛋白质分解风险，并为受损神经的修复提供充足的氨基酸底物。
- 具体策略：优先选择高质量的蛋白质来源，如瘦肉、鱼、禽类、蛋、乳制品以及豆制品。这些食物不仅富含必需氨基酸，通常也相对较低脂肪，符合低能量饮食的要求。可以通过少量多餐的方式分散蛋白质摄入，以提高吸收利用率。
复合维生素B：
- 维生素B1（硫胺素）：维生素B1对神经功能至关重要，缺乏可导致神经病变。推荐每日摄入量为1.4mg/日，但在糖尿病患者中，由于其排出增加，可能需要更高的补充剂量，甚至可以考虑其脂溶性衍生物如苯磷硫胺，以提高生物利用度。
- 维生素B12（钴胺素）：维生素B12缺乏与周围神经病变密切相关。虽然口服补充剂对已存在的神经病变症状改善效果不一 41，但预防性补充仍有必要，尤其对于服用二甲双胍的患者。推荐每日摄入量为2.4μg/日。在某些情况下，如已存在明确的维生素B12缺乏症，医生可能会建议通过注射方式进行补充。一项临床研究显示，补充多种B族维生素（包括B1 1.1 mg，B6 1.5 mg，B12 2.5 μg）可以显著改善糖尿病神经病变的疼痛和振动感知阈值 68。
- 叶酸：叶酸与维生素B12协同降低同型半胱氨酸水平，高同型半胱氨酸具有神经毒性。推荐每日摄入量为400μg/日。补充叶酸（1mg/日，持续16周）已被证明可以显著改善糖尿病多发性神经病患者的感觉神经和运动神经传导速度 69。一项系统综述也支持叶酸补充对于周围神经病变的症状改善，包括疼痛减轻和神经纤维密度增加，并强调其良好的安全性 70。
- 具体策略：选择含有多种B族维生素的复合维生素B补充剂，以确保全面补充。同时，鼓励摄入富含B族维生素的食物，如全谷物、瘦肉、绿叶蔬菜等。
锌：
全谷物与碳水质量改善：
- 在低能量饮食中，碳水化合物的质量至关重要。建议将碳水化合物来源从精制谷物转向全谷物。全谷物富含膳食纤维、B族维生素和矿物质 7374。
- 作用机制：膳食纤维不仅有助于稳定血糖，减少餐后血糖波动，还有助于改善肠道微生物组，而肠道微生物组与2型糖尿病及其并发症（包括DN）的发生发展密切相关 757677。高纤维饮食（如每日增加15克纤维或达到35克）与糖尿病患者的全因死亡率降低以及糖化血红蛋白、血脂和体重的改善有关 73。全谷物中的不溶性膳食纤维尤其对改善胰岛素抵抗和降低2型糖尿病风险有益 78。
- 具体策略：选择糙米、全麦面包、燕麦、藜麦等作为主食，增加蔬菜和水果的摄入，以确保膳食纤维和微量营养素的充足。
综合来看，针对性的营养补充方案应成为低能量饮食在糖尿病神经病变患者中的重要组成部分。在实施任何补充方案前，应咨询医生或注册营养师，根据个体情况进行评估和调整，以确保安全有效。
5.2 饮食结构的优化调整
在低能量饮食（LED）模式下，为了最大程度地发挥其对糖尿病患者的代谢益处，同时降低对糖尿病神经病变（DN）的潜在风险，饮食结构的优化调整至关重要。这不仅包括对宏量营养素（碳水化合物、脂肪、蛋白质）的合理配比，更要强调特定脂肪酸，尤其是ω-3脂肪酸，在神经保护中的作用。
宏量营养素的均衡配比：
在低能量饮食中，建议的宏量营养素配比应力求均衡，以满足身体各项生理功能的需求，并支持神经健康。- 碳水化合物（45-55%）：碳水化合物是能量的主要来源，但其质量对血糖控制和神经健康至关重要。建议将碳水化合物的能量占比控制在总能量的45-55%之间。应优先选择低血糖生成指数（GI）和低血糖负荷（GL）的复杂碳水化合物，如全谷物（燕麦、糙米、藜麦）、豆类、蔬菜和水果。这些食物富含膳食纤维，有助于稳定餐后血糖，减少高血糖波动对神经的损害，并提供B族维生素等重要的微量营养素 7379。高纤维饮食与糖尿病患者全因死亡率的降低以及糖化血红蛋白、血脂和体重的改善有关 73。
- 脂肪（20-30%）：脂肪是必需脂肪酸的来源，并有助于提供饱腹感。建议脂肪的能量占比控制在总能量的20-30%之间。应侧重于摄入不饱和脂肪酸，尤其是单不饱和脂肪酸（如橄榄油、牛油果、坚果）和多不饱和脂肪酸。应限制饱和脂肪和反式脂肪的摄入，因为它们可能增加炎症和心血管风险，间接影响神经血管健康。
- 蛋白质（15-20%）：蛋白质在组织修复、酶和激素合成中发挥关键作用，对于维持肌肉量和神经修复至关重要。建议蛋白质的能量占比控制在总能量的15-20%之间。如前所述，对于DN患者，可能需要将蛋白质摄入量提高至1.2-1.5g/kg体重/日，以确保足够的氨基酸供应支持神经修复。优质蛋白质来源包括瘦肉、鱼、禽类、豆制品和乳制品。
ω-3脂肪酸对神经炎症的抑制作用：
ω-3多不饱和脂肪酸（omega-3 polyunsaturated fatty acids, PUFAs），特别是二十碳五烯酸（EPA）和二十二碳六烯酸（DHA），在抑制神经炎症方面发挥着关键作用，对糖尿病神经病变患者尤其重要 8081。- 作用机制：神经炎症是糖尿病神经病变病理过程中的重要环节。ω-3脂肪酸能够调节神经炎症，其机制包括：
- 抑制促炎介质：ω-3脂肪酸可以竞争性地抑制花生四烯酸（一种ω-6脂肪酸）代谢，从而减少促炎性介质（如前列腺素E2和白三烯B4）的生成。
- 促进抗炎介质：ω-3脂肪酸是合成一系列抗炎性脂质介质（如分辨素、保护素和马雷素）的前体，这些介质能够积极参与炎症的消退过程。
- 调节微胶质细胞极化：ω-3脂肪酸，特别是DHA，能够平衡微胶质细胞M1/M2极化，抑制M1型微胶质细胞产生的促炎因子（如TNF-α、IL-1β），同时促进M2型微胶质细胞产生的抗炎因子，从而减轻神经炎症 8283。微胶质细胞极化失衡是神经炎症和神经退行性疾病的关键驱动因素 83。
- 抑制NF-κB和p38 MAPK信号通路：ω-3脂肪酸可以抑制细胞内促炎信号通路，如NF-κB和p38 MAPK通路，从而减少炎症细胞因子的表达 8283。
- 食物来源：富含ω-3脂肪酸的食物主要包括深海鱼类（如三文鱼、鲭鱼、沙丁鱼）、亚麻籽、奇亚籽和核桃。
- 具体策略：建议糖尿病神经病变患者增加富含ω-3脂肪酸的食物摄入，每周至少食用两次深海鱼。对于饮食摄入不足或有特定需求者，可在医生或营养师指导下，考虑补充鱼油等ω-3脂肪酸补充剂。
- 作用机制：神经炎症是糖尿病神经病变病理过程中的重要环节。ω-3脂肪酸能够调节神经炎症，其机制包括：
通过精细化调整低能量饮食的宏量营养素配比，并特别强调ω-3脂肪酸的摄入，可以更好地支持神经功能，减轻神经炎症，从而为糖尿病神经病变的管理提供有力的营养支持。
5.3 个体化监测与干预
针对低能量饮食（LED）对糖尿病神经病变（DN）的潜在影响，实施个体化监测与干预策略至关重要。这不仅能及时发现和纠正LED可能带来的不良后果，还能根据患者的具体情况，动态调整能量限制强度和营养支持方案，从而在实现代谢改善的同时，最大限度地保护神经功能。
1. 动态评估流程建立：
- 神经传导速度（NCV）：NCV是评估大纤维神经功能受损程度的客观指标。建议DN患者在LED干预前后及定期随访中进行NCV检测，以评估运动和感觉神经传导功能的改变。如果NCV出现显著下降，提示可能存在神经损伤加重，需要重新评估LED的强度、宏量营养素配比及微量营养素补充情况。
- 血清同型半胱氨酸（Hcy）：Hcy水平升高是神经毒性的一个重要指标，与叶酸、维生素B12和维生素B6缺乏密切相关。在LED期间，特别是存在B族维生素摄入不足风险的患者，应定期监测血清Hcy水平。若Hcy水平持续升高，则需及时调整B族维生素的补充剂量，以降低神经损伤风险。
- 皮肤神经纤维密度（IENFD）：IENFD是诊断小纤维神经病变的敏感指标，尤其适用于评估DN的早期病变。对于怀疑或已诊断为小纤维神经病变的患者，可在LED干预前后进行皮肤活检以评估IENFD的变化。IENFD的进一步下降提示神经损伤可能在进展，这可能需要更积极的营养干预或调整LED方案。
2. 整合营养风险筛查（NRS-2002）：
营养风险筛查（Nutrition Risk Screening, NRS-2002）是一种广泛应用于临床的营养风险评估工具，通过评估患者的体重指数（BMI）、体重减轻情况、近期进食量以及疾病严重程度等因素，来识别存在营养风险的患者。
- 筛查目的：在启动LED前，所有DN患者均应进行NRS-2002筛查。对于筛查结果提示中高营养风险的患者，应谨慎考虑LED的实施，或在严格的营养监测和支持下进行。
- 调整能量限制强度：
- 低风险患者：对于无明显营养风险或BMI较高的肥胖DN患者，可在密切监测下实施较为严格的LED，但仍需确保宏量营养素和微量营养素的充足性。
- 中高风险患者：对于存在营养不良风险或BMI较低的DN患者，应采取更为温和的能量限制策略，或暂时推迟LED的实施，优先纠正营养不良状态。能量限制的程度应个体化，例如，可以将能量赤字设定为250-500 kcal/日，而非极低热量饮食。同时，需确保足够的蛋白质和关键微量营养素摄入。
- 动态监测与再评估：NRS-2002并非一次性评估工具，应在LED实施过程中定期（如每月或每季度）进行再评估。如果患者在LED期间出现新的营养风险或既有风险加重，应立即调整LED方案，包括增加能量摄入、强化营养补充、调整宏量营养素比例，并密切关注DN的进展。
通过将动态神经功能评估与系统的营养风险筛查相结合，可以为糖尿病神经病变患者提供更为安全、有效的低能量饮食管理策略。这种个体化的监测和干预方法，有助于平衡血糖控制和体重管理的需求与神经健康保护之间的关系。
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参考文献
1Diabetic neuropathy: cutting-edge research and future directions.PubMed
Yang Yang, Bing Zhao, Yuanzhe Wang, et al.
Signal Transduct Target Ther. 2025 Apr 25;10(1):132. doi: 10.1038/s41392-025-02175-1.
Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.
2The diabetic neuropathies.PubMed
Clifton Gooch, David Podwall
Neurologist. 2004 Nov;10(6):311-22. doi: 10.1097/01.nrl.0000144733.61110.25.
BACKGROUND: Diabetes remains the most common cause of neuropathy in the United States and is a significant source of morbidity and mortality, accounting for substantial suffering and billions of dollars in health care expenditures each year. REVIEW SUMMARY: Our insight into the pathophysiology of the diabetic neuropathies has increased considerably over the last decade. aided by advances in the basic science of diabetes itself. A wide variety of potential mechanisms for nerve injury in diabetes has been identified, including the polyol pathway of glucose metabolism, oxidative nerve injury, the deposition of advanced glycosylation end products within the nerve and the effects of vascular insufficiency, among others. Diabetic neuropathy may take a variety of clinical forms beyond the well-known distal symmetric neuropathy, many of which are often misdiagnosed or overlooked entirely, sometimes with serious consequences for the patient. Proper therapy after diagnosis is also critical and may include not only primary management, but also treatment of painful diabetic neuropathy through an expanding repertoire of increasingly effective pharmacologic agents. Though primary treatment trials have not yet provided effective therapies, ongoing and future trials offer continuing promise. CONCLUSIONS: The diabetic neuropathies are exceedingly common, but often improperly diagnosed and incompletely treated. A proper understanding of the mechanisms underlying these diseases and the clinical recognition of their various forms is highly important as appropriate primary and symptomatic management can substantially reduce the morbidity and mortality associated with these disorders.
3How curcumin affects hyperglycemia-induced optic nerve damage: A short review.PubMed
İzem Olcay Şahin
J Chem Neuroanat. 2021 Apr;113:101932. doi: 10.1016/j.jchemneu.2021.101932. Epub 2021 Feb 10.
Considered to be one of the most important non-contagious systemic diseases worldwide, diabetes mellitus is still a topical issue on the health agenda with the problems it causes. Exposure to long-term hyperglycemia causes diabetic complications (diabetic neuropathy, nephropathy and retinopathy). The optic nerve can suffer damage by both diabetic retinopathy and neuropathy during diabetes, both because it is formed by axons of retinal ganglion cells and these axons belong to the central nervous system. The issue of hyperglycemia on the optic nerve have been described as diabetic papillopathy, posterior ischemic optic neuropathy, nonarteritic anterior ischemic optic neuropathy and optic atrophy in clinical studies. Experimental studies indicated axon-myelin degeneration in addition to microvascular and ultrastructural changes caused by the hyperglycemia-induced optic nerve damage. Although there are several proposed biochemical mechanisms to cause these damages, oxidative stress emerges as an important factor among them. Oxidative stress leads to pathological state on the nerve cells by affecting the DNA, protein and lipids at different levels. These are causing deterioration on nerve conduction velocity, myelin sheath and nerve structure, neurotrophic support system, glial cells and nerve function. Curcumin, as an important antioxidant, can be an ideal prophylactic agent to eliminate damages on optic nerve. Curcumin helps to regulate the balance of antioxidant and reactive oxygen species by targeting various molecules (NF-κB, STAT3, MAPK, Mfn2, Nrf2, pro-inflammatory cytokines). In addition, it shows healing or preventive effects on myelin sheath damage via regulating ferritin protein in oligodendrocytes. It is also effective in preventing neurovascular damage.
4Activation of 20-HETE Synthase Triggers Oxidative Injury and Peripheral Nerve Damage in Type 2 Diabetic Mice.PubMed
Mary Haddad, Stéphanie Eid, Frederic Harb, et al.
J Pain. 2022 Aug;23(8):1371-1388. doi: 10.1016/j.jpain.2022.02.011. Epub 2022 Mar 24.
Diabetic Peripheral Neuropathy (DPN), highly prevalent among patients with diabetes, is characterized by peripheral nerve dysfunction. Reactive Oxygen Species (ROS) overproduction has been suggested to orchestrate diabetic complications including DPN. Untargeted antioxidant therapy has exhibited limited efficacy, highlighting a critical need to explore ROS sources altered in a cell-specific manner in DPN. Cytochromes P450 (CYP) enzymes are prominent sources of ROS. Particularly, the 20-HETE synthase, CYP4A, is reported to mediate diabetes-induced renal, retinal, and cardiovascular injuries. This work investigates the role of CYP4A/20-HETE in DPN and their mechanisms of action. Non-obese type 2 Diabetic mice (MKR) were used and treated with a CYP4A-inhibitor (HET0016) or AMPK-activator (Metformin). Peripheral nerves of MKR mice reflect increased CYP4A and 20-HETE levels, concurrent with altered myelin proteins and sensorimotor deficits. This was associated with increased ROS production and altered Beclin-1 and LC3 protein levels, indicative of disrupted autophagic responses in tandem with AMPK inactivation. AMPK activation via Metformin restored nerve integrity, reduced ROS production, and regulated autophagy. Interestingly, similar outcomes were revealed upon HET0016 treatment whereby ROS production, autophagic responses, and AMPK signaling were normalized in diabetic mice. Altogether, the results highlight hyperglycemia-mediated oxidative injury in DPN through a novel CYP4A/20-HETE/AMPK pathological axis. PERSPECTIVE: To our knowledge, this is the first study to highlight the role of CYPs/20-HETE-induced oxidative injury in the pathogenesis of diabetic peripheral neuropathy. Targeting the identified pathological axis CYP4A/20-HETE/AMPK may be of clinical potential in predicting and alleviating peripheral nerve injury in patients with Type 2 Diabetes Mellitus.
5Aldose reductase inhibitors.PubMed
M Oka, N Kato
J Enzyme Inhib. 2001 Dec;16(6):465-73. doi: 10.1080/14756360127568.
Aldose reductase ([EC1.1.1.21]: AR) acts on the first step of the polyol metabolic pathway to catalyze the reduction of glucose to sorbitol with NADPH as a coenzyme. Hyperactivity of the pathway in individuals with high blood glucose level is closely related to the onset or progression of diabetic complications. AR inhibitors have therefore been noted as possible pharmacotherapeutic agents for the treatment of diabetic complications. One AR inhibitor has been on the market in Japan, while some potent inhibitors are in clinical trials. Reviewed are the physiological roles of AR, the chemical structures of AR inhibitors, interactions of AR inhibitors with AR using X-ray studies, and the following potencies of AR inhibitors: in vitro activities for AR, in vitro selectivities between AR and aldehyde reductase, their pharmacological effects in vivo, and their effectiveness in clinical trials. Also discussed are directions for the design of future AR inhibitors.
6Polyol pathway and diabetic peripheral neuropathy.PubMed
Peter J Oates
Int Rev Neurobiol. 2002;50:325-92. doi: 10.1016/s0074-7742(02)50082-9.
This chapter critically examines the concept of the polyol pathway and how it relates to the pathogenesis of diabetic peripheral neuropathy. The two enzymes of the polyol pathway, aldose reductase and sorbitol dehydrogenase, are reviewed. The structure, biochemistry, physiological role, tissue distribution, and localization in peripheral nerve of each enzyme are summarized, along with current informaiton about the location and structure of their genes, their alleles, and the possible links of each enzyme and its alleles to diabetic neuropathy. Inhibitors of pathway enzyme and results obtained to date with pathway inhibitors in experimental models and human neuropathy trials are updated and discussed. Experimental and clinical data are analyzed in the context of a newly developed metabolic odel of the in vivo relationship between nerve sorbitol concentration and metabolic flux through aldose reuctase. Overall, the data will be interpreted as supporting the hypothesis that metabolic flux through the polyol pathway, rather than nerve concentration of sorbitol, is the predominant polyol pathway-linked pathogeneic factor in diabetic preipheral nerve. Finally, key questions and future directions for bsic and clinical research in this area are considered. It is concluded that robust inhibition of metabolic flux through the polyol pathway in peripheral nerve will likely result in substantial clinical benefit in treating and preventing the currently intractable condition of diabetic peripheral neuropathy. To accomplish this, it is imperative to develop and test a new generation of "super-potent" polyol pathway inhibitors.
7Diabetic neuropathies: features and mechanisms.PubMed
D W Zochodne
Brain Pathol. 1999 Apr;9(2):369-91. doi: 10.1111/j.1750-3639.1999.tb00233.x.
Diabetic neuropathies include both focal neuropathies and diffuse polyneuropathy. Polyneuropathy, the most common of the diabetic neuropathies excluding focal entrapment, has not yet been explained by a single disease mechanism despite intensive investigation. A number of abnormalities appear to cascade into a 'vicious cycle' of progressive microvascular disease associated with motor, sensory and autonomic fiber loss. These abnormalities include excessive polyol (sugar alcohol) flux through the aldose reductase pathway, functional and structural alterations of nerve microvessels, nerve and ganglia hypoxia, oxidative stress, nonspecific glycosylation of axon and microvessel proteins, and impairment in the elaboration of trophic factors critical for peripheral nerves and their ganglia. While an initiating role for nerve ischemia in the development of polyneuropathy has been proposed, the evidence for it can be questioned. The role of sensory and autonomic ganglia in the development of polyneuropathy has had relatively less attention despite the possibility that they may be vulnerable to a variety of insults, particularly neurotrophin deficiency. Superimposed on the deficits of polyneuropathy is the failure of diabetic nerves to regenerate as effectively as nondiabetics. Polyneuropathy has not yet yielded to specific forms of treatment but a variety of new trials addressing plausible hypotheses have been initiated. This review will summarize some of the clinical, pathological and experimental work applied toward understanding human diabetic neuropathy and will emphasize ideas on pathogenesis.
8Advanced glycation end-products: a review.PubMed
R Singh, A Barden, T Mori, et al.
Diabetologia. 2001 Feb;44(2):129-46. doi: 10.1007/s001250051591.
Advanced glycation end-products are a complex and heterogeneous group of compounds that have been implicated in diabetes related complications. At present it is not known if they are the cause or the consequence of the complications observed. We discuss the chemistry of advanced glycated end-product formation and their patho-biochemistry particularly in relation to the diabetic microvascular complications of retinopathy, neuropathy and nephropathy as well as their role in the accelerated vasculopathy observed in diabetes. The concept of carbonyl stress as a cause for advanced glycated end-product toxicity is mentioned. We discuss alterations in the concentrations of advanced glycated end-products in the body, particularly in relation to changes occurring with age, diabetes and its complications such as nephropathy. Problems relating to current methods of advanced glycated end-product detection and measurement are highlighted including the lack of a universally established method of detection or unit of measurement. Agents used for the treatment of advanced glycated end-product accumulation are reviewed, with an emphasis on the results of the recent phase III trials using aminoguanidine and diabetes related complications.
9Advanced Glycation End-Products and Diabetic Neuropathy of the Retina.PubMed
Toshiyuki Oshitari
Int J Mol Sci. 2023 Feb 2;24(3):2927. doi: 10.3390/ijms24032927.
Diabetic retinopathy is a tissue-specific neurovascular impairment of the retina in patients with both type 1 and type 2 diabetes. Several pathological factors are involved in the progressive impairment of the interdependence between cells that consist of the neurovascular units (NVUs). The advanced glycation end-products (AGEs) are one of the major pathological factors that cause the impairments of neurovascular coupling in diabetic retinopathy. Although the exact mechanisms for the toxicities of the AGEs in diabetic retinopathy have not been definitively determined, the AGE-receptor of the AGE (RAGE) axis, production of reactive oxygen species, inflammatory reactions, and the activation of the cell death pathways are associated with the impairment of the NVUs in diabetic retinopathy. More specifically, neuronal cell death is an irreversible change that is directly associated with vision reduction in diabetic patients. Thus, neuroprotective therapies must be established for diabetic retinopathy. The AGEs are one of the therapeutic targets to examine to ameliorate the pathological changes in the NVUs in diabetic retinopathy. This review focuses on the basic and pathological findings of AGE-induced neurovascular abnormalities and the potential therapeutic approaches, including the use of anti-glycated drugs to protect the AGE-induced impairments of the NVUs in diabetic retinopathy.
10Skin AGEs and diabetic neuropathy.PubMed
Stella Papachristou, Kalliopi Pafili, Nikolaos Papanas
BMC Endocr Disord. 2021 Feb 23;21(1):28. doi: 10.1186/s12902-021-00697-7.
Advanced glycation end-products (AGEs) are heterogeneous molecules produced by the non-enzymatic glycation of proteins, lipids, or nucleic acids during hyperglycaemia. Accumulation of AGEs in the peripheral nerves has recently been proposed as an additional risk factor for the development of diabetic neuropathy (DN). The gold standard for measurement of tissue-bound AGEs is tissue biopsy. However, their assessment with the newer, fast and simple method of skin autofluorescence (sAF) has recently gained special interest by virtue of its non-invasive, highly reproducible nature and its acceptable correlation with the reference method of skin biopsy. Accumulation of tissue AGEs evaluated by sAF has been shown to independently correlate with DN. Importantly, increasing evidence underscores their potential value as early biomarkers of the latter. Further important associations include diabetic nephropathy, diabetic retinopathy and cardiovascular autonomic neuropathy. However, the value of the implementation of screening with skin AGEs for DN remains unclear. The aim of the present review is to critically summarise current evidence on the association between skin AGEs and diabetic microvascular complications, with a particular emphasis on diabetic neuropathy, and to note the most important limitations of existing knowledge. Longer follow-up studies are also highly anticipated to clarify its role and provide data on patient selection and cost-effectiveness.
11Advanced glycation end products in musculoskeletal system and disorders.PubMed
Akinobu Suzuki, Akito Yabu, Hiroaki Nakamura
Methods. 2022 Jul;203:179-186. doi: 10.1016/j.ymeth.2020.09.012. Epub 2020 Sep 26.
The human population is ageing globally, and the number of old people is increasing yearly. Diabetes is common in the elderly, and the number of diabetic patients is also increasing. Elderly and diabetic patients often have musculoskeletal disorder, which are associated with advanced glycation end products (AGEs). AGEs are heterogeneous molecules derived from non-enzymatic products of the reaction of glucose or other sugar derivatives with proteins or lipids, and many different types of AGEs have been identified. AGEs are a biomarker for ageing and for evaluating disease conditions. Fluorescence, spectroscopy, mass spectrometry, chromatography, and immunological methods are commonly used to measure AGEs, but there is no standardized evaluation method because of the heterogeneity of AGEs. The formation of AGEs is irreversible, and they accumulate in tissue, eventually causing damage. AGE accumulation has been confirmed in neuromusculoskeletal tissues, including bones, cartilage, muscles, tendons, ligaments, and nerves, where they adversely affect biomechanical properties by causing charge changes and forming cross-linkages. AGEs also bind to receptors, such as the receptor for AGEs (RAGE), and induce inflammation by intracellular signal transduction. These mechanisms cause many varied aging and diabetes-related pathological conditions, such as osteoporosis, osteoarthritis, sarcopenia, tendinopathy, and neuropathy. Understanding of AGEs related pathomechanism may lead to develop novel methods for the prevention and therapy of such disorders which affect patients' quality of life. Herein, we critically review the current methodology used for detecting AGEs, and present potential mechanisms by which AGEs cause or exacerbate musculoskeletal disorders.
12Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management.PubMed
Troels S Jensen, Pall Karlsson, Sandra S Gylfadottir, et al.
Brain. 2021 Jul 28;144(6):1632-1645. doi: 10.1093/brain/awab079.
Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30-40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes.
13Diabetic autonomic neuropathy.PubMed
Aaron I Vinik, Raelene E Maser, Braxton D Mitchell, et al.
Diabetes Care. 2003 May;26(5):1553-79. doi: 10.2337/diacare.26.5.1553.
Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, approximately 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brittle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal [GI], genitourinary, and cardiovascular). GI disturbances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal incontinence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to consideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; measurement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve function; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an increased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of autonomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing)or longitudinal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing requires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recommended tests for assessing CAN is readily performed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of autonomic dysfunction earlier) serves to establish a baseline, with which 1-year interval tests can be compared. Regular HRV testing provides early detection and thereby promotes timely diagnostic and therapeutic interventions. HRV testing may also facilitate differential diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and dizziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to improve metabolic control and to use therapies such as ACE inhibitors and beta-blockers, proven to be effective for patients with CAN.
14Cardiac Autonomic Neuropathy in Diabetes Mellitus.PubMed
Shruti Agashe, Steven Petak
Methodist Debakey Cardiovasc J. 2018 Oct-Dec;14(4):251-256. doi: 10.14797/mdcj-14-4-251.
Cardiovascular autonomic neuropathy (CAN) is a severely debilitating yet underdiagnosed condition in patients with diabetes. The prevalence can range from 2.5% (based on the primary prevention cohort in the Diabetes Control and Complications Trial) to as high as 90% of patients with type 1 diabetes. Clinical manifestations range from orthostasis to myocardial infarction. The diagnosis is made using multiple autonomic function tests to assess both sympathetic and parasympathetic function. The pathophysiology of CAN is complex, likely multifactorial, and not completely understood. Treatment is limited to symptomatic control of orthostatic hypotension, which is a late complication, and current strategies to reverse CAN are limited. This review explores the epidemiology, pathophysiology, clinical manifestations, diagnosis, and complications of CAN as well as current treatment options.
15Cardiovascular autonomic neuropathy in diabetes: an update with a focus on management.PubMed
Aikaterini Eleftheriadou, Vincenza Spallone, Abd A Tahrani, et al.
Diabetologia. 2024 Dec;67(12):2611-2625. doi: 10.1007/s00125-024-06242-0. Epub 2024 Aug 9.
Cardiovascular autonomic neuropathy (CAN) is an under-recognised yet highly prevalent microvascular complication of diabetes. CAN affects approximately 20% of people with diabetes, with recent studies highlighting the presence of CAN in prediabetes (impaired glucose tolerance and/or impaired fasting glucose), indicating early involvement of the autonomic nervous system. Understanding of the pathophysiology of CAN continues to evolve, with emerging evidence supporting a potential link between lipid metabolites, mitochondrial dysfunction and genetics. Recent advancements, such as streamlining CAN detection through wearable devices and monitoring of heart rate variability, present simplified and cost-effective approaches for early CAN detection. Further research on the optimal use of the extensive data provided by such devices is required. Despite the lack of specific pharmacological interventions targeting the underlying pathophysiology of autonomic neuropathy, several studies have suggested a favourable impact of newer glucose-lowering agents, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, where there is a wealth of clinical trial data on the prevention of cardiovascular events. This review delves into recent developments in the area of CAN, with emphasis on practical guidance to recognise and manage this underdiagnosed condition, which significantly increases the risk of cardiovascular events and mortality in diabetes.
16Diabetic Gastroparesis.PubMed
Adil E Bharucha, Yogish C Kudva, David O Prichard
Endocr Rev. 2019 Oct 1;40(5):1318-1352. doi: 10.1210/er.2018-00161.
This review covers the epidemiology, pathophysiology, clinical features, diagnosis, and management of diabetic gastroparesis, and more broadly diabetic gastroenteropathy, which encompasses all the gastrointestinal manifestations of diabetes mellitus. Up to 50% of patients with type 1 and type 2 DM and suboptimal glycemic control have delayed gastric emptying (GE), which can be documented with scintigraphy, 13C breath tests, or a wireless motility capsule; the remainder have normal or rapid GE. Many patients with delayed GE are asymptomatic; others have dyspepsia (i.e., mild to moderate indigestion, with or without a mild delay in GE) or gastroparesis, which is a syndrome characterized by moderate to severe upper gastrointestinal symptoms and delayed GE that suggest, but are not accompanied by, gastric outlet obstruction. Gastroparesis can markedly impair quality of life, and up to 50% of patients have significant anxiety and/or depression. Often the distinction between dyspepsia and gastroparesis is based on clinical judgement rather than established criteria. Hyperglycemia, autonomic neuropathy, and enteric neuromuscular inflammation and injury are implicated in the pathogenesis of delayed GE. Alternatively, there are limited data to suggest that delayed GE may affect glycemic control. The management of diabetic gastroparesis is guided by the severity of symptoms, the magnitude of delayed GE, and the nutritional status. Initial options include dietary modifications, supplemental oral nutrition, and antiemetic and prokinetic medications. Patients with more severe symptoms may require a venting gastrostomy or jejunostomy and/or gastric electrical stimulation. Promising newer therapeutic approaches include ghrelin receptor agonists and selective 5-hydroxytryptamine receptor agonists.
17Vesicourethral function in diabetic patients: association of abnormal nerve conduction velocity with vesicourethral dysfunction.PubMed
T Mitsui, H Kakizaki, S Kobayashi, et al.
Neurourol Urodyn. 1999;18(6):639-45. doi: 10.1002/(sici)1520-6777(1999)18:6<639::aid-nau14>3.0.co;2-r.
This study was undertaken to examine diabetic vesicourethral dysfunction in association with nerve conduction velocity. Uroflowmetry, water cystometry, International Prostate Symptom Score (IPSS), and nerve conduction velocity were analyzed in 29 diabetic patients (21 men and eight women; a mean age, 58.0 years). Nerve conduction velocity was measured for sensory nerve conduction velocity (SCV) of the sural nerve and motor nerve conduction velocity (MCV) of the peroneal nerve. Normal voiding was defined as continuous flow at the normal flow rate and residual urine <50 mL. Results of uroflowmetry and cystometry were compared with those of nerve conduction velocity. Eleven of 29 patients (38%) had voiding dysfunction. A vesical denervation supersensitivity test was negative in all patients. The mean IPSS was not significant different between patients with or without voiding dysfunction. Incidence of bladder volume at first desire to void >300 mL and maximum bladder capacity >500 mL were significantly higher in patients with abnormal SCV than those with normal SCV (P < 0.03 and 0.001, respectively). Eleven of 16 patients with abnormal MCV showed voiding dysfunction, whereas all patients with normal MCV showed normal voiding (P < 0.001). These results suggest that lower urinary tract symptoms alone cannot predict diabetic vesicourethral dysfunction and that diabetic vesicourethral dysfunction is highly correlated with abnormal nerve conduction velocity. Neurourol. Urodynam. 18:639-645, 1999.
18Electrophysiologic testing in diabetic neuropathy.PubMed
Bruce Perkins, Vera Bril
Handb Clin Neurol. 2014;126:235-48. doi: 10.1016/B978-0-444-53480-4.00018-7.
Electrophysiologic studies provide objective data concerning nerve and muscle function. This information enables the diagnosis of disease states and monitoring of disease progression. This chapter describes the changes in electrophysiologic function in both prediabetes and diabetes and discusses the utility of this testing in patients with diabetes. Both the strengths and limitations of electrophysiology are discussed.
19The prevalence of peripheral neuropathy in newly diagnosed patients with non-insulin-dependent diabetes mellitus.PubMed
N Weerasuriya, S Siribaddana, I Wijeweera, et al.
Ceylon Med J. 1998 Mar;43(1):19-21.
INTRODUCTION: Neuropathy is considered to be a longterm complication of diabetes. AIMS: To determine the prevalence of peripheral neuropathy in 112 Sri Lankan patients with recently diagnosed non-insulin-dependent diabetes and a control population of 100 people. METHODS: A diagnosis of peripheral neuropathy was made using a clinical symptom score, clinical examination, quantitative sensory testing and electrophysiological studies. RESULTS: 9.8% of diabetic patients at diagnosis had peripheral neuropathy, 2.6% had foot ulcers, 7.1% had signs of neuropathy, abnormal vibration perception threshold and nerve conduction abnormalities and 15.1% had abnormal nerve conduction velocity without signs or symptoms of neuropathy. The peroneal nerve conduction velocity was higher in diabetic patients when compared to controls. There was an inverse correlation between nerve conduction velocity and fasting blood glucose in diabetic patients (p < 0/05). This association was stronger for peroneal nerve conduction velocity (r = -0.73) than for median nerve motor conduction velocity (r = -0.42). CONCLUSIONS: Symptomatic peripheral neuropathy is common among Sri Lankans with newly diagnosed non-insulin-dependent diabetes. This may be due to a later presentation of diabetes or a genetic predisposition.
20Epidermal innervation in diabetes.PubMed
Gigi Ebenezer, Michael Polydefkis
Handb Clin Neurol. 2014;126:261-74. doi: 10.1016/B978-0-444-53480-4.00020-5.
The skin is innervated by small sensory and autonomic fibers. In the epidermis, sensory fibers are present as unmyelinated C fibers that terminate as free nerve endings. The determination of epidermal nerve fiber (ENF) density using the immunohistochemical method is a powerful tool that provides insight into a population of nerve fibers that is prominently altered in small fiber neuropathy. The superficial location of epidermal nerve fibers allows repeated sampling of these nerves in a relatively noninvasive fashion, and in sites that cannot be assessed through conventional electrodiagnostic techniques. These features have allowed investigators to diagnose diabetic neuropathy earlier in the course of disease. ENF density holds promise as a biomarker for neuropathic pain and is a sensitive indicator of neuropathic progression. Finally, the ability to injure these fibers in a standardized fashion has led to novel measures of human axonal regeneration that may provide a more sensitive ruler by which to assess promising regenerative compounds in clinical trials.
21Dapagliflozin for Small Nerve Fibre Regeneration in Diabetic Peripheral Neuropathy: A Randomised Controlled Study (DINE).PubMed
Umanath Adhikari, Hoda Gad, Debajyoti Chatterjee, et al.
J Peripher Nerv Syst. 2025 Mar;30(1):e70011. doi: 10.1111/jns.70011.
OBJECTIVES: There are currently no FDA-approved disease-modifying therapies for diabetic peripheral neuropathy (DPN). We evaluated the effect of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in Type 2 diabetes mellitus (T2DM) with DPN. RESEARCH DESIGN AND METHODS: In this prospective, open-label, randomised, controlled study, 40 participants with DPN were randomised to receive add-on 10 mg dapagliflozin OD (Group A) to existing oral antidiabetic drugs (OAD) (n = 22) or continue OADs as a standard of care (Group B) (n = 18). Participants underwent assessment of neuropathic symptoms and signs (MNSI), vibration perception threshold (VPT), corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fibre length (CNFL) and skin biopsy to assess intraepidermal nerve fibre density (IENFD) and plasma markers of oxidative stress at randomisation and after 6 months. RESULTS: HbA1c decreased in Group A (p = 0.002) and Group B (p = 0.003), with no change in weight, body mass index (BMI) or lipids. Total MNSI increased in Group A (p = 0.01) with no change in Group B (p = 0.06). IENFD increased significantly in Group A (p = 0.01) and Group B (p = 0.01), while CNFD (p = 0.002), CNBD (p < 0.001) and CNFL (p = 0.025) increased in Group A with no change in Group B. There was a significant increase in glutathione peroxidase (p = 0.02) in Group A with no change in Group B, and a decrease in malondialdehyde in both groups (p < 0.001). CONCLUSIONS: In participants with T2DM and DPN, dapagliflozin was associated with small nerve fibre regeneration and improvement in markers of oxidative stress. TRIAL REGISTRATION: Clinical Trial Registry India, CRTI Reg. No (CTRI/2022/06/043236); ClinicalTrials.gov Identifier: NCT05162690.
22Foretinib mitigates cutaneous nerve fiber loss in experimental diabetic neuropathy.PubMed
Simeon C Daeschler, Jennifer Zhang, Tessa Gordon, et al.
Sci Rep. 2022 May 19;12(1):8444. doi: 10.1038/s41598-022-12455-3.
Diabetes is by far, the most common cause of neuropathy, inducing neurodegeneration of terminal sensory nerve fibers associated with loss of sensation, paresthesia, and persistent pain. Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons by rescuing mitochondrial activity and has been proven safe in prospective clinical trials. Here we aimed at investigating a potential neuroprotective effect of Foretinib in experimental diabetic neuropathy. A mouse model of streptozotocin induced diabetes was used that expresses yellow fluorescent protein (YFP) in peripheral nerve fibers under the thy-1 promoter. Streptozotocin-injected mice developed a stable diabetic state (blood glucose > 270 mg/dl), with a significant reduction of intraepidermal nerve fiber density by 25% at 5 weeks compared to the non-diabetic controls. When diabetic mice were treated with Foretinib, a significantly greater volume of the cutaneous nerve fibers (67.3%) in the plantar skin was preserved compared to vehicle treated (37.8%) and non-treated (44.9%) diabetic mice while proximal nerve fiber morphology was not affected. Our results indicate a neuroprotective effect of Foretinib on cutaneous nerve fibers in experimental diabetic neuropathy. As Foretinib treated mice showed greater weight loss compared to vehicle treated controls, future studies may define more sustainable treatment regimen and thereby may allow patients to take advantage of this neuroprotective drug in chronic neurodegenerative diseases like diabetic neuropathy.
23Types and Concentrations of Blood-Based Biomarkers in Adults With Peripheral Neuropathies: A Systematic Review and Meta-analysis.PubMed
Joel Fundaun, Melissa Kolski, Miguel Molina-Álvarez, et al.
JAMA Netw Open. 2022 Dec 1;5(12):e2248593. doi: 10.1001/jamanetworkopen.2022.48593.
IMPORTANCE: Peripheral neuropathies are common conditions and can result in numbness, paresthesia, motor deficits, and pain. There is increasing evidence for the use of biomarkers as clinical indicators of the presence, severity, and prognosis of nerve lesions; however, biomarker identification has largely been focused on disorders of the central nervous system, and less is known about their role in the peripheral nervous system. OBJECTIVE: To assess blood-based biomarker concentrations associated with nerve involvement in patients with peripheral neuropathy compared with control participants. DATA SOURCES: Ovid, MEDLINE, Embase, and CINAHL were searched from inception to September 23, 2021. STUDY SELECTION: Observational studies reporting on blood biomarkers in patients diagnosed with peripheral neuropathy were included. This review was preregistered on PROSPERO and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were abstracted by 1 investigator and independently reviewed by a second. DATA EXTRACTION AND SYNTHESIS: Data were meta-analyzed when at least 2 studies reported the same biomarker with comparable methodology. Fixed-effects models were used when only 2 studies were included; random-effects models were used when more than 2 studies were included. MAIN OUTCOMES AND MEASURES: The outcome of interest was concentration of biomarkers. RESULTS: This review included 36 studies reporting on 4414 participants, including 2113 control participants and 2301 patients with peripheral neuropathy with 13 distinct peripheral neuropathy diagnoses. Diabetic neuropathy was the most common neuropathy diagnosis (13 studies), followed by Charcot-Marie-Tooth disease (6 studies) and Guillain-Barre syndrome (6 studies). Overall, 16 different blood-based biomarkers associated with nerve involvement were evaluated. The most used were neurofilament light chain, S100B, brain-derived neurotrophic factor, and neuron-specific enolase. Patients with peripheral neuropathy demonstrated significantly higher levels of neurofilament light chain compared with controls (standardized mean difference [SMD], 0.93 [95% CI, 0.82 to 1.05]; P < .001). There were no significant differences in levels of S100B (SMD, 1.10 [95% CI, -3.08 to 5.28]; P = .38), brain-derived neurotrophic factor (SMD, -0.52 [95% CI, -2.23 to 1.19]; P = .40), or neuron-specific enolase (SMD, -0.00 [95% CI, -1.99 to 1.98]; P = .10) in patients with peripheral neuropathy compared with control participants. CONCLUSIONS AND RELEVANCE: The findings of this systematic review and meta-analysis support the use of neurofilament light chain as a blood-based measure associated with the presence of neuronal injury in patients with peripheral neuropathy.
24Effects of intermittent very-low calorie diet on glycemic control and cardiovascular risk factors in obese patients with type 2 diabetes mellitus: A randomized controlled trial.PubMed
Mongkontida Umphonsathien, Peedaporn Rattanasian, Siriporn Lokattachariya, et al.
J Diabetes Investig. 2022 Jan;13(1):156-166. doi: 10.1111/jdi.13619. Epub 2021 Jul 30.
AIMS/INTRODUCTION: Very few studies assess the effectiveness of different protocols of intermittent very-low calorie diet (VLCD) in patients with diabetes. This study was designed to compare the effects of 2 days/week and 4 days/week of intermittent VLCD on glycemic control, diabetes remission, metabolic parameters and quality of life in patients with type 2 diabetes and obesity. MATERIALS AND METHODS: Participants with obesity and type 2 diabetes were recruited and randomly assigned to three groups, consisting of control, 2 days/week and 4 days/week of intermittent VLCD. In the intermittent VLCD groups, participants received a 600-kcal diet per day on restricted days and ad libitum food consumption on non-restricted days. Glycemic control, rate of diabetes remission, metabolic parameters and quality of life were evaluated at baseline, weeks 2, 10 and 20. RESULTS: A total of 40 participants were enrolled. The mean body mass index was 30.1 ± 5.9 kg/m , and the mean glycated hemoglobin was 7.4 ± 1.2%. At week 20, there was an improvement in glycemic control in both intermittent VLCD groups with significant decreases in glycated hemoglobin levels and insulin resistance index throughout the study periods. Diabetes remission without the need for medications was equally found in 29% of participants in both intermittent VLCD groups. Serum triglyceride, bodyweight, body mass index and fat mass were also significantly decreased in both VLCD groups. No serious adverse events were encountered. CONCLUSION: Intermittent VLCD was highly effective in achieving optimal glycemic control. The effects of 2 days/week and 4 days/week of intermittent VLCD on diabetes remission were relatively similar.
25Metabolic effects of very-low calorie diet, Semaglutide, or combination of the two, in individuals with type 2 diabetes mellitus.PubMed
Oluwaseun Anyiam, Bethan Phillips, Katie Quinn, et al.
Clin Nutr. 2024 Aug;43(8):1907-1913. doi: 10.1016/j.clnu.2024.06.034. Epub 2024 Jul 2.
BACKGROUND & AIMS: Very-low calorie diets (VLCD) and the glucagon-like peptide-1 receptor agonist (GLP1RA) Semaglutide induce significant weight loss and improve glycaemic control in individuals with type 2 diabetes (T2D). This pilot study was conducted to explore the comparative short-term effects of these interventions individually, and in combination, on weight, body composition and metabolic outcomes. METHODS: Thirty individuals with T2D (age 18-75 years, BMI 27-50 kg m) were randomly assigned to receive Semaglutide (SEM), 800 kilocalorie/day VLCD (VLCD), or both in combination (COMB) for 12 weeks. Measurement of weight and glycated haemoglobin (HbA1c), dual energy X-ray absorptiometry, and intravenous glucose tolerance tests (IVGTT) were performed at baseline and post-intervention. Diet diaries were utilised to assess compliance. Insulin first phase response during IVGTT provided a marker of pancreatic beta-cell function, and insulin sensitivity was estimated using HOMA-IR. RESULTS: Significantly greater reductions in body weight and fat mass were observed in VLCD and COMB, than SEM (p < 0.01 v both). VLCD and COMB resulted in a 5.4 and 7 percentage-point greater weight loss than SEM, respectively. HbA1c and fasting glucose reduced significantly in all groups, however fasting insulin and HOMA-IR improved in VLCD and COMB only. Insulin first phase response during IVGTT increased in SEM and COMB, and this increase was significantly greater in COMB than VLCD (p < 0.01). CONCLUSION: VLCD elicited greater short-term losses of weight and fat mass than Semaglutide. Adding VLCD to Semaglutide stimulated further weight loss than Semaglutide alone. The combination did not yield any additive effects on weight and body composition above VLCD alone, but did provoke greater improvements in pancreatic beta-cell function. Thus, combination of Semaglutide and VLCD warrants further exploration as a novel approach to T2D management.
26Very low calorie diets and total diet replacement in type 2 diabetes: where are we now?PubMed
Roy Taylor
Drug Ther Bull. 2024 Feb 28;62(3):39-42. doi: 10.1136/dtb.2022.000055.
Management of type 2 diabetes has now been simplified by the understanding that the condition is caused by excess fat in the liver together with suppression of beta cell function by the associated excess liver export of fat. These factors can be reversed by substantial weight loss leading to remission in the early years after diagnosis, or at least major decrease in cardiovascular risks and improvement in glucose control for all. Weight loss by any means is successful, but it is most easily achieved by rapid action using a low or very low calorie diet of around 800 kcal/day followed by sustained modest restraint of dietary habits. Oral hypoglycaemic agents and one antihypertensive drug can be withdrawn on day 1 of the weight loss diet, raising the importance of appropriate deprescribing.
27Very-Low-Calorie Ketogenic Diet as a Safe and Valuable Tool for Long-Term Glycemic Management in Patients with Obesity and Type 2 Diabetes.PubMed
Eleonora Moriconi, Elisabetta Camajani, Andrea Fabbri, et al.
Nutrients. 2021 Feb 26;13(3):758. doi: 10.3390/nu13030758.
Obesity-related type 2 diabetes represents one of the most difficult challenges for the healthcare system. This retrospective study aims to determine the efficacy, safety and durability of a very-low-calorie ketogenic diet (VLCKD), compared to a standard low-calorie diet (LCD) on weight-loss, glycemic management, eating behavior and quality of life in patients with type 2 diabetes (T2DM) and obesity. Thirty patients with obesity and T2DM, aged between 35 and 75 years, who met the inclusion criteria and accepted to adhere to a VLCKD or a LCD nutritional program, were consecutively selected from our electronic database. Fifteen patients followed a structured VLCKD protocol, fifteen followed a classical LCD. At the beginning of the nutritional protocol, all patients were asked to stop any antidiabetic medications, with the exception of metformin. Data were collected at baseline and after 3 (T1) and 12 (T2) months. At T1 and T2, BMI was significantly reduced in the VLCKD group ( < 0.001), whereas it remained substantially unchanged in the LCD group. HbA1c was significantly reduced in the VLCKD group ( = 0.002), whereas a slight, although not significant, decrease was observed in the LCD group. Quality of life and eating behavior scores were improved in the VLCKD group, whereas no significant changes were reported in the LCD group, both at T1 and T2. At the end of the study, in the VLCKD group 26.6% of patients had stopped all antidiabetic medications, and 73.3% were taking only metformin, whereas 46.6% of LCD patients had to increase antidiabetic medications. The study confirms a valuable therapeutic effect of VLCKD in the long-term management of obesity and T2DM and its potential contribution to remission of the disease.
28Impact of weight loss on the metabolic syndrome.PubMed
C C Case, P H Jones, K Nelson, et al.
Diabetes Obes Metab. 2002 Nov;4(6):407-14. doi: 10.1046/j.1463-1326.2002.00236.x.
AIM: Individuals with the metabolic syndrome (MS), a clustering of risk factors [triglycerides, glucose, high-density lipoprotein cholesterol, blood pressure (BP), abdominal obesity] defined by the National Cholesterol Education Program (NCEP), are at high risk for coronary heart disease and type 2 diabetes mellitus, and may benefit from aggressive lifestyle modification. METHODS: We reviewed 1 year of consecutive patients' charts to determine the prevalence of the MS in obese individuals enrolled in a medically supervised rapid weight loss programme, the correlation of weight change with the components of the MS, and response to diet-induced weight loss. RESULTS: Out of 185 individuals, 125 (68%) met the NCEP definition of the MS. A moderate decrease in weight (6.5%) induced by a very low calorie diet (VLCD) resulted in substantial reductions of systolic (11.1 mmHg) and diastolic (5.8 mmHg) blood pressure (BP), glucose (17 mg/dl), triglycerides (94 mg/dl) and total cholesterol (37 mg/dl) at 4 weeks (all p < 0.001). These improvements were sustained at the end of active weight loss (average 16.7 weeks; total weight loss 15.1%), with further significant reductions in BP and triglycerides. Weight loss was related to the changes in each criterion of the metabolic syndrome. CONCLUSIONS: The MS is prevalent in two-thirds of obese individuals enrolling in a structured weight loss programme. Moderate weight loss with a VLCD markedly improved all aspects of the MS.
29Investigating the Effectiveness of Very Low-Calorie Diets and Low-Fat Vegan Diets on Weight and Glycemic Markers in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.PubMed
Anjali Kashyap, Alexander Mackay, Ben Carter, et al.
Nutrients. 2022 Nov 17;14(22):4870. doi: 10.3390/nu14224870.
Caloric restriction and vegan diets have demonstrated protective effects for diabetes, however their role in improving clinically relevant outcomes has not been summarized. Our aim was to evaluate the evidence for low-calorie diets (VLCD) and vegan diets on weight and glycemic control in the management of patients with Type 2 Diabetes. Database searches were conducted using Cochrane Library, MEDLINE (Ovid) and Embase. Systematic Review Registration: CRD42022310299. Methodological quality of studies was assessed using Cochrane RoB Tool for RCTs, Cochrane ROBINS-I RoB Tool for non-RCTs and NIH Quality Assessment tool for other studies. Sixteen studies with a total of 834 individuals were included and assessed to have a moderate to high risk of bias. Statistically significant changes in weight, BMI, and HbA1c were not observed in vegan diet cohorts. However, LDL cholesterol was significantly decreased by vegan diet. VLCDs significantly improved glycaemic control, with reductions in fasting glucose, pooled mean difference (MD) -1.51 mmol/L (95% CI -2.89, -0.13; = 0.03; 2 studies) and HbA1c, pooled MD -0.66% (95% CI -1.28, -0.03; = 0.04; 3 studies) compared to non-dietary therapy. Both diets suggested a trend towards improved weight loss and anthropometric markers vs. control. VLCD diet intervention is associated with improvement in glycaemia control in patients with Type 2 Diabetes.
30Effect of calorie restriction in comparison to usual diet or usual care on remission of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.PubMed
Ahmad Jayedi, Sheida Zeraattalab-Motlagh, Hossein Shahinfar, et al.
Am J Clin Nutr. 2023 May;117(5):870-882. doi: 10.1016/j.ajcnut.2023.03.018. Epub 2023 Mar 25.
BACKGROUND: Limited evidence is available on the dose-dependent effects of calorie restriction in patients with type 2 diabetes. OBJECTIVES: We aimed to gather available evidence on the effect of calorie restriction on the management of type 2 diabetes. METHODS: We systematically searched PubMed, Scopus, CENTRAL, Web of Science, and gray literature until November 2022 for randomized trials >12 wk looking at the effect of a prespecified calorie-restricted diet on remission of type 2 diabetes. We performed random-effects meta-analyses to estimate the absolute effect (risk difference) at 6-mo (6 ± 3 mo) and 12-mo (12 ± 3 mo) follow-ups. Then, we performed dose-response meta-analyses to estimate the mean difference (MD) for the effects of calorie restriction on cardiometabolic outcomes. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to judge the certainty of evidence. RESULTS: Twenty-eight randomized trials with 6281 participants were included. Using a remission definition of an HbA1c level of <6.5% without antidiabetic medication use, calorie-restricted diets increased remission by 38 more per 100 patients (95% CI: 9 more, 67 more; n = 5 trials; GRADE = moderate) at 6 mo and by 13 more per 100 patients (95% CI: 10 more, 18 more; n = 4; GRADE = moderate) at 12 mo in comparison to usual diet or usual care. Using a definition of HbA1c of <6.5% after at least 2-mo cessation of antidiabetic medications, remission increased by 34 more per 100 patients (95% CI: 15 more, 53 more; n = 1; GRADE = very low) at 6 mo and by 16 more per 100 patients (95% CI: 4 more, 49 more; n = 2; GRADE = low) at 12 mo. At 6 mo, each 500-kcal/d decrease in energy intake resulted in clinically meaningful reductions in body weight (MD: -6.33 kg; 95% CI: -7.76, -4.90; n = 22; GRADE = high) and HbA1c (MD: -0.82%; 95% CI: -1.05, -0.59; n = 18; GRADE = high), which attenuated remarkably at 12 mo. CONCLUSIONS: Calorie-restricted diets may be effective intervention for type 2 diabetes remission, especially when coupled with an intensive lifestyle modification program. This systematic review was registered in PROSPERO as CRD42022300875 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID = 300875). Am J Clin Nutr 2023;xxx:xx-xx.
31Treatment of metabolic syndrome.PubMed
Arati Wagh, Neil J Stone
Expert Rev Cardiovasc Ther. 2004 Mar;2(2):213-28. doi: 10.1586/14779072.2.2.213.
The metabolic syndrome is intended to identify patients who have increased risk of diabetes and/or a cardiac event due to the deleterious effects of weight gain, sedentary lifestyle, and/or an atherogenic diet. The National Cholesterol Education Program's Adult Treatment Panel III definition uses easily measured clinical findings of increased abdominal circumference, elevated triglycerides, low high-density lipoprotein-cholesterol, elevated fasting blood glucose and/or elevated blood pressure. Three of these five are required for diagnosis. The authors also note that other definitions of metabolic syndrome focus more on insulin resistance and its key role in this syndrome. This review focuses on how treatment might affect each of the five components. Abdominal obesity can be treated with a variety of lower calorie diets along with regular exercise. Indeed, all of the five components of the metabolic syndrome are improved by even modest amounts of weight loss achieved with diet and exercise. For those with impaired fasting glucose tolerance, there is good evidence that a high fiber, low saturated fat diet with increased daily exercise can reduce the incidence of diabetes by almost 60%. Of note, subjects who exercise the most, gain the most benefit. Metformin has also been shown to be helpful in these subjects. Thiazolidinedione drugs may prove useful, but further studies are needed. Although intensified therapeutic lifestyle change will help the abnormal lipid profile, some patients may require drug therapy. This review also discusses the use of statins, fibrates, and niacin. Likewise, while hypertension in the metabolic syndrome benefits from therapeutic lifestyle change, physicians should also consider angiotensin converting enzyme inhibitor drugs or angiotensin receptor blockers, due to their effects on preventing complications of diabetes, such as progression of diabetic nephropathy and due to their effects on regression of left ventricular hypertrophy. Aspirin should be considered in those with at least a 10% risk of a coronary event over 10 years. Finally, three related conditions, nonalcoholic fatty liver disease, polycystic ovary syndrome and protease inhibitor associated lipodystrophy improve with therapeutic lifestyle change. Although metformin is shown to be useful with polycystic ovary syndrome, the data supporting drug therapy for the other syndromes is less convincing. More robust studies are needed before any firm recommendations can be made.
32Diet and exercise in the prevention and treatment of type 2 diabetes mellitus.PubMed
Faidon Magkos, Mads F Hjorth, Arne Astrup
Nat Rev Endocrinol. 2020 Oct;16(10):545-555. doi: 10.1038/s41574-020-0381-5. Epub 2020 Jul 20.
Evidence from observational studies and randomized trials suggests that prediabetes and type 2 diabetes mellitus (T2DM) can develop in genetically susceptible individuals in parallel with weight (that is, fat) gain. Accordingly, studies show that weight loss can produce remission of T2DM in a dose-dependent manner. A weight loss of ~15 kg, achieved by calorie restriction as part of an intensive management programme, can lead to remission of T2DM in ~80% of patients with obesity and T2DM. However, long-term weight loss maintenance is challenging. Obesity and T2DM are associated with diminished glucose uptake in the brain that impairs the satiating effect of dietary carbohydrate; therefore, carbohydrate restriction might help maintain weight loss and maximize metabolic benefits. Likewise, increases in physical activity and fitness are an important contributor to T2DM remission when combined with calorie restriction and weight loss. Preliminary studies suggest that a precision dietary management approach that uses pretreatment glycaemic status to stratify patients can help optimize dietary recommendations with respect to carbohydrate, fat and dietary fibre. This approach might lead to improved weight loss maintenance and glycaemic control. Future research should focus on better understanding the individual response to dietary treatment and translating these findings into clinical practice.
33Influences of weight loss on long-term diabetes outcomes.PubMed
Lorna S Aucott
Proc Nutr Soc. 2008 Feb;67(1):54-9. doi: 10.1017/S0029665108006022.
Increasing rates of type 2 diabetes (T2DM) follow the obesity 'epidemic', with 86% of patients with T2DM being overweight and over half being obese. Literature has highlighted that being overweight or obese increases the risk of diabetes. Weight loss for obese patients is associated with clinical improvements, although this evidence is mostly from short-term studies. As part of a Health Technology Assessment systematic review the long-term (> or =2 years) effects of weight loss on change in diabetes-related outcome measures for those with diabetes, or risk of developing diabetes for those without diabetes, was investigated in obese individuals. Eleven studies published between 1966 and 2001 fulfilled the inclusion criteria (Caucasian, BMI >28 kg/m2, adults, no eating disorders, weight loss and changes in diabetes-outcome measures). Results of these studies indicated that intentional weight loss reduces the risk of developing diabetes in the long term and those participants with T2DM often have reduced clinical symptoms and mortality risk. These results have been verified and enhanced by literature published since this review. A similar systematic review was conducted as part of a six-phase project, the PRevent Obesity GRowing Economic Synthesis Study. This review excluded BMI >34 kg/m2 and was restricted to lifestyle interventions (or intentional weight loss). Limited information relating to diabetes was gained, with only a non-significant increasing trend for mortality from diabetes for severe weight cycling practices being suggested. Other results indicated a relationship between weight loss and fasting plasma glucose, but because of the heterogeneity of participation groups and lack of definition in relation to diabetes this relationship was not formalised. In summary, weight loss is beneficial for long-term diabetes outcomes for overweight, obese and morbidly-obese participants. There is little research evidence for those individuals who are overweight or just obese, indicating areas of future research in terms of prevention of both obesity and diabetes.
34The protein-sparing modified fast for obese patients with type 2 diabetes: what to expect.PubMed
Julia Chang, Sangeeta R Kashyap
Cleve Clin J Med. 2014 Sep;81(9):557-65. doi: 10.3949/ccjm.81a.13128.
The protein-sparing modified fast (PSMF) is a very-low-calorie diet containing mostly protein and little carbohydrate. This article reviews the principles of the PSMF and its potential benefits in terms of weight loss, glycemic control, insulin resistance, cardiovascular risk factors, and related complications for patients with type 2 diabetes.
35Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy.PubMed
Inês Preguiça, André Alves, Sara Nunes, et al.
Nutrients. 2020 Jan 18;12(1):250. doi: 10.3390/nu12010250.
Unhealthy dietary habits are major modifiable risk factors for the development of type 2 diabetes mellitus, a metabolic disease with increasing prevalence and serious consequences. Microvascular complications of diabetes, namely diabetic peripheral neuropathy (DPN), retinopathy (DR), and nephropathy (DN), are associated with high morbidity rates and a heavy social and economic burden. Currently, available therapeutic options to counter the evolution of diabetic microvascular complications are clearly insufficient, which strongly recommends further research. Animal models are essential tools to dissect the molecular mechanisms underlying disease progression, to unravel new therapeutic targets, as well as to evaluate the efficacy of new drugs and/or novel therapeutic approaches. However, choosing the best animal model is challenging due to the large number of factors that need to be considered. This is particularly relevant for models induced by dietary modifications, which vary markedly in terms of macronutrient composition. In this article, we revisit the rodent models of diet-induced DPN, DR, and DN, critically comparing the main features of these microvascular complications in humans and the criteria for their diagnosis with the parameters that have been used in preclinical research using rodent models, considering the possible need for factors which can accelerate or aggravate these conditions.
36Co-treatment of Astragaloside IV with Vitamin D in Diabetic Peripheral Neuropathic Rats: Protective Effects and Potential Mechanisms.PubMed
Fengyan Tang, Bo Zhao, Li Zhang, et al.
Curr Mol Pharmacol. 2024;17:e18761429267000. doi: 10.2174/0118761429267000231004111024.
OBJECTIVE: The potential mechanism underlying the protective effect of Astragaloside IV (AS-IV) co-treatment with 1, 25-dihydroxy-vitamin D (Vit-D) on neuropathy in diabetic high-fat rats was investigated. METHODS: The rat diabetic hyperlipidemia (DH) model was established via streptozotocin and a high-fat diet (HFD). After co-treatment (of AS-IV and Vit-D at respective doses of 50 mg/kg via oral gavage and 30000 IU/kg via intramuscular injection), blood glucose levels, markers of inflammation and oxidative stress, as well as apoptosis and histopathology were evaluated with appropriate techniques. RESULTS: Co-treatment could effectively reduce blood glucose levels substantially (p< 0.01), improve weight loss, and decrease oral glucose tolerance. Reduced respective sensory and motor nerve conduction velocities in rats were substantially improved (p<0.01) after co-treatment. Also, we observed obvious improvement in DH-induced injured nerve fiber myelin structure and other organ pathologies in co-treated rats. Besides, we observed up-regulated expressions of peroxisomal-proliferator activated receptor-alpha (PPAR-α) and Vit-D receptors (VDR) (p< 0.01) through the western blotting technique. Using the same technique, we also discovered reduced levels of interleukin (IL)1 beta, IL-6, and tumor necrosis factor-alpha, coupled with increased IL-10 and superoxide dismutase levels (p< 0.01). Importantly, co-treatment could effectively exert antioxidative and anti-inflammatory effects. Also, co-treatment resulted in the up-regulation of PPAR-α and VDR expressions, inhibition of the renin-angiotensin-aldosterone system, and promotion of β-cell sensitivity to insulin. CONCLUSION: The combined application of AS-IV and Vit-D exhibited health effects such as anti-oxidation, regulation of inflammatory factors, and promotion of cell repair, which may be considered as the mechanisms underlying treatment of diabetic peripheral neuropathy and improvement in biochemical indicators.
37Characterisation of pain responses in the high fat diet/streptozotocin model of diabetes and the analgesic effects of antidiabetic treatments.PubMed
Frederika Maria Byrne, Sharon Cheetham, Steven Vickers, et al.
J Diabetes Res. 2015;2015:752481. doi: 10.1155/2015/752481. Epub 2015 Feb 9.
Chronic pain is a common complication of diabetes. The aim of the present study was to characterise pain behaviour in a high fat diet/streptozotocin (HFD/STZ) model of diabetes in the rat, investigate spinal mechanisms, and determine the effects of antidiabetic interventions. Three-week consumption of a high fat diet followed by single injection of STZ (45 mgkg(-1)) produced sustained changes in plasma insulin and glucose until day 120. Hindpaw mechanical withdrawal thresholds were significantly lowered in the model, but mechanically evoked responses of spinal neurones were unaltered, compared to HFD/vehicle rats. HFD/STZ rats had significantly lower numbers of spinal Iba-1 positive cells (morphologically identified as activated microglia) and spinal GFAP immunofluorescence (a marker of astrogliosis) in the spinal cord at day 50, compared to time-matched controls. The PPARγ ligand pioglitazone (10 mgkg(-1)) did not alter HFD/STZ induced metabolic changes or hindpaw withdrawal thresholds of HFD/STZ rats. Daily linagliptin (3 mgkg(-1)) and metformin (200 mgkg(-1)) from day 4 after model induction did not alter plasma glucose or insulin in HFD/STZ rats but significantly prevented changes in the mechanical withdrawal thresholds. The demonstration that currently prescribed antidiabetic drugs prevent aberrant pain behaviour supports the use of this model to investigate pain mechanisms associated with diabetes.
38Function of Adenosine 2A Receptor in High-Fat Diet-Induced Peripheral Neuropathy.PubMed
Ji Li, Huan-Qiu Liu, Xin-Bai Li, et al.
J Diabetes Res. 2020 May 22;2020:7856503. doi: 10.1155/2020/7856503. eCollection 2020.
Peripheral diabetic neuropathy (DPN) is a complication observed in up to half of all patients with type 2 diabetes. DPN has also been shown to be associated with obesity. High-fat diet (HFD) affects glucose metabolism, and the impaired glucose tolerance can lead to type 2 diabetes. There is evidence to suggest a role of adenosine 2A receptors (A2ARs) and semaphorin 3A (Sema3a) signaling in DPN. The link between the expression of Sema3a and A2AR in DPN was hypothesized, but the underlying mechanisms remain poorly understood. In this study, we investigated the regulation of Sema3a by A2AR in the spinal cord and the functional implications thereof in DPN. We examined the expression of A2ARs and Sema3a, as well as Neuropilin 1 and Plexin A, the coreceptors of Sema3a, in the dorsal horn of the lumbar spinal cord of an animal model with HFD-induced diabetes. Our results demonstrate that HFD dysregulates the A2AR-mediated Sema3a expression, with functional implications for the type 2 diabetes-induced peripheral neuropathy. These observations could stimulate clinical studies to improve our understanding on the subject.
39Thiamine and diabetes: back to the future?PubMed
Elena Beltramo, Aurora Mazzeo, Massimo Porta
Acta Diabetol. 2021 Nov;58(11):1433-1439. doi: 10.1007/s00592-021-01752-4. Epub 2021 Jun 5.
The first reports of a link between thiamine and diabetes date back to the 1940s. Some years later, a role for thiamine deficiency in diabetic neuropathy became evident, and some pilot studies evaluated the putative effects of thiamine supplementation. However, the administration of thiamine and its lipophilic derivative benfotiamine for the treatment of this complication gained consensus only at the end of the '90 s. The first evidence of the beneficial effects of thiamine on microvascular cells involved in diabetic complications dates to 1996: from then on, several papers based on in vitro and animal models have addressed the potential use of this vitamin in counteracting diabetic microangiopathy. A few pilot studies in humans reported beneficial effects of thiamine administration on diabetic nephropathy, but, despite all promising proofs-of-concept, the possible role of thiamine in counteracting development or progression of retinopathy has not been addressed until now. Thiamine is a water-soluble vitamin, rapidly expelled from the body, with no issues of over-dosage or accumulation; unfortunately, it is non-patentable, and neither industry nor independent donors are interested in investing in large-scale randomized controlled clinical trials to investigate its potential in diabetes and its complications. Consequently, science will not be able to disprove a promising hypothesis and, more importantly, diabetic people remain deprived of a possible way to ameliorate their condition.
40[Efficacy of thiamine pyrophosphate or carboxylase in the salvage of diabetic foot].PubMed
J Carmona-Cervantes
Acta Ortop Mex. 2014 May-Jun;28(3):168-72.
Diabetic foot represents one of the most common complications in patients with a long standing disease. The etiology is neuropathy, infections and ischemia that together contribute to the sequence of tissue necrosis, ulceration and gangrene. Since treatment is very difficult, we must look for several options to solve these problems caused by chronic hyperglycemia. Thiamine pyrophosphate or carboxylase perform multiple metabolic and non-metabolic activities that are considered important in the resolution of diabetic impairments, therefore, this work shows the results when using it in patients with diabetic foot. 29 patients with diabetic foot were treated between January 1998 and July 2012: 19 Wagner type III and 12 Wagner type IV. Management was the administration of antibiotics, partial surgical procedures and thiamine pyrophosphate. The infectious process was controlled, the appearance of granulation tissue and scarring of the lesion in a period of 2 to 6 months depending on the severity of the problem. Given the clinical data and evolution of the patients, we conclude that the administration of thiamine pyrophosphate was able to control metabolic and non-metabolic dysfunctions that lead to complications in diabetic patients, therefore we must consider it a tool in the treatment of diabetic patients in general and for diabetic foot salvage in particular.
41Vitamin B supplementation for diabetic peripheral neuropathy.PubMed
Bhavani Jayabalan, Lian Leng Low
Singapore Med J. 2016 Feb;57(2):55-9. doi: 10.11622/smedj.2016027.
Vitamin B12 deficiency has been associated with significant neurological pathology, especially peripheral neuropathy. This review aims to examine the existing evidence on the effectiveness of vitamin B12 supplementation for the treatment of diabetic peripheral neuropathy. A search of PubMed and the Cochrane Central Register of Controlled Trials for all relevant randomised controlled trials was conducted in December 2014. Any type of therapy using vitamin B12 or its coenzyme forms was assessed for efficacy and safety in diabetics with peripheral neuropathy. Changes in vibration perception thresholds, neuropathic symptoms and nerve conduction velocities, as well as the adverse effects of vitamin B12 therapy, were assessed. Four studies comprising 363 patients met the inclusion criteria. This review found no evidence that the use of oral vitamin B12 supplements is associated with improvement in the clinical symptoms of diabetic neuropathy. Furthermore, the majority of studies reported no improvement in the electrophysiological markers of nerve conduction.
42Associations between long-term metformin use, the risk of vitamin B12 deficiency, and neuropathy: An All of Us research Program study.PubMed
Aryana Sepassi, Jiayuan Wang, Sophia Yankowski, et al.
Diabetes Res Clin Pract. 2025 Oct;228:112424. doi: 10.1016/j.diabres.2025.112424. Epub 2025 Aug 22.
AIMS: The primary objective of this study is to investigate the associations between long-term metformin use, vitamin B12 status, and peripheral neuropathy. Secondarily, we aim to explore the effect of time since diagnosis on the relationships between metformin use, vitamin B12 deficiency, and peripheral neuropathy. METHODS: A retrospective observational cross-sectional analysis was conducted using NIH's All of Us database. The risk of vitamin B12 deficiency and peripheral neuropathy was compared among long-term metformin users (≥4 years), short-term users (<4 years), and non-metformin users via a series of unadjusted and adjusted logistic regression models. RESULTS: Among 14,808 adults with type 2 diabetes mellitus (T2DM), 9,136 (61.70 %) used metformin, of whom 5,609 (37.95 %) were long-term users. Following adjustment for confounders, long-term users exhibited a 67 % and 38 % higher likelihood of vitamin B12 deficiency than non-users and short-term users respectively (p < 0.001). Peripheral neuropathy prevalence was 39 % higher among long-term users compared to short-term users (p < 0.001), with a non-statistically significant difference compared to non-users. CONCLUSIONS: Long-term metformin use is associated with both an increased risk of vitamin B12 deficiency and peripheral neuropathy in patients with T2DM. Providers should consider routinely assessing vitamin B12 status in long-term users, particularly when evaluating peripheral neuropathy symptoms.
43Vitamin B12 status and peripheral neuropathy in patients with type 2 diabetes mellitus.PubMed
Kareem Mousa Khalaf, Mahmod Shakir Khudhair, Ammar Waham Ashor
J Pak Med Assoc. 2019 Aug;69(Suppl 3)(8):S40-S44.
OBJECTIVE: To assess the status of vitamin B12 in patients with type 2 diabetes, and to explore any association between its deficiency and diabetic peripheral neuropathy. METHODS: This cross-sectional observational study was conducted from August, 2017, to April, 2018, at the Specialized Centre for Endocrinology and Diabetes in Baghdad, Iraq. Type 2 diabetics using metformin were subjected to clinical examination for retinopathy using fundoscopy, and peripheral neuropathy using the Michigan Neuropathy Screening Instrument. Additionally, patients were asked to fill a questionnaire and their medical records were reviewed. Blood samples were obtained for the measurement of biomarkers. Vitamin B12 deficiency was recorded at ≤187 pg/ml. Data was analysed using SPSS 25. RESULTS: Of the 66 patients, 39(59%) were males and 27(41%) were females. The overall mean age was 53.3}9.2 years and the mean duration of diabetes was 104}71.8 months. The mean dose of metformin was 1135}496 mg and the duration of metformin use was 72}62 months. Overall, 19(29%) patients suffered from vitamin B12 deficiency. However, no significant difference was found between normal and deficit groups regarding the parameters that may affect vitamin B12 level. Also, no significant correlations were found between vitamin B12 concentration and the dose (p=0.16) or the duration of metformin use (p=0.09). CONCLUSIONS: High prevalence of vitamin B12 deficiency was observed in metformin-treated patients with type 2 diabetes. However, the deficiency had no correlation with the rate of peripheral neuropathy.
44[The pathogenesis of diabetic and hepatic neuropathies].PubMed
G Winkler, P Kempler
Orv Hetil. 2001 Nov 11;142(45):2459-67.
The pathomechanism of neuropathies associated with diabetes and chronic liver diseases are poorly understood. Both metabolic and vascular factors are involved in the pathogenesis of diabetic neuropathy. It seems likely, that microangiopathy on the one hand and changes of various metabolic pathways due to hyperglycaemia on the other hand are much more related to each other than it was suggested previously. Nitric oxide may be the link between the metabolic and vascular hypotheses of diabetic neuropathy. Both reduced endoneurinal blood flow and increased oxidative stress leads to reduced nitric oxide synthetase activity. There are widespread inter-relationships between the most relevant metabolic changes included polyol pathway hyperactivity, reduced myoinosit concentration, advanced glycation end products formation, increased oxidative stress and lipid peroxidation. Changes of hemorheological conditions and primary hemostasis leeds to hyperviscosity just as to increased activity of the coagulation system. Among patients with chronic alcoholic liver diseases the direct toxic effect of alcohol is of particular relevance, however, malabsorption, impairment of axoplasmatic transport, changes of intermedier metabolism as well as thiamine and pyridoxine deficiency are of importance as well. The role of decreased insulin sensitivity and various degrees of glucose intolerance related to chronic liver diseases are still underestimated. Impairment of proteoglycan metabolism as well as increased oxydative stress are thought to be important factors in the pathogenesis of both diabetic and hepatic neuropathies. Glucose autooxidation and enhanced lipid peroxidation contribute to increased oxidative stress in patients with diabetes and chronic liver diseases as well. Vitamin E deficiency, autoimmun processes, circulating immune complexes, cryoglobulinemia, just as changes of vascular responsiveness associated with nitric oxide activity plays a role in the development of neural damage of hepatic origin. Most likely, similarly to diabetes mellitus, vascular changes contribute to the development of neuropathy in patients with chronic liver diseases.
45Effect of zinc deficiency on mouse renal interstitial fibrosis in diabetic nephropathy.PubMed
Xiuli Zhang, Dan Liang, Xu Lian, et al.
Mol Med Rep. 2016 Dec;14(6):5245-5252. doi: 10.3892/mmr.2016.5870. Epub 2016 Oct 20.
There is emerging evidence that tubulointerstitial fibrosis is the final common pathway of the majority of chronic progressive renal diseases, including diabetic nephropathy (DN). Zinc, an essential dietary element, has been suggested to be important for a number of protein functions during fibrosis in vivo and in vitro. However, the effect of zinc deficiency (ZnD) on renal interstitial fibrosis in DN remains unclear. The present study investigated the effect and the underlying mechanisms of ZnD on renal interstitial fibrosis during DN using an streptozotocin‑induced model of diabetes with immunofluorescence staining and western blot analysis. The present study identified that dietary zinc restriction significantly decreased zinc concentrations in the plasma and mouse kidney. ZnD enhanced albuminuria and extracellular matrix protein expression, associated with diabetic renal interstitial fibrosis by activation of renal interstitial fibroblasts and regulation of the expression of fibrosis‑associated factors, which may be mediated by the activation of fibroblasts via the TGF‑β/Smad signaling pathway. The data indicates that ZnD serves an important role in the pathogenic mechanisms of renal interstitial fibrosis during the development of DN.
46Interaction between magnesium and methylglyoxal in diabetic polyneuropathy and neuronal models.PubMed
Alexander Strom, Klaus Strassburger, Martin Schmuck, et al.
Mol Metab. 2021 Jan;43:101114. doi: 10.1016/j.molmet.2020.101114. Epub 2020 Nov 6.
OBJECTIVE: The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Because reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy. METHODS: In a cross-sectional study, serum magnesium and plasma methylglyoxal levels were measured in recently diagnosed type 2 diabetes patients with (n = 51) and without (n = 184) diabetic sensorimotor polyneuropathy from the German Diabetes Study baseline cohort. Peripheral nerve function was assessed using nerve conduction velocity and quantitative sensory testing. Human neuroblastoma cells (SH-SY5Y) and mouse dorsal root ganglia cells were used to characterize the neurotoxic effect of methylglyoxal and/or neuroprotective effect of magnesium. RESULTS: Here, we demonstrate that serum magnesium concentration was reduced in recently diagnosed type 2 diabetes patients with diabetic sensorimotor polyneuropathy and inversely associated with plasma methylglyoxal concentration. Magnesium, methylglyoxal, and, importantly, their interaction were strongly interrelated with methylglyoxal-dependent nerve dysfunction and were predictive of changes in nerve function. Magnesium supplementation prevented methylglyoxal neurotoxicity in differentiated SH-SY5Y neuron-like cells due to reduction of intracellular methylglyoxal formation, while supplementation with the divalent cations zinc and manganese had no effect on methylglyoxal neurotoxicity. Furthermore, the downregulation of mitochondrial activity in mouse dorsal root ganglia cells and consequently the enrichment of triosephosphates, the primary source of methylglyoxal, resulted in neurite degeneration, which was completely prevented through magnesium supplementation. CONCLUSIONS: These multifaceted findings reveal a novel putative pathophysiological pathway of hypomagnesemia-induced carbonyl stress leading to neuronal damage and merit further investigations not only for diabetic sensorimotor polyneuropathy but also other neurodegenerative diseases associated with magnesium deficiency and impaired energy metabolism.
47Serum folate and cobalamin levels and urinary dimethylarsinic acid in US children and adults.PubMed
Jianmin Zhu, Yanhui Gao, Dianjun Sun, et al.
Environ Sci Pollut Res Int. 2018 Jun;25(17):17168-17175. doi: 10.1007/s11356-018-1951-0. Epub 2018 Apr 12.
Nutritional status could affect arsenic metabolism and toxicity in the general population chronically exposed to low levels of inorganic arsenic. In this study, we examined the association of serum folate and cobalamin with urinary concentrations of dimethylarsinic acid (DMA), the most abundant metabolite of inorganic arsenic measured in urine, in children and adults who participated in the 2003-2006 US National Health and Nutrition Examination Surveys. A total of 1161 children (aged 6-19 years) and 1938 adults (aged 20-85 years) were analyzed for the association using multivariate general linear models, adjusting for potential confounders. We observed a positive association between serum levels of folate and cobalamin and creatinine-corrected urinary concentrations of DMA in both children and adults. Furthermore, serum levels of folate and cobalamin were inversely associated with homocysteine (Hcy). These results suggest that dietary intake of folate and cobalamin may exhibit protective functions against arsenic toxicity by increasing arsenic metabolism to the less toxic metabolite DMA and decreasing serum levels of Hcy.
48Alterations in homocysteine metabolism among alcohol dependent patients--clinical, pathobiochemical and genetic aspects.PubMed
Ulrich C Lutz
Curr Drug Abuse Rev. 2008 Jan;1(1):47-55. doi: 10.2174/1874473710801010047.
Addiction research focusing on homocysteine metabolism and its association with aspects of alcohol dependence has revealed important findings. Recent literature on this topic has been taken into account for the review provided. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the homocysteine metabolism. Plasma homocysteine levels are influenced by the single-nucleotide polymorphism (SNP) MTHFR C677T. Besides genetic factors, environmental factors have an impact on homocysteine plasma levels too. Thus, chronic alcohol intake is associated with elevated homocysteine plasma concentrations. Elevation of plasma homocysteine concentration is considered as a predictor for the occurrence of alcohol withdrawal seizures and--as homocysteine is a cardiovascular risk factor--might contribute to the higher risk for myocardial infarction among alcohol dependent patients. Homocysteine acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has excitotoxic effects. Furthermore, it has been demonstrated that homocysteine has neurotoxic effects especially on dopaminergic neurons. As the rewarding effects of alcohol are mediated by the dopaminergic system, a homocysteine-dependent impairment of the reward system possibly leads to an altered drinking behaviour according to the deficit hypothesis of addiction. Homocysteine is involved in the metabolism of methyl groups and DNA-methylation plays a role in regulation of gene expression. Therefore it has been suggested that homocysteine is an important epigenetic factor. It remains to be determined whether alcohol dependent patients benefit from homocysteine lowering strategies, e.g., via supplementation of folate, vitamin B6 and B12. In this respect it is not clear yet, if a supplementation therapy can reduce the risk for the occurrence of alcohol withdrawal seizures.
49How Increased Dietary Folic Acid Intake Impacts Health Outcomes Through Changes in Inflammation, Angiogenesis, and Neurotoxicity.PubMed
Siddarth Gunnala, Lori M Buhlman, Nafisa M Jadavji
Nutrients. 2025 Apr 7;17(7):1286. doi: 10.3390/nu17071286.
Dietary folic acid supplementation is well known for playing a crucial role in the closure of the neural tube. Individuals have continued to increase dietary intake of folic acid in counties with mandatory fortication laws in place. Some studies have demonstrated adverse health effects in individuals with high dietary intake of folic acid. Nutrition is a modifiable risk factor for ischemic stroke. Specifically, elevated levels of homocysteine, they can be reduced by increasing intake of vitamins, such as folic acid, a B-vitamin. Hypoxia, when levels of oxygen are reduced, is a major component of cardiovascular diseases. The aim of this review paper was to summarize how increased dietary intake of folic acid interaction with hypoxia to impact health outcomes. Our survey of the literature found that increased dietary intake of folic acid promotes inflammation, angiogenesis, and neurotoxicity. We also report negative actions of increased dietary intake of folic acid with vitamin B12 and genetic deficiencies in one-carbon metabolism. Increased dietary intake of folic acid also results in elevated levels of unmetabolized folic acid in the population, of which the impact on health risks has not yet been determined. Our review of the literature emphasizes that a more comprehensive understanding of the action between increased dietary intake of folic acid on disease outcomes could pave the way for improved public health guidelines. Furthermore, adequate knowledge of an individual's one-carbon metabolism status can inform proactive management for patients at higher risk of experiencing negative health outcomes.
50Plasma Homocysteine Concentration is Associated with the Expression Level of Folate Receptor 3.PubMed
Ren Yoshitomi, Kai Nakayama, Shuya Yamashita, et al.
Sci Rep. 2020 Jun 24;10(1):10283. doi: 10.1038/s41598-020-67288-9.
Folic acid and folate receptors (FOLRs) play an important role in the downregulation of homocysteine (Hcy), a risk factor of Alzheimer's disease, thrombosis, neuropsychiatric illness and fractures. While several studies have reported that FOLR1 and FOLR2 import folic acid into cells, the role of FOLR3 remains unknown. In this study, we evaluated the impact of FOLR3 on the metabolism of Hcy alongside its protective effect against homocysteine-induced neurotoxicity. To reveal the role of FOLR3, we constructed FOLR3-overexpressed HEK293 cells (FOLR3 cells) and evaluated cell growth, folic acid intake and Hcy-induced neurotoxicity. Subjects with a high expression of FOLR3 exhibited low levels of plasma homocysteine. The ectopic expression of FOLR3 enhanced cell growth, and the enhanced effect was neutralised by folic acid-deficient media. The Western blot analysis revealed that FOLR3 is secreted into cell supernatant. The folic acid intake of FOLR3 cells was higher than that of wild-type cells. Supernatant from FOLR3 cells showed a protective effect on Hcy-induced cytotoxicity. FOLR3 expression in plasma is negatively correlated with plasma homocysteine. Our study emphasizes the role of FOLR3 in the intake of folic acid into cells on the one hand and its protective role in Hcy-induced cytotoxicity on the other.
51Vitamin B12 neuropathy is not due to failure to methylate myelin basic protein.PubMed
R Deacon, P Purkiss, R Green, et al.
J Neurol Sci. 1986 Jan;72(1):113-7. doi: 10.1016/0022-510x(86)90040-7.
It has been proposed that the biochemical lesion in subacute combined degeneration of the cord due to vitamin B12 deficiency, is impaired methylation of residue 107 (arginine) in myelin basic protein. We have examined myelin basic protein in brains of rats in which vitamin B12 was inactivated by exposure to nitrous oxide for up to 7 days. In addition brains of fruit bats in which vitamin B12 neuropathy had been produced by feeding washed, and hence vitamin B12-free fruit, were examined. There was no difference in the methylation of arginine 107 in myelin basic protein in these animals as compared to healthy control animals. Rats given an inhibitor of transmethylation reactions (cycloleucine) showed the expected fall in methylation of myelin basic protein.
52Vitamins in neuropathy: pathophysiological and therapeutic roles.PubMed
Peng Chen, Xue-Jun Song
Curr Opin Neurol. 2023 Oct 1;36(5):388-393. doi: 10.1097/WCO.0000000000001194. Epub 2023 Jul 31.
PURPOSE OF REVIEW: Vitamin deficiency is a risk factor in the development of peripheral neuropathy, which leads to complex and severe diseases. This review provides an update overview of the literature on the roles of vitamins in peripheral neuropathy, highlighting their pathophysiological and therapeutic roles. RECENT FINDINGS: The importance and clinical manifestations and implications of the vitamins and vitamin deficiencies are further demonstrated in peripheral neuropathy and the associated diseases. Vitamin deficiency is common in various severe and complex diseases such as diabetes, chemotherapy, acute nutritional axonal neuropathy, dermatitis, complex regional pain syndrome, postherpetic neuralgia, carpal tunnel syndrome, and so forth and some rare clinical case reports. There is evidence that deficiencies of almost all vitamins are associated with diabetic neuropathy. Vitamin supplementation may serve as an effective therapeutic strategy. SUMMARY: The vitamins play critical roles in maintaining physiological functions, and vitamin deficiencies cause peripheral neuropathy with various severe and complex diseases. The therapeutic benefits of vitamins and further understanding of the mechanisms for vitamin treatment effects should be emphasized and highlighted. More clinical trials are needed to establish optimal treatment strategies for vitamins in the various neuropathies. A large range of people/patients screening for vitamin deficiencies may be considered in order to provide early diagnosis and timely medical assistance.
53Bioactive Compounds and Their Neuroprotective Effects in Diabetic Complications.PubMed
Yoon Sin Oh
Nutrients. 2016 Jul 30;8(8):472. doi: 10.3390/nu8080472.
Hyperglycemia, hyperlipidemia and impaired insulin signaling during the development of diabetes can cause diabetic complications, such as diabetic neuropathy, resulting in significant morbidity and mortality. Although various therapeutics are available for the treatment of diabetic neuropathy, no absolute cure exists, and additional research is necessary to comprehensively understand the underlying pathophysiological pathways. A number of studies have demonstrated the potential health benefits of bioactive compounds, i.e., flavonoids and vitamins, which may be effective as supplementary treatments for diabetes and its complications. In this review, we highlight the most recent reports about the mechanisms of action of bioactive compounds (flavonoids and vitamins) possessing potential neuroprotective properties in diabetic conditions. Additional clinical studies are required to determine the appropriate dose and duration of bioactive compound supplementation for neuroprotection in diabetic patients.
54Lycorine improves peripheral nerve function by promoting Schwann cell autophagy via AMPK pathway activation and MMP9 downregulation in diabetic peripheral neuropathy.PubMed
Qingqing Yuan, Xiang Zhang, Wandi Wei, et al.
Pharmacol Res. 2022 Jan;175:105985. doi: 10.1016/j.phrs.2021.105985. Epub 2021 Dec 1.
Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus and no effective therapy is approved. Here, lycorine, a natural alkaloid, was identified as a potential drug for DPN by the bioinformatics analysis of GEO datasets and Connectivity Map database. Lycorine administration improved peripheral nerve function and autophagy-associated proteins of diabetic mice. Again, in vitro high glucose-cultured rat Schwann cells (RSC96) showed enhanced autophagosome marker LC3-II with the treatment of lycorine. Additionally, beclin-1 and Atg3 were decreased in high glucose-stimulated RSC96 cells, which were reversed by lycorine treatment. Furthermore, DPN-associated differentially expressed genes (DEGs) from GEO datasets and lycorine-drug targets from PubChem and PharmMapper were visually analyzed and revealed that MMP9 was both DPN-associated DEGs and lycorine-drug target. Functional enrichment analysis of MMP9-relevant genes showed that cell energy metabolism was involved. Moreover, lycorine reduced high glucose-enhanced MMP9 expression in RSC96 cells. Overexpression of MMP9 attenuated lycorine-induced the expression of beclin-1, Atg3 and LC3-II in high glucose-cultured RSC96 cells. In addition, AMPK pathway activation was confirmed in lycorine-treated high glucose-cultured RSC96 cells. Then AMPK pathway inhibition attenuated lycorine-reduced MMP9 expression in high glucose-treated RSC96 cells. Molecular docking analysis revealed that lycorine bound the domain of AMPK containing Thr 172 site, which affected AMPK (Thr 172) phosphorylation. Finally, AMPK pathway activation and MMP9 downregulation were also revealed in the sciatic nerves of diabetic mice administrated with lycorine. Taken together, lycorine was advised to promote Schwann cell autophagy via AMPK pathway activation and MMP9 downregulation-induced LC3-II transformation in diabetic peripheral neuropathy.
55Augmenting brain metabolism to increase macro- and chaperone-mediated autophagy for decreasing neuronal proteotoxicity and aging.PubMed
Ben Loos, Daniel J Klionsky, Esther Wong
Prog Neurobiol. 2017 Sep;156:90-106. doi: 10.1016/j.pneurobio.2017.05.001. Epub 2017 May 11.
Accumulation of toxic protein aggregates in the nerve cells is a hallmark of neuronal diseases and brain aging. Mechanisms to enhance neuronal surveillance to improve neuronal proteostasis have a direct impact on promoting neuronal health and forestalling age-related decline in brain function. Autophagy is a lysosomal degradative pathway pivotal for neuronal protein quality control. Different types of autophagic mechanisms participate in protein handling in neurons. Macroautophagy targets misfolded and aggregated proteins in autophagic vesicles to the lysosomes for destruction, while chaperone-mediated autophagy (CMA) degrades specific soluble cytosolic proteins delivered to the lysosomes by chaperones. Dysfunctions in macroautophagy and CMA contribute to proteo- and neuro-toxicity associated with neurodegeneration and aging. Thus, augmenting or preserving both autophagic mechanisms pose significant benefits in delaying physiological and pathological neuronal demises. Recently, life-style interventions that modulate metabolite ketone bodies, energy intake by caloric restriction and energy expenditure by exercise have shown to enhance both autophagy and brain health. However, to what extent these interventions affect neuronal autophagy to promote brain fitness remains largely unclear. Here, we review the functional connections of how macroautophagy and CMA are affected by ketone bodies, caloric restriction and exercise in the context of neurodegeneration. A concomitant assessment of yeast Saccharomyces cerevisiae is performed to reveal the conserved nature of such autophagic responses to substrate perturbations. In doing so, we provide novel insights and integrated evidence for a potential adjuvant therapeutic strategy to intervene in the neuronal decline in neurodegenerative diseases by controlling both macroautophagy and CMA fluxes favorably.
56Effects of caloric restriction on retinal aging and neurodegeneration.PubMed
Annagrazia Adornetto, Luigi Antonio Morrone, Andrea Satriano, et al.
Prog Brain Res. 2020;256(1):189-207. doi: 10.1016/bs.pbr.2020.07.005. Epub 2020 Aug 18.
Glaucoma is the most common neurodegenerative cause of irreversible blindness worldwide. Restricted caloric regimens are an attractive approach for delaying the progression of neurodegenerative diseases. Here we review the current literature on the effects of caloric restriction on retinal neurons, under physiological and pathological conditions. We focused on autophagy as one of the mechanisms modulated by restricted caloric regimens and involved in the death of retinal ganglion cells (RGCs) over the course of glaucoma.
57Astrocytes as Perspective Targets of Exercise- and Caloric Restriction-Mimetics.PubMed
Ulyana Lalo, Yuriy Pankratov
Neurochem Res. 2021 Oct;46(10):2746-2759. doi: 10.1007/s11064-021-03277-2. Epub 2021 Mar 7.
Enhanced mental and physical activity can have positive effects on the function of aging brain, both in the experimental animals and human patients, although cellular mechanisms underlying these effects are currently unclear. There is a growing evidence that pre-clinical stage of many neurodegenerative diseases involves changes in interactions between astrocytes and neurons. Conversely, astrocytes are strategically positioned to mediate the positive influence of physical activity and diet on neuronal function. Thus, development of therapeutic agents which could improve the astroglia-neuron communications in ageing brain is of crucial importance. Recent advances in studies of cellular mechanisms of brain longevity suggest that astrocyte-neuron communications have a vital role in the beneficial effects of caloric restriction, physical exercise and their pharmacological mimetics on synaptic homeostasis and cognitive function. In particular, our recent data indicate that noradrenaline uptake inhibitor atomoxetine can enhance astrocytic Ca-signaling and astroglia-driven modulation of synaptic plasticity. Similar effects were exhibited by caloric restriction-mimetics metformin and resveratrol. The emerged data also suggest that astrocytes could be involved in the modulatory action of caloric restriction and its mimetics on neuronal autophagy. Still, the efficiency of astrocyte-targeting compounds in preventing age-related cognitive decline is yet to be fully explored, in particular in the animal models of neurodegenerative diseases and autophagy impairment.
58Dietary Intake and Type 2 Diabetes.PubMed
Omorogieva Ojo
Nutrients. 2019 Sep 11;11(9):2177. doi: 10.3390/nu11092177.
This editorial aims to examine the risk factors associated with type 2 diabetes and to discuss the evidence relating to dietary strategies for managing people with this condition. It is clear from the evidence presented that a range of dietary interventions can provide useful approaches for managing people with type 2 diabetes, including the regulation of blood glucose and lipid parameters, and for reducing the risks of acute and chronic diabetic complications.
59Obesity and symptoms suggestive of gastroparesis in patients with type 2 diabetes and neuropathy.PubMed
Mona Boaz, Julia Kislov, Ram Dickman, et al.
J Diabetes Complications. 2011 Sep-Oct;25(5):325-8. doi: 10.1016/j.jdiacomp.2011.06.005. Epub 2011 Aug 2.
BACKGROUND: Associated with neuropathy, symptoms suggestive of gastroparesis are common in patients with type 2 diabetes mellitus (T2DM) and include nausea, vomiting, bloating and early satiety. Gastric motor abnormalities have been reported in obese patients, and obesity is associated with T2DM. An association between obesity and gastroparesis symptoms in diabetic patients with neuropathy has not been investigated. METHODS: In this nested case-control study, 161 patients with neuropathy were identified from within a cross-sectional survey of 380 T2DM patients. Of these, 134 (83.2%, "cases") had at least one cardinal symptom suggestive of gastroparesis. The remaining symptom-free subjects served as controls. Logistic and general linear modeling was used to assess associations between obesity and the presence and number of symptoms. RESULTS: Subjects were 66.6±10 years of age. Cases were significantly more likely than controls to be obese (89% vs. 77%, P=.04), female (55.6% vs. 33.3%) and hypertensive (90.2% vs. 63%, P=.001) and to report adherence to diet (87.4% vs. 66.7%, P=.007). In a logistic regression model including sex, hypertension, antiaggregant therapy, adherence to diet therapy and an obesity-by-sex interaction term, obesity emerged as a significant independent predictor of any cardinal symptom suggestive of gastroparesis (odds ratio 9.86, 95% confidence interval 1.4-69.2, P=.02). Obesity was also identified as a significant independent predictor of number of cardinal symptoms suggestive of gastroparesis in the general linear model. Obese subjects reported significantly more early satiety (61.5% vs. 35.2%, P=.001), fullness (63.7% vs. 40.8%, P=.004), bloating (70.3% vs. 49.3%, P=.006) and abdominal distention (71.4 vs. 50.7%, P=.007) than nonobese subjects. Further, obese subjects reported more cardinal symptoms suggestive of gastroparesis symptoms (4.2±2.4 vs. 3.1±2.5, P=.01). CONCLUSIONS: Obesity emerged as a significant independent predictor of cardinal symptoms suggestive of gastroparesis in patients with T2DM and neuropathy. This finding suggests that mechanisms in addition to neuropathy play a role in the generation of symptoms suggestive of gastroparesis in this patient population.
60Diet, physical activity or both for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus.PubMed
Bianca Hemmingsen, Gabriel Gimenez-Perez, Didac Mauricio, et al.
Cochrane Database Syst Rev. 2017 Dec 4;12(12):CD003054. doi: 10.1002/14651858.CD003054.pub4.
BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether diet, physical activity or both can prevent or delay T2DM and its associated complications in at-risk people is unknown. OBJECTIVES: To assess the effects of diet, physical activity or both on the prevention or delay of T2DM and its associated complications in people at increased risk of developing T2DM. SEARCH METHODS: This is an update of the Cochrane Review published in 2008. We searched the CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, ICTRP Search Portal and reference lists of systematic reviews, articles and health technology assessment reports. The date of the last search of all databases was January 2017. We continuously used a MEDLINE email alert service to identify newly published studies using the same search strategy as described for MEDLINE up to September 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of two years or more. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology for data collection and analysis. We assessed the overall quality of the evidence using GRADE. MAIN RESULTS: We included 12 RCTs randomising 5238 people. One trial contributed 41% of all participants. The duration of the interventions varied from two to six years. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains.Eleven trials compared diet plus physical activity with standard or no treatment. Nine RCTs included participants with impaired glucose tolerance (IGT), one RCT included participants with IGT, impaired fasting blood glucose (IFG) or both, and one RCT included people with fasting glucose levels between 5.3 to 6.9 mmol/L. A total of 12 deaths occurred in 2049 participants in the diet plus physical activity groups compared with 10 in 2050 participants in the comparator groups (RR 1.12, 95% CI 0.50 to 2.50; 95% prediction interval 0.44 to 2.88; 4099 participants, 10 trials; very low-quality evidence). The definition of T2DM incidence varied among the included trials. Altogether 315 of 2122 diet plus physical activity participants (14.8%) developed T2DM compared with 614 of 2389 comparator participants (25.7%) (RR 0.57, 95% CI 0.50 to 0.64; 95% prediction interval 0.50 to 0.65; 4511 participants, 11 trials; moderate-quality evidence). Two trials reported serious adverse events. In one trial no adverse events occurred. In the other trial one of 51 diet plus physical activity participants compared with none of 51 comparator participants experienced a serious adverse event (low-quality evidence). Cardiovascular mortality was rarely reported (four of 1626 diet plus physical activity participants and four of 1637 comparator participants (the RR ranged between 0.94 and 3.16; 3263 participants, 7 trials; very low-quality evidence). Only one trial reported that no non-fatal myocardial infarction or non-fatal stroke had occurred (low-quality evidence). Two trials reported that none of the participants had experienced hypoglycaemia. One trial investigated health-related quality of life in 2144 participants and noted that a minimal important difference between intervention groups was not reached (very low-quality evidence). Three trials evaluated costs of the interventions in 2755 participants. The largest trial of these reported an analysis of costs from the health system perspective and society perspective reflecting USD 31,500 and USD 51,600 per quality-adjusted life year (QALY) with diet plus physical activity, respectively (low-quality evidence). There were no data on blindness or end-stage renal disease.One trial compared a diet-only intervention with a physical-activity intervention or standard treatment. The participants had IGT. Three of 130 participants in the diet group compared with none of the 141 participants in the physical activity group died (very low-quality evidence). None of the participants died because of cardiovascular disease (very low-quality evidence). Altogether 57 of 130 diet participants (43.8%) compared with 58 of 141 physical activity participants (41.1%) group developed T2DM (very low-quality evidence). No adverse events were recorded (very low-quality evidence). There were no data on non-fatal myocardial infarction, non-fatal stroke, blindness, end-stage renal disease, health-related quality of life or socioeconomic effects.Two trials compared physical activity with standard treatment in 397 participants. One trial included participants with IGT, the other trial included participants with IGT, IFG or both. One trial reported that none of the 141 physical activity participants compared with three of 133 control participants died. The other trial reported that three of 84 physical activity participants and one of 39 control participants died (very low-quality evidence). In one trial T2DM developed in 58 of 141 physical activity participants (41.1%) compared with 90 of 133 control participants (67.7%). In the other trial 10 of 84 physical activity participants (11.9%) compared with seven of 39 control participants (18%) developed T2DM (very low-quality evidence). Serious adverse events were rarely reported (one trial noted no events, one trial described events in three of 66 physical activity participants compared with one of 39 control participants - very low-quality evidence). Only one trial reported on cardiovascular mortality (none of 274 participants died - very low-quality evidence). Non-fatal myocardial infarction or stroke were rarely observed in the one trial randomising 123 participants (very low-quality evidence). One trial reported that none of the participants in the trial experienced hypoglycaemia. One trial investigating health-related quality of life in 123 participants showed no substantial differences between intervention groups (very low-quality evidence). There were no data on blindness or socioeconomic effects. AUTHORS' CONCLUSIONS: There is no firm evidence that diet alone or physical activity alone compared to standard treatment influences the risk of T2DM and especially its associated complications in people at increased risk of developing T2DM. However, diet plus physical activity reduces or delays the incidence of T2DM in people with IGT. Data are lacking for the effect of diet plus physical activity for people with intermediate hyperglycaemia defined by other glycaemic variables. Most RCTs did not investigate patient-important outcomes.
61Adiponectin, resistin and leptin response to dietary intervention in diabetic nephropathy.PubMed
Lucyna Kozłowska, Andrzej Rydzewski, Bartosz Fiderkiewicz, et al.
J Ren Nutr. 2010 Jul;20(4):255-62. doi: 10.1053/j.jrn.2010.01.009. Epub 2010 May 26.
OBJECTIVE: Adipokines play an important role in metabolic regulations. Obesity, diabetes, and renal disturbances affect adipokine profile by influencing their complex effects on metabolism. Our objective was to assess the effect of low-energy diet intervention on serum adiponectin, leptin, and resistin levels in diabetic nephropathy. METHODS: Seventeen subjects with diabetes type 2 and nephropathy participated in the study. After estimation of individual resting metabolic rates by indirect calorimetry, diets introducing 20% energy deficit were applied. At baseline and after 2 months of dieting, the following parameters were measured: body composition by dual x-ray spectrometry and serum adiponectin (Adp), leptin (Lep), resistin (Res), insulin, urea, creatinine, glucose, glycosylated hemoglobin, C-reactive protein, and tumor necrosis factor-alpha concentrations. Homeostatic model assessment (HOMA) was used to quantify insulin resistance. RESULTS: Total energy, protein, and fat intakes diminished significantly with intentional dieting. Significant decreases in total body fat mass (FM) and its percentage in body mass (FM%) and trunk and gynoid fat mass, as well as in serum resistin and tumor necrosis factor-alpha levels, were also observed. Responses of adipokines to dietary treatment varied individually. Generally, they were affected by FM. Alterations in Lep concentrations correlated negatively with baseline FM, FM%, and android and gynoid fat mass and positively with changes in intake of protein, carbohydrates, and total energy of the consumed diet. Changes in Adp were inversely related to FM after therapy. Alterations in Res concentrations correlated positively with android fat mass before therapy and initial Lep levels. Adiponectin was inversely related to HOMA index before and after treatment. CONCLUSIONS: Low-energy diet applied in diabetic nephropathy may decrease serum resistin levels and inflammation. In addition, responses of all adipokines to dieting appear to be affected by body fat mass, especially android fat mass.
62Mouse models of diabetic neuropathy.PubMed
Kelli A Sullivan, John M Hayes, Timothy D Wiggin, et al.
Neurobiol Dis. 2007 Dec;28(3):276-85. doi: 10.1016/j.nbd.2007.07.022. Epub 2007 Jul 31.
Diabetic neuropathy (DN) is a debilitating complication of type 1 and type 2 diabetes. Rodent models of DN do not fully replicate the pathology observed in human patients. We examined DN in streptozotocin (STZ)-induced [B6] and spontaneous type 1 diabetes [B6Ins2(Akita)] and spontaneous type 2 diabetes [B6-db/db, BKS-db/db]. Despite persistent hyperglycemia, the STZ-treated B6 and B6Ins2(Akita) mice were resistant to the development of DN. In contrast, DN developed in both type 2 diabetes models: the B6-db/db and BKS-db/db mice. The persistence of hyperglycemia and development of DN in the B6-db/db mice required an increased fat diet while the BKS-db/db mice developed severe DN and remained hyperglycemic on standard mouse chow. Our data support the hypothesis that genetic background and diet influence the development of DN and should be considered when developing new models of DN.
63Modulation of diet-induced mechanical allodynia by metabolic parameters and inflammation.PubMed
Michael A Cooper, Janelle M Ryals, Pau-Yen Wu, et al.
J Peripher Nerv Syst. 2017 Mar;22(1):39-46. doi: 10.1111/jns.12199.
Dietary-associated diseases have increased tremendously in our current population, yet key molecular changes associated with high-fat diets that cause clinical pre-diabetes, obesity, hyperglycemia, and peripheral neuropathy remain unclear. This study examines molecular and metabolic aspects altered by voluntary exercise and a high-fat diet in the mouse dorsal root ganglion. Mice were examined for changes in mRNA and proteins encoding anti-inflammatory mediators, metabolic-associated molecules, and pain-associated ion channels. Proteins involved in the synaptosomal complex and pain-associated TRP ion channels decrease in the dorsal root ganglion of high-fat exercise animals relative to their sedentary controls. Exercise reversed high-fat diet induced mechanical allodynia without affecting weight gain, elevated blood glucose, and utilization of fat as a fuel source. Independent of weight or fat mass changes, high-fat exercised mice display reduced inflammation-associated mRNAs. The benefits of exercise on abnormal peripheral nerve function appear to occur independent of systemic metabolic changes, suggesting that the utilization of fats and inflammation in the peripheral nervous system may be key for diet-induced peripheral nerve dysfunction and the response to exercise.
64An improved model of type 2 diabetes with effects on glucose tolerance, neuropathy and retinopathy with and without obesity.PubMed
Asia M Wiggins, Robert E Sorge
Physiol Behav. 2022 May 1;248:113740. doi: 10.1016/j.physbeh.2022.113740. Epub 2022 Feb 12.
RATIONALE: Type 2 diabetes (T2D) costs billions of dollars annually, is also associated with pain (diabetic neuropathy), as well as retinopathy, lower urinary tract/urinary bladder dysfunction, depression, and systemic inflammation, affecting quality of life for patients. To that end, animal models are utilized to explore potential treatments, but may not reflect the complexity of the condition. OBJECTIVE: We aimed to test an improved model of T2D that more closely mimics the clinical mechanisms and symptoms in an outbred strain of mouse. FINDINGS: Male and female CD-1 mice (n = 72) were fed one of four diets: regular chow (REG), our Standard American Diet (SAD), a revised SAD (SAD2), or the commonly-used high-fat diet (HFD). Overall, HFD- and SAD-fed mice had significant weight gain and increased fat mass. Following injury, the SAD- and SAD2-fed mice showed protracted recovery, but the HFD-fed mice did not. Similarly, SAD- and SAD2-fed mice showed impaired retinal function compared to REG-fed mice, but the HFD-fed mice did not. CONCLUSIONS: The SAD and SAD2 more closely model the problematic dietary intake and subsequent clinical symptoms associated with T2D. POTENTIAL IMPACT OF STUDY: The adjusted SAD2 may be a better representation of a human-translatable diet than the SAD and HFD, and may allow for increased advances in the investigation of T2D-related symptoms.
65Whole-Mount Adult Ear Skin Imaging Reveals Defective Neuro-Vascular Branching Morphogenesis in Obese and Type 2 Diabetic Mouse Models.PubMed
Tomoko Yamazaki, Wenling Li, Ling Yang, et al.
Sci Rep. 2018 Jan 11;8(1):430. doi: 10.1038/s41598-017-18581-7.
Obesity and type 2 diabetes are frequently associated with peripheral neuropathy. Though there are multiple methods for diagnosis and analysis of morphological changes of peripheral nerves and blood vessels, three-dimensional high-resolution imaging is necessary to appreciate the pathogenesis with an anatomically recognizable branching morphogenesis and patterning. Here we established a novel technique for whole-mount imaging of adult mouse ear skin to visualize branching morphogenesis and patterning of peripheral nerves and blood vessels. Whole-mount immunostaining of adult mouse ear skin showed that peripheral sensory and sympathetic nerves align with large-diameter blood vessels. Diet-induced obesity (DIO) mice exhibit defective vascular smooth muscle cells (VSMCs) coverage, while there is no significant change in the amount of peripheral nerves. The leptin receptor-deficient db/db mice, a severe obese and type 2 diabetic mouse model, exhibit defective VSMC coverage and a large increase in the amount of smaller-diameter nerve bundles with myelin sheath and unmyelinated nerve fibers. Interestingly, an increase in the amount of myeloid immune cells was observed in the DIO but not db/db mouse skin. These data suggest that our whole-mount imaging method enables us to investigate the neuro-vascular and neuro-immune phenotypes in the animal models of obesity and diabetes.
66The Role of Iron and Nerve Inflammation in Diabetes Mellitus Type 2-Induced Peripheral Neuropathy.PubMed
Sabine Paeschke, Petra Baum, Klaus V Toyka, et al.
Neuroscience. 2019 May 15;406:496-509. doi: 10.1016/j.neuroscience.2019.03.005. Epub 2019 Mar 10.
Peripheral diabetic neuropathy (PDN) is one of the most common complications of diabetes mellitus. Previous studies showed an association between dietary iron load and inflammation in the development of PDN in a rat model of type 1 diabetes (T1D). Here we investigated the role of iron and neural inflammation in development of PDN in a animal model of obesity and type 2 diabetes (T2D). 3-month-old db/db mice were fed with a high, standard or low iron diet for 4 months. High iron chow lead to a significant increase in motor nerve conduction velocities compared to mice on standard and low iron chow. Direct beneficiary effects on lowering blood glucose and HbA1c concentrations were shown in the high iron treated diabetic mice. Numbers of pro-inflammatory M1 macrophages were reduced in nerve sections, and anti-inflammatory M2 macrophages were increased in db/db mice on high iron diet compared to other groups. These results confirm and extend our previous findings in STZ-diabetic rats by showing that dietary non-hem iron supplementation may partly prevent the development of PDN in opposition to iron restriction. The identification of these dietary iron effects on the metabolic and inflammatory mechanisms of PDN supports a role of dietary iron and leads us to suggest testing for iron levels in human diabetic patients.
67The Effect of Bariatric Surgery on Peripheral Polyneuropathy: a Systematic Review and Meta-analysis.PubMed
Rokhsareh Aghili, Mojtaba Malek, Kiarash Tanha, et al.
Obes Surg. 2019 Sep;29(9):3010-3020. doi: 10.1007/s11695-019-04004-1.
Neurological complications such as peripheral neuropathies are the most common complications among patients with morbid obesity following bariatric surgery. Reduction in nutrient intake especially thiamin may develop polyneuropathy, while neuropathic symptoms improved in patients with diabetes independent of glycemic control after bariatric surgery. The aim of the present review is to investigate the effect of bariatric surgery on peripheral neuropathy. Electronic literature search was done via scientific search engines. After the removal of duplicates and selection of articles of interest, 4 studies were included. A random effects model was applied in this meta-analysis. Considering the pooled analysis, bariatric surgery was significantly associated with Neuropathy Symptoms Score (NSS) (ES = - 3.393, 95% CI (- 4.507, - 2.278), and P value < 0.0001). Reduction in NSS for patients with type 2 diabetes and BMI < 35 kg/m who were insulin-dependent was more than patients with morbid obesity without diabetes. Furthermore, neuropathy disability score (NDS) significantly decreased in patients having bariatric surgery (ES = - 0.626, 95% CI (- 1.120, - 0.132), and P value < 0.013). The NDS significantly decreased in patients with type 2 diabetes and BMI < 35 kg/m treated with insulin as well as patients with morbid obesity and type 2 diabetes. In subgroup of patients with follow-up of more than 6 months after surgery, a significant reduction in NDS was detected while this reduction was not significant in patients with a follow-up of 6 months or less. Bariatric surgery had a positive effect on peripheral neuropathy, though many studies showed neuropathy as one of the complications of bariatric surgery.
68Efficacy and Safety of the Combination of Palmitoylethanolamide, Superoxide Dismutase, Alpha Lipoic Acid, Vitamins B12, B1, B6, E, Mg, Zn and Nicotinamide for 6 Months in People with Diabetic Neuropathy.PubMed
Triantafyllos Didangelos, Eleni Karlafti, Evangelia Kotzakioulafi, et al.
Nutrients. 2024 Sep 10;16(18):3045. doi: 10.3390/nu16183045.
AIM: To investigate the efficacy of Palmitoylethanolamide (PEA, 300 mg), Superoxide Dismutase (SOD, 70 UI), Alpha Lipoic Acid (ALA, 300 mg), vitamins B6 (1.5 mg), B1 (1.1 mg), B12 (2.5 mcg), E (7.5 mg), nicotinamide (9 mg), and minerals (Mg 30 mg, Zn 2.5 mg) in one tablet in people with Diabetic Neuropathy (DN). PATIENTS-METHODS: In the present pilot study, 73 people (age 63.0 ± 9.9 years, 37 women) with type 2 Diabetes Mellitus (DMT2) (duration 17.5 ± 7.3 years) and DN were randomly assigned to receive either the combination of ten elements (2 tablets/24 h) in the active group ( = 36) or the placebo ( = 37) for 6 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured vibration perception threshold (VPT) with biothesiometer, and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Sudomotor function was assessed with SUDOSCAN, which measures electrochemical skin conductance in hands and feet (ESCH and ESCF). Pain score (PS) was assessed with Pain DETECT questionnaire. Quality of life was assessed by questionnaire. RESULTS: In the active group, there was a large improvement of pain (PS from 20.9 to 13.9, < 0.001). There was also a significant improvement of vitamin B12 (B12) levels, MNSIQ, SNCV, VPT, and ESCF (222.1 vs. 576.3 pg/ mL, < 0.001; 6.1 vs. 5.9, = 0.017; 28.8 vs. 30.4, = 0.001; 32.1 vs. 26.7, = 0.001; and 72.2 vs. 74.8, < 0.001 respectively). In the placebo group, neither pain (21.6 vs. 21.7, = 0.870) or any other aforementioned parameters changed significantly, and MNSIE worsened (2.9 vs. 3.4, < 0.001). As a result, changes from baseline to follow-up in pain, B12 levels, VPT, and MNSIQ differed significantly between the two groups ( < 0.001, 0.025, 0.009, and <0.001, respectively). CARTs, SNAP, ESCH did not significantly change in either of the two groups. CONCLUSIONS: The combination of the ten elements in one tablet for 6 months at a daily dose of two tablets in people with DN significantly improves pain, vibration perception threshold, and B12 levels.
69Effect of folic acid supplementation on nerve conduction velocity in diabetic polyneuropathy patients.PubMed
Tayebeh Mottaghi, Fariborz Khorvash, Mohammadreza Maracy, et al.
Neurol Res. 2019 Apr;41(4):364-368. doi: 10.1080/01616412.2019.1565180. Epub 2019 Feb 7.
OBJECTIVES: In diabetic polyneuropathy (DPN) patients, the effect of folic acid and homocysteine has been related to components of nerve conduction velocity (NCV). The objective of this study was to determine the effect of folic acid supplementation on NCV in DPN patients. METHODS: Patients were randomized to receive either 1 mg of folic acid (n = 40) or placebo (n = 40) for 16 weeks. Blood samples were collected to assess serum folic acid and homocysteine concentrations, and NCV was performed for assessment of diabetic neuropathy. RESULTS: At 16 weeks, in the supplemented group, serum levels of folic acid (p < 0.001) increased, homocysteine concentrations decreased (p < 0.001), with no change in serum vitamin B12 levels. There was a significant increase in sensory sural amplitude (p < 0.001), and components of motor nerves, including amplitude (p = 0.001) and velocity (p < 0.001), but decreased onset latency of peroneal (p = 0.019) and tibial (p = 0.011) motor nerves. CONCLUSION: Our data suggest that supplementation with 1 mg of folic acid for 16 weeks may be useful for enhancing NCV in DPN patients.
70Folate Supplementation for Peripheral Neuropathy: A Systematic Review.PubMed
Ana Carolina Alves Maues, Mònica Gemma Moren Abat, María Benlloch, et al.
Nutrients. 2025 Oct 20;17(20):3299. doi: 10.3390/nu17203299.
BACKGROUND: Peripheral neuropathy (PN) represents a considerable and rapidly growing global health burden, with diabetic PN alone impacting nearly half of diabetic patients. Evidence from experimental studies highlighted that folate supplementation may protect nerve health by supporting myelin maintenance, minimizing oxidative stress, and enhancing neurotrophic factors. Nevertheless, its clinical efficacy and safety in managing PN have not yet been established. This study seeks to evaluate the role of folate in managing PN regarding the efficacy and safety endpoints. METHODS: Up to July 2025, a comprehensive search of four electronic databases, encompassing PubMed, Scopus, Web of Science, and Cochrane Library, was executed, collecting studies evaluating the folate in managing PN. Outcomes included pain scores, symptom improvement endpoints, Neuropathy Total Symptom Score (NTSS) scores, epidermal nerve fiber density (ENFD), biomarkers, and side effects. RESULTS: The narrative synthesis demonstrated consistent symptomatic benefits with pain reductions reaching 3 points, with symptom resolution rates of 87.5% and NTSS-6 score enhancements varying from 0.9 to 1.5 points. Notably, objective structural improvements in ENFD were observed, with increases reaching 97%. Furthermore, folate showed an excellent safety and tolerability profile with only one adverse event reported among 1367 individuals. Folate significantly decreased homocysteine and high-sensitivity C-reactive protein (hs-CRP) levels. CONCLUSIONS: Folate showed promising symptomatic benefits for peripheral neuropathy, with objective structural improvements (ENFD) and favourable biomarker changes (homocysteine, hs-CRP reduction), with an excellent safety profile.
71Zinc supplementation alleviates diabetic peripheral neuropathy by inhibiting oxidative stress and upregulating metallothionein in peripheral nerves of diabetic rats.PubMed
Fangyao Liu, Feiyu Ma, Gengbin Kong, et al.
Biol Trace Elem Res. 2014 May;158(2):211-8. doi: 10.1007/s12011-014-9923-9. Epub 2014 Mar 11.
We investigated the effect of zinc supplementation on the expression of metallothionein, lipid peroxidation (malondialdehyde, MDA), and poly(ADP-ribose) polymerase-1 (PARP-1) in the sciatic nerve, motor nerve conduction velocity of the left sciatic posterior tibial nerve in streptozotocin (STZ)-induced diabetic rats. Twenty-four male rats were equally divided into four groups. The first group served as untreated controls although the second group received 5 mg/kg/day zinc chloride. The third group was treated with STZ to induce diabetes, and the fourth group was treated with STZ and supplemented with zinc. A gradual but insignificant decline in motor nerve conduction velocity was observed at 2 weeks of induction of diabetes. Zinc supplementation markedly attenuated the decrease in motor nerve conduction velocity at week 8 post-induction of diabetes. Furthermore, the tactile response threshold of diabetic rats receiving normal saline was lower than that of diabetic rats receiving zinc supplementation. Additionally, zinc supplementation accentuated the increase in the mRNA transcript levels of metallothionein but attenuated the increase in the mRNA transcript levels of PARP-1. At week 8 post-induction of diabetes, diabetic rats receiving normal saline had markedly higher MDA contents than diabetic rats receiving zinc supplementation. In conclusion, the present study shows that zinc has a protective effect against diabetes-induced peripheral nerve damage by stimulating metallothionein synthesis and downregulating oxidative stress.
72Zinc Intake, Zinc Bioavailability and Plasma Zinc in Obese Adolescents with Clinical Insulin Resistance Following Low Energy Diets.PubMed
Mandy Ho, Anne-Louise M Heath, Megan Gow, et al.
Ann Nutr Metab. 2016;69(2):135-141. doi: 10.1159/000450728. Epub 2016 Oct 18.
BACKGROUND: Zinc has a critical role in metabolism and growth. This study aims to determine the effects of low-energy diets differing in macronutrient composition on zinc intake, estimated zinc bioavailability (phytate:zinc molar ratio) and plasma zinc concentration and associations between zinc status and cardiometabolic markers in obese adolescents with clinical insulin resistance (IR). METHODS: Eighty-seven obese adolescents (10-17 years, body mass index z-score 2.3 ± 0.37) with clinical IR were randomized to a low-energy diet (6.0-8.0 MJ), which was either high carbohydrate or moderate carbohydrate with increased protein. Twenty-four-hour dietary recalls were collected at 6, 9 and 12 weeks. Plasma zinc concentration and cardiometabolic markers were assessed at baseline and 12 weeks. RESULTS: Zinc intake did not differ between the 2 diet groups (p = 0.612). The high-carbohydrate group had a higher phytate intake (894 vs. 671 mg, p = 0.018) and phytate:zinc molar ratio (9.4 vs. 7.4, p = 0.009) than the increased-protein group. Plasma zinc concentration did not change from baseline in either of the diet groups, but correlated positively with zinc intake (r = 0.235, p = 0.042) and % energy from protein (r = 0.383, p = 0.001), and inversely with % energy from carbohydrate (r = -0.296, p = 0.010). CONCLUSIONS: Low energy diets for obese adolescents at risk of diabetes may need increased protein content to optimize zinc bioavailability.
73Dietary fibre and whole grains in diabetes management: Systematic review and meta-analyses.PubMed
Andrew N Reynolds, Ashley P Akerman, Jim Mann
PLoS Med. 2020 Mar 6;17(3):e1003053. doi: 10.1371/journal.pmed.1003053. eCollection 2020 Mar.
BACKGROUND: Fibre is promoted as part of a healthy dietary pattern and in diabetes management. We have considered the role of high-fibre diets on mortality and increasing fibre intake on glycaemic control and other cardiometabolic risk factors of adults with prediabetes or diabetes. METHODS AND FINDINGS: We conducted a systematic review of published literature to identify prospective studies or controlled trials that have examined the effects of a higher fibre intake without additional dietary or other lifestyle modification in adults with prediabetes, gestational diabetes, type 1 diabetes, and type 2 diabetes. Meta-analyses were undertaken to determine the effects of higher fibre intake on all-cause and cardiovascular mortality and increasing fibre intake on glycaemic control and a range of cardiometabolic risk factors. For trials, meta regression analyses identified further variables that influenced the pooled findings. Dose response testing was undertaken; Grading of Recommendations Assessment, Development and Evaluation (GRADE) protocols were followed to assess the quality of evidence. Two multicountry cohorts of 8,300 adults with type 1 or type 2 diabetes followed on average for 8.8 years and 42 trials including 1,789 adults with prediabetes, type 1, or type 2 diabetes were identified. Prospective cohort data indicate an absolute reduction of 14 fewer deaths (95% confidence interval (CI) 4-19) per 1,000 participants over the study duration, when comparing a daily dietary fibre intake of 35 g with the average intake of 19 g, with a clear dose response relationship apparent. Increased fibre intakes reduced glycated haemoglobin (HbA1c; mean difference [MD] -2.00 mmol/mol, 95% CI -3.30 to -0.71 from 33 trials), fasting plasma glucose (MD -0.56 mmol/L, 95% CI -0.73 to -0.38 from 34 trials), insulin (standardised mean difference [SMD] -2.03, 95% CI -2.92 to -1.13 from 19 trials), homeostatic model assessment of insulin resistance (HOMA IR; MD -1.24 mg/dL, 95% CI -1.72 to -0.76 from 9 trials), total cholesterol (MD -0.34 mmol/L, 95% CI -0.46 to -0.22 from 27 trials), low-density lipoprotein (LDL) cholesterol (MD -0.17 mmol/L, 95% CI -0.27 to -0.08 from 21 trials), triglycerides (MD -0.16 mmol/L, 95% CI -0.23 to -0.09 from 28 trials), body weight (MD -0.56 kg, 95% CI -0.98 to -0.13 from 18 trials), Body Mass Index (BMI; MD -0.36, 95% CI -0·55 to -0·16 from 14 trials), and C-reactive protein (SMD -2.80, 95% CI -4.52 to -1.09 from 7 trials) when compared with lower fibre diets. All trial analyses were subject to high heterogeneity. Key variables beyond increasing fibre intake were the fibre intake at baseline, the global region where the trials were conducted, and participant inclusion criteria other than diabetes type. Potential limitations were the lack of prospective cohort data in non-European countries and the lack of long-term (12 months or greater) controlled trials of increasing fibre intakes in adults with diabetes. CONCLUSIONS: Higher-fibre diets are an important component of diabetes management, resulting in improvements in measures of glycaemic control, blood lipids, body weight, and inflammation, as well as a reduction in premature mortality. These benefits were not confined to any fibre type or to any type of diabetes and were apparent across the range of intakes, although greater improvements in glycaemic control were observed for those moving from low to moderate or high intakes. Based on these findings, increasing daily fibre intake by 15 g or to 35 g might be a reasonable target that would be expected to reduce risk of premature mortality in adults with diabetes.
74Effects of dietary fiber and its components on metabolic health.PubMed
James M Lattimer, Mark D Haub
Nutrients. 2010 Dec;2(12):1266-89. doi: 10.3390/nu2121266. Epub 2010 Dec 15.
Dietary fiber and whole grains contain a unique blend of bioactive components including resistant starches, vitamins, minerals, phytochemicals and antioxidants. As a result, research regarding their potential health benefits has received considerable attention in the last several decades. Epidemiological and clinical studies demonstrate that intake of dietary fiber and whole grain is inversely related to obesity, type two diabetes, cancer and cardiovascular disease (CVD). Defining dietary fiber is a divergent process and is dependent on both nutrition and analytical concepts. The most common and accepted definition is based on nutritional physiology. Generally speaking, dietary fiber is the edible parts of plants, or similar carbohydrates, that are resistant to digestion and absorption in the small intestine. Dietary fiber can be separated into many different fractions. Recent research has begun to isolate these components and determine if increasing their levels in a diet is beneficial to human health. These fractions include arabinoxylan, inulin, pectin, bran, cellulose, β-glucan and resistant starch. The study of these components may give us a better understanding of how and why dietary fiber may decrease the risk for certain diseases. The mechanisms behind the reported effects of dietary fiber on metabolic health are not well established. It is speculated to be a result of changes in intestinal viscosity, nutrient absorption, rate of passage, production of short chain fatty acids and production of gut hormones. Given the inconsistencies reported between studies this review will examine the most up to date data concerning dietary fiber and its effects on metabolic health.
75Gut Microbiota and Complications of Type-2 Diabetes.PubMed
Camelia Oana Iatcu, Aimee Steen, Mihai Covasa
Nutrients. 2021 Dec 30;14(1):166. doi: 10.3390/nu14010166.
The gut microbiota has been linked to the emergence of obesity, metabolic syndrome and the onset of type 2 diabetes through decreased glucose tolerance and insulin resistance. Uncontrolled diabetes can lead to serious health consequences such as impaired kidney function, blindness, stroke, myocardial infarction and lower limb amputation. Despite a variety of treatments currently available, cases of diabetes and resulting complications are on the rise. One promising new approach to diabetes focuses on modulating the gut microbiota with probiotics, prebiotics, synbiotics and fecal microbial transplantation. Differences in gut microbiota composition have been observed in preclinical animal models as well as patients with type 2 diabetes and complications such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cerebrovascular disease, coronary heart disease and peripheral artery disease compared to healthy controls. Severity of gut microbiota dysbiosis was associated with disease severity and restoration with probiotic administration in animal models and human patients has been associated with improvement of symptoms and disease progression. Characterizing the gut microbiota dysbiosis in different diseases and determining a causal relationship between the gut microbiota and disease can be beneficial in formulating therapeutic interventions for type 2 diabetes and associated complications. In this review, we present the most important findings regarding the role of the gut microbiota in type 2 diabetes and chronic complications as well as their underlying mechanisms.
76Gut Microbiota: An Important Player in Type 2 Diabetes Mellitus.PubMed
Zheng Zhou, Bao Sun, Dongsheng Yu, et al.
Front Cell Infect Microbiol. 2022 Feb 15;12:834485. doi: 10.3389/fcimb.2022.834485. eCollection 2022.
Type 2 diabetes mellitus (T2DM) is one of the common metabolic diseases in the world. Due to the rise in morbidity and mortality, it has become a global health problem. To date, T2DM still cannot be cured, and its intervention measures mainly focus on glucose control as well as the prevention and treatment of related complications. Interestingly, the gut microbiota plays an important role in the development of metabolic diseases, especially T2DM. In this review, we introduce the characteristics of the gut microbiota in T2DM population, T2DM animal models, and diabetic complications. In addition, we describe the molecular mechanisms linking host and the gut microbiota in T2DM, including the host molecules that induce gut microbiota dysbiosis, immune and inflammatory responses, and gut microbial metabolites involved in pathogenesis. These findings suggest that we can treat T2DM and its complications by remodeling the gut microbiota through interventions such as drugs, probiotics, prebiotics, fecal microbiota transplantation (FMT) and diets.
77Gut microbiota in the pathogenesis and therapeutic approaches of diabetes.PubMed
Lucilla Crudele, Raffaella Maria Gadaleta, Marica Cariello, et al.
EBioMedicine. 2023 Nov;97:104821. doi: 10.1016/j.ebiom.2023.104821. Epub 2023 Oct 5.
The gut-liver axis plays a prominent role in the pathogenesis and therapy of metabolic diseases such as diabetes. The intestinal specific origin of several hormones that guide both inter- and post-prandial metabolism of carbohydrates and lipids, drives the attention of scientists and clinicians on the gut as a major site to intervene with novel diagnostic or prognostic markers. The role of intestinal ecology in the metabolic syndrome was postulated when gut microbiota was directly connected with inflammation, hyperinsulinemia, and diabetes. There have been several discoveries with the role of gut microbiota and gut-liver axis in diabetes. Also, there are several trials ongoing on the therapeutic efficacy of probiotic administration in diabetes and its complications. Here we point to the metabolic action of microbiota and discuss the actual state of the art on gut microbiota as a novel prognostic biomarker with a putative therapeutic role in diabetes.
78Impact of Dietary Fiber Consumption on Insulin Resistance and the Prevention of Type 2 Diabetes.PubMed
Martin O Weickert, Andreas F H Pfeiffer
J Nutr. 2018 Jan 1;148(1):7-12. doi: 10.1093/jn/nxx008.
Large prospective cohort studies consistently show associations of a high dietary fiber intake (>25 g/d in women and >38 g/d in men) with a 20-30% reduced risk of developing type 2 diabetes (T2D), after correction for confounders. It is less well recognized that these effects appear to be mainly driven by high intakes of whole grains and insoluble cereal fibers, which typically are nonviscous and do not relevantly influence postprandial glucose responses [i.e., glycemic index (GI)] or are strongly fermented by the gut microbiota in the colon. In contrast, a dietary focus on soluble, viscous, gel-forming, more readily fermentable fiber intakes derived from fruit and certain vegetables yields mixed results and generally does not appear to reduce T2D risk. Although disentangling types of fiber-rich foods and separating these from possible effects related to the GI is an obvious challenge, the common conclusion that key metabolic effects of high-fiber intake are explained by mechanisms that should mainly apply to the soluble, viscous type can be challenged. More recently, studies in humans and animal models focused on gaining mechanistic insights into why especially high-cereal-fiber (HCF) diets appear to improve insulin resistance (IR) and diabetes risk. Although effects of HCF diets on weight loss are only moderate and comparable to other types of dietary fibers, possible novel mechanisms have emerged, which include the prevention of the absorption of dietary protein and modulation of the amino acid metabolic signature. Here we provide an update of our previous review from 2008, with a focus on mechanistic insights of how HCF diets may improve IR and the risk of developing T2D.
79Effect of low glycaemic index or load dietary patterns on glycaemic control and cardiometabolic risk factors in diabetes: systematic review and meta-analysis of randomised controlled trials.PubMed
Laura Chiavaroli, Danielle Lee, Amna Ahmed, et al.
BMJ. 2021 Aug 4;374:n1651. doi: 10.1136/bmj.n1651.
OBJECTIVE: To inform the update of the European Association for the Study of Diabetes clinical practice guidelines for nutrition therapy. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, and the Cochrane Library searched up to 13 May 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials of three or more weeks investigating the effect of diets with low glycaemic index (GI)/glycaemic load (GL) in diabetes. OUTCOME AND MEASURES: The primary outcome was glycated haemoglobin (HbA1c). Secondary outcomes included other markers of glycaemic control (fasting glucose, fasting insulin); blood lipids (low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), non-HDL-C, apo B, triglycerides); adiposity (body weight, BMI (body mass index), waist circumference), blood pressure (systolic blood pressure (SBP) and diastolic blood pressure (DBP)), and inflammation (C reactive protein (CRP)). DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias. Data were pooled by random effects models. GRADE (grading of recommendations assessment, development, and evaluation) was used to assess the certainty of evidence. RESULTS: 29 trial comparisons were identified in 1617 participants with type 1 and 2 diabetes who were predominantly middle aged, overweight, or obese with moderately controlled type 2 diabetes treated by hyperglycaemia drugs or insulin. Low GI/GL dietary patterns reduced HbA1c in comparison with higher GI/GL control diets (mean difference −0.31% (95% confidence interval −0.42 to −0.19%), P<0.001; substantial heterogeneity, I2=75%, P<0.001). Reductions occurred also in fasting glucose, LDL-C, non-HDL-C, apo B, triglycerides, body weight, BMI, systolic blood pressure (dose-response), and CRP (P<0.05), but not blood insulin, HDL-C, waist circumference, or diastolic blood pressure. A positive dose-response gradient was seen for the difference in GL and HbA1c and for absolute dietary GI and SBP (P<0.05). The certainty of evidence was high for the reduction in HbA1c and moderate for most secondary outcomes, with downgrades due mainly to imprecision. CONCLUSIONS: This synthesis suggests that low GI/GL dietary patterns result in small important improvements in established targets of glycaemic control, blood lipids, adiposity, blood pressure, and inflammation beyond concurrent treatment with hyperglycaemia drugs or insulin, predominantly in adults with moderately controlled type 1 and type 2 diabetes. The available evidence provides a good indication of the likely benefit in this population. STUDY REGISTRATION: ClinicalTrials.gov NCT04045938.
80Omega-3 Polyunsaturated Fatty Acids in Depression.PubMed
Anna Serefko, Monika Elżbieta Jach, Marlena Pietraszuk, et al.
Int J Mol Sci. 2024 Aug 8;25(16):8675. doi: 10.3390/ijms25168675.
Omega-3 polyunsaturated fatty acids have received considerable attention in the field of mental health, in particular regarding the treatment of depression. This review presents an overview of current research on the role of omega-3 fatty acids in the prevention and treatment of depressive disorders. The existing body of evidence demonstrates that omega-3 fatty acids, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have antidepressant effects that can be attributed to their modulation of neuroinflammation, neurotransmitter function, and neuroplasticity. Nevertheless, clinical trials of omega-3 supplementation have yielded inconsistent results. Some studies have demonstrated significant reductions in depressive symptoms following omega-3 treatment, whereas others have shown minimal to no beneficial impact. A range of factors, encompassing dosage, the ratio of EPA to DHA, and baseline nutritional status, have been identified as having a potential impact on the noted results. Furthermore, it has been suggested that omega-3 fatty acids may act as an adjunctive treatment for those undergoing antidepressant treatment. Notwithstanding these encouraging findings, discrepancies in study designs and variability in individual responses underscore the necessity of further research in order to establish uniform, standardized guidelines for the use of omega-3 fatty acids in the management of depressive disorders.
81DHA/EPA (Omega-3) and LA/GLA (Omega-6) as Bioactive Molecules in Neurodegenerative Diseases.PubMed
Christina Kousparou, Maria Fyrilla, Anastasis Stephanou, et al.
Int J Mol Sci. 2023 Jun 27;24(13):10717. doi: 10.3390/ijms241310717.
Neurodegenerative diseases are characterized by neuroinflammation, neuronal depletion and oxidative stress. They coincide with subtle chronic or flaring inflammation, sometimes escalating with infiltrations of the immune system cells in the inflamed parts causing mild to severe or even lethal damage. Thus, neurodegenerative diseases show all features of autoimmune diseases. Prevalence of neurodegenerative diseases has dramatically increased in recent decades and unfortunately, the therapeutic efficacy and safety profile of available drugs is moderate. The beneficial effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) polyunsaturated fatty acids (omega-3 PUFAs) are nowadays highlighted by a plethora of studies. They play a role in suppression of inflammation, gene expression, cellular membrane fluidity/permeability, immune functionality and intracellular/exocellular signaling. The role of omega-6 polyunsaturated fatty acids, such as linoleic acid (LA), gamma linolenic acid (GLA), and arachidonic acid (AA), on neuroprotection is controversial, as some of these agents, specifically AA, are proinflammatory, whilst current data suggest that they may have neuroprotective properties as well. This review provides an overview of the existing recent clinical studies with respect to the role of omega-3 and omega-6 PUFAs as therapeutic agents in chronic, inflammatory, autoimmune neurodegenerative diseases as well as the dosages and the period used for testing.
82Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury.PubMed
Xiangrong Chen, Chunnuan Chen, Sining Fan, et al.
J Neuroinflammation. 2018 Apr 20;15(1):116. doi: 10.1186/s12974-018-1151-3.
BACKGROUND: Microglial polarization and the subsequent neuroinflammatory response are contributing factors for traumatic brain injury (TBI)-induced secondary injury. High mobile group box 1 (HMGB1) mediates the activation of the NF-κB pathway, and it is considered to be pivotal in the late neuroinflammatory response. Activation of the HMGB1/NF-κB pathway is closely related to HMGB1 acetylation, which is regulated by the sirtuin (SIRT) family of proteins. Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are known to have antioxidative and anti-inflammatory effects. We previously demonstrated that ω-3 PUFA inhibited TBI-induced microglial activation and the subsequent neuroinflammatory response by regulating the HMGB1/NF-κB signaling pathway. However, no studies have elucidated if ω-3 PUFA affects the HMGB1/NF-κB pathway in a HMGB1 deacetylation of dependent SIRT1 manner, thus regulating microglial polarization and the subsequent neuroinflammatory response. METHODS: The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, rotarod test, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and HMGB1, were used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1/NF-κB signaling pathway activation to evaluate the effects of ω-3 PUFA supplementation. The impact of SIRT1 deacetylase activity on HMGB1 acetylation and the interaction between HMGB1 and SIRT1 were assessed to evaluate anti-inflammation effects of ω-3 PUFAs, and also, whether these effects were dependent on a SIRT1-HMGB1/NF-κB axis to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. RESULTS: The results of our study showed that ω-3 PUFA supplementation promoted a shift from the M1 microglial phenotype to the M2 microglial phenotype and inhibited microglial activation, thus reducing TBI-induced inflammatory factors. In addition, ω-3 PUFA-mediated downregulation of HMGB1 acetylation and its extracellular secretion was found to be likely due to increased SIRT1 activity. We also found that treatment with ω-3 PUFA inhibited HMGB1 acetylation and induced direct interactions between SIRT1 and HMGB1 by elevating SIRT1 activity following TBI. These events lead to inhibition of HMGB1 nucleocytoplasmic translocation/extracellular secretion and alleviated HMGB1-mediated activation of the NF-κB pathway following TBI-induced microglial activation, thus inhibiting the subsequent inflammatory response. CONCLUSIONS: The results of this study suggest that ω-3 PUFA supplementation attenuates the inflammatory response by modulating microglial polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway, leading to neuroprotective effects following experimental traumatic brain injury.
83ω-3 DPA Protected Neurons from Neuroinflammation by Balancing Microglia M1/M2 Polarizations through Inhibiting NF-κB/MAPK p38 Signaling and Activating Neuron-BDNF-PI3K/AKT Pathways.PubMed
Baiping Liu, Yongping Zhang, Zhiyou Yang, et al.
Mar Drugs. 2021 Oct 20;19(11):587. doi: 10.3390/md19110587.
Microglia M1 phenotype causes HPA axis hyperactivity, neurotransmitter dysfunction, and production of proinflammatory mediators and oxidants, which may contribute to the etiology of depression and neurodegenerative diseases. Eicosapentaenoic acid (EPA) may counteract neuroinflammation by increasing n-3 docosapentaenoic acid (DPA). However, the cellular and molecular mechanisms of DPA, as well as whether it can exert antineuroinflammatory and neuroprotective effects, are unknown. The present study first evaluated DPA's antineuroinflammatory effects in lipopolysaccharide (LPS)-activated BV2 microglia. The results showed that 50 μM DPA significantly decreased BV2 cell viability after 100 ng/mL LPS stimulation, which was associated with significant downregulation of microglia M1 phenotype markers and proinflammatory cytokines but upregulation of M2 markers and anti-inflammatory cytokine. Then, DPA inhibited the activation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65 pathways, which results were similar to the effects of NF-κB inhibitor, a positive control. Second, BV2 cell supernatant was cultured with differentiated SH-SY5Y neurons. The results showed that the supernatant from LPS-activated BV2 cells significantly decreased SH-SY5Y cell viability and brain-derived neurotrophic factor (BDNF), TrkB, p-AKT, and PI3K expression, which were significantly reversed by DPA pretreatment. Furthermore, DPA neuroprotection was abrogated by BDNF-SiRNA. Therefore, n-3 DPA may protect neurons from neuroinflammation-induced damage by balancing microglia M1 and M2 polarizations, inhibiting microglia-NF-κB and MAPK p38 while activating neuron-BDNF/TrkB-PI3K/AKT pathways.