Kim Yoo, Rouse Michael, González-Mariscal Isabel, Egan Josephine M, O'Connell Jennifer F
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd, Suite 100, Baltimore, MD 21224 USA.
Nutr Metab (Lond). 2019 Jul 25;16:48. doi: 10.1186/s12986-019-0377-0. eCollection 2019.
Although type 2 diabetes mellitus (T2DM) is primarily characterized by sustained high levels of circulating glucose, other factors, such as obesity, chronic inflammation, fatty liver, and islet dysfunction significantly contribute to the development of this disease. To date, curcumin (CUR), a natural polyphenol and primary component of turmeric, shows putative therapeutic properties such as reducing the incidence of obesity-related diseases in mice. However, the mechanism by which CUR regulates insulin levels remains unclear.
This study investigates how dietary CUR improves insulin clearance and maintains a proper range of circulating insulin level in the diet-induced obesity (DIO) mouse model. Male C57BL/6 J mice were fed a control, a high fat/high sugar (HFS) or a HFS diet containing 0.4% (w/w) curcumin (HFS + CUR) ( = 16 per group) for 16 weeks.
Mice given HFS + CUR had reduced body weight and fat accumulation in the liver and had lower blood insulin levels under fasting conditions compared to mice on HFS alone, resulting from significantly improved insulin clearance via upregulation of hepatic insulin-degrading enzyme (IDE). We also observed restoration of phosphoinositide 3-kinase (PI3K), especially class Ia catalytic subunits, p110α and p110β, and class Ib regulatory subunit, p101, and phosphorylated protein kinase B (AKT) expression levels in liver on HFS + CUR diet. Additionally, HFS + CUR fed mice had significantly smaller islets of Langerhans and increased glucagon contents compared to HFS fed mice, indicating less secretion of insulin in pancreas. The expression of thioredoxin interacting protein (TXNIP), a pro-oxidant and pro-apoptotic protein, was significantly elevated in mouse and human islets cultured under HFS mimicking conditions, which was mitigated by CUR treatment.
CUR supplementation in obese subjects may alleviate the burden imposed by HFS diets. Our data indicate administration of dietary CUR reinstates PI3K, AKT and IDE levels in obese mice. Additionally, CUR treatment preserves islet integrity by downregulation of TXNIP transcription levels. Therefore, dietary CUR may have the potential to serve as a novel therapeutic agent to address the underlying links of obesity and T2DM.
尽管2型糖尿病（T2DM）的主要特征是循环葡萄糖水平持续升高，但其他因素，如肥胖、慢性炎症、脂肪肝和胰岛功能障碍，对该疾病的发展也有显著影响。迄今为止，姜黄素（CUR）作为一种天然多酚和姜黄的主要成分，显示出具有潜在治疗特性，如降低小鼠肥胖相关疾病的发病率。然而，CUR调节胰岛素水平的机制仍不清楚。
本研究调查了饮食中的CUR如何改善饮食诱导肥胖（DIO）小鼠模型中的胰岛素清除率，并维持循环胰岛素水平在适当范围内。雄性C57BL/6 J小鼠分别喂食对照饮食、高脂肪/高糖（HFS）饮食或含0.4%（w/w）姜黄素的HFS饮食（HFS+CUR）（每组16只），持续16周。
与仅喂食HFS的小鼠相比，喂食HFS+CUR的小鼠体重减轻，肝脏脂肪堆积减少，空腹条件下血液胰岛素水平较低，这是由于通过上调肝脏胰岛素降解酶（IDE）显著改善了胰岛素清除率。我们还观察到，喂食HFS+CUR饮食的小鼠肝脏中磷酸肌醇3激酶（PI3K），特别是Ia类催化亚基p110α和p110β以及Ib类调节亚基p101和磷酸化蛋白激酶B（AKT）的表达水平恢复。此外，与喂食HFS的小鼠相比，喂食HFS+CUR的小鼠胰岛明显更小，胰高血糖素含量增加，表明胰腺中胰岛素分泌减少。在模拟HFS条件下培养的小鼠和人类胰岛中，促氧化剂和促凋亡蛋白硫氧还蛋白相互作用蛋白（TXNIP）的表达显著升高，而CUR处理可减轻这种升高。
肥胖受试者补充CUR可能减轻HFS饮食带来的负担。我们的数据表明，饮食中添加CUR可恢复肥胖小鼠的PI3K、AKT和IDE水平。此外，CUR治疗通过下调TXNIP转录水平来维持胰岛完整性。因此，饮食中的CUR可能有潜力作为一种新型治疗剂来解决肥胖与T2DM之间的潜在联系。
