Does insulin sensitivity impact the potential of metformin to slow aging?

摘要 NIA发布PA-18-025号以探索“…”二甲双胍延缓有害衰老的临床转译潜力 改变或延长健康的人类寿命。在PA-18-025中，迫切需要探索哪些因素 在更昂贵的大规模临床试验之前，有可能调整二甲双胍的临床疗效。虽然 二甲双胍对患者人群的健康益处有流行病学支持，目前尚不清楚这些 保护作用延伸到那些没有疾病的人。因此，有必要进行人体研究。 确定哪些没有慢性病的受试者受益于二甲双胍治疗。回溯性分析 我们实验室的一项随机、双盲临床试验显示，对胰岛素敏感的受试者没有 运动训练期间服用二甲双胍对胰岛素敏感性的影响或负面影响。这些 数据表明，在一些受试者中，二甲双胍具有有害的代谢结果，可能会加速衰老。 有数据支持和驳斥二甲双胍抑制线粒体复合体I的作用和/或 线粒体重塑。这个应用程序的总体目标是确定受试者目前是否 疾病受益于二甲双胍治疗。在人类身上有两个关键问题仍然没有得到回答 研究对象：1)先前的代谢健康是否影响对二甲双胍的反应，以及2)是否长期影响 二甲双胍治疗可导致线粒体重塑和功能改变。为了更好地理解 临床相关剂量的二甲双胍预防慢性疾病的翻译潜力 该提案旨在确定先天代谢健康如何影响对二甲双胍治疗的反应，以及 确定骨骼肌线粒体重塑与线粒体功能的关系 二甲双胍治疗。这些假设是：1)在不服用T2D的受试者中，二甲双胍治疗将改善胰岛素 胰岛素抵抗个体的敏感性和糖调节，但会降低胰岛素敏感性和 胰岛素敏感性受试者的糖调节，以及2)长期二甲双胍治疗将重塑 一种降低胰岛素敏感受试者线粒体功能但改善线粒体功能的方法 胰岛素抵抗受试者的功能。为了检验这些假设，一项为期12周的随机、双盲 临床试验将在40-75岁、无疾病、按胰岛素敏感性分层的受试者中进行。 (胰岛素敏感和胰岛素抵抗)。训练前和训练后的评估包括高胰岛素血症 正常血糖钳夹测量肝脏和外周胰岛素敏感性，持续血糖监测 确定糖调节，并提出基于血液的衰老生物标记物。此外，新型稳定器的使用 同位素标记结合蛋白质组学分析将确定个体和复杂的特定线粒体重塑。 该方法将与蛋白质修饰和周转分析相结合，进行综合分析 二甲双胍对骨骼肌线粒体的影响。到这个项目完成时，预计 将有证据帮助进一步描述谁可能受益于二甲双胍治疗以延缓衰老。

SUMMARY NIA issued PA-18-025 to explore “…clinical translational potential of metformin to delay deleterious aging changes or to extend healthy human life span.” Within PA-18-025 was the critical need to explore what factors potentially modulate the clinical effectiveness of metformin before more costly large-scale clinical trials. Although there is epidemiological support for health benefits of metformin in patient populations, it is not clear if these protective effects extend to those free of disease. Therefore, there is a need to perform human studies determining which subjects free of chronic disease benefit from metformin treatment. Retrospective analysis of a randomized, double-blinded clinical trial in our lab revealed that subjects who were insulin sensitive had no effect or negative effects on insulin sensitivity when taking metformin during an exercise training program. These data suggest that in some subjects, metformin has detrimental metabolic outcomes that could accelerate aging. There are data both in support of and refuting that metformin inhibits mitochondrial complex I action and/or mitochondrial remodeling. The overall objective of this application is to determine if subjects currently free of disease benefit from metformin treatment. There are two critical questions that remain unanswered in human subjects: 1) does antecedent metabolic health influence responses to metformin, and 2) does long-term treatment with metformin lead to mitochondrial remodeling and changes in function. To better understand the translational potential of a clinically relevant dose of metformin for the prevention of chronic conditions, this proposal aims to determine how antecedent metabolic health affects the response to metformin treatment, and identify the relationship between skeletal muscle mitochondrial remodeling and mitochondrial function with metformin treatment. The hypotheses are that: 1) metformin treatment in subjects free of T2D will improve insulin sensitivity and glucoregulation in insulin resistant individuals, but will decrease insulin sensitivity and glucoregulation in insulin sensitive subjects, and 2) long-term metformin treatment will remodel mitochondria in a way that decreases mitochondrial function in subjects that are insulin sensitive, but improves mitochondrial function in subjects that are insulin resistant. To test these hypotheses, a 12-week randomized, double-blind clinical trial will be performed in subjects 40-75 yrs of age, free of disease, and stratified by insulin sensitivity (insulin sensitive and insulin resistant). Pre and post-training assessments include the hyperinsulinemic- euglycemic clamp to measure hepatic and peripheral insulin sensitivity, continuous glucose monitoring to determine glucoregulation, and proposed blood-based biomarkers of aging. Further, the use of novel stable isotope labeling with proteomic analysis will determine individual and complex-specific mitochondrial remodeling. This approach will be combined with analysis of protein modification and turnover to comprehensively analyze mitochondrial effects of metformin treatment in skeletal muscle. By completion of this project, it is expected that there will be evidence that helps further delineate who may benefit from metformin treatment to slow aging.