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

胰岛素敏感性是否会影响二甲双胍延缓衰老的潜力？

• 批准号: 10579890
• 负责人: Benjamin Francis Miller
• 金额: $ 56.67万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579890
• 关键词: 5' -AMP-activated protein kinase; Acceleration; Aerobic Exercise; Affect; Age; Aging; Chronic; Chronic Disease; Clinical Trials; Clinical effectiveness; Complex; Complication; Continuous Glucose Monitor; Data; Disease; Dose; Double-Blind Method; Enrollment; Epidemiology; Exercise; FRAP1 gene; Fasting; Glucose Clamp; Goals; Health; Health Benefit; Hepatic; Human; Hyperinsulinism; Hypoglycemic Agents; Individual; Insulin; Insulin Resistance; Knowledge; Lead; Longevity; Measures; Metabolic; Metformin; Methods; Mission; Mitochondria; Mitochondrial Proteins; Muscle Mitochondria; National Institute on Aging; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Placebos; Population; Post-Translational Protein Processing; Prevention; Process; Protein Analysis; Proteomics; Public Health; Randomized; Research; Research Design; Respiration; Risk Factors; Secondary to; Skeletal Muscle; Specific qualifier value; Stable Isotope Labeling; Testing; Training; Training Programs; Translations; blood glucose regulation; blood-based biomarker; clinical translation; clinically relevant; cost; design; exercise training; experimental study; human subject; improved; inhibitor; insulin sensitivity; novel; patient population; pill; placebo group; prevent; protective effect; protein degradation; response; sedentary; translational potential

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.

总结 NIA发布PA-18-025，以探索“......二甲双胍延缓有害衰老的临床转化潜力 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 在进行更昂贵的大规模临床试验之前，潜在地调节二甲双胍的临床有效性。虽然 有流行病学支持二甲双胍在患者人群中的健康益处，尚不清楚这些益处是否 保护作用延伸到那些没有疾病的人。因此，需要进行人体研究 确定哪些无慢性疾病的受试者受益于二甲双胍治疗。回顾性分析 我们实验室的一项随机、双盲临床试验显示，胰岛素敏感的受试者没有 在运动训练计划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，在某些受试者中，二甲双胍具有可能加速衰老的有害代谢结果。 有数据支持和反驳二甲双胍抑制线粒体复合物I作用和/或 线粒体重塑本申请的总体目标是确定受试者目前是否无 二甲双胍治疗的益处。人类有两个关键的问题仍然没有答案 受试者：1）既往代谢健康是否会影响二甲双胍的反应，2）长期代谢健康是否会影响二甲双胍的反应。 二甲双胍治疗导致线粒体重塑和功能改变。更好地了解 临床相关剂量的二甲双胍预防慢性疾病的转化潜力， 该提案旨在确定先前的代谢健康如何影响二甲双胍治疗的反应， 确定骨骼肌线粒体重塑和线粒体功能之间的关系， 二甲双胍治疗。假设为：1）无T2 D受试者的二甲双胍治疗将改善胰岛素水平 胰岛素抵抗个体的敏感性和葡萄糖调节，但会降低胰岛素敏感性， 2）长期二甲双胍治疗将重塑胰岛素敏感受试者的线粒体， 降低胰岛素敏感受试者的线粒体功能，但改善线粒体功能的方法 在胰岛素抵抗的受试者中发挥作用。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、无疾病的受试者中进行，并按胰岛素敏感性分层 （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- 正葡萄糖钳夹法测量肝脏和外周胰岛素敏感性，连续葡萄糖监测， 确定葡萄糖调节，并提出基于血液的衰老生物标志物。此外，使用新型稳定的 同位素标记与蛋白质组学分析将确定个体和复合体特异性线粒体重塑。 该方法将与蛋白质修饰和周转分析相结合， 二甲双胍治疗对骨骼肌线粒体的影响。预计到该项目完成时， 将有证据有助于进一步描述谁可能受益于二甲双胍治疗以减缓衰老。