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: 10382424
• 负责人: Benjamin Francis Miller
• 金额: $ 62.52万
• 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/10382424
• 关键词: 5' -AMP-activated protein kinase; Aerobic Exercise; Affect; Age; Aging; Chronic; Chronic Disease; Clinical; Clinical Trials; Clinical effectiveness; Complex; Complication; Data; Disease; Dose; Double-Blind Method; Enrollment; Epidemiology; Exercise; FRAP1 gene; Fasting; Glucose Clamp; Goals; Health; Health Benefit; Hepatic; Human; 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; clinically relevant; cost; design; exercise training; experimental study; glucose monitor; 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