Antecedent Metabolic Health and Metformin Aging Study

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 trial 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 Type 2 diabetes 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.

Inclusion criteria

• 40-75 years of age (inclusive)
• Free of chronic disease
• Comprehension of the protocol as indicated by an ability to respond to questions about the study after reading the consent form.
• Able to use and be contacted by telephone.
• Able to speak, read, and understand English, and complete a questionnaire in English
• Independently mobile

Exclusion criteria

• Pregnancy
• Heart disease (history, abnormal ECG, abnormal stress ECG)
• Cerebrovascular disease (history)
• Cancer (history)
• Chronic respiratory disease (history, forced expiratory volume at one second/forced vital capacity [FEV1/FVC] < 70, FEV1 < 80% predicted)
• Chronic liver disease (history, alanine transaminase [ALT] > 52 IU/L)
• Diabetes (history, HbA1C ≥ 6.5, fasting blood glucose≥126 mg/dl, oral glucose tolerance test [OGTT] ≥ 200 mg/dl at 2 hrs)
• Impaired kidney function (eGFR ,45 mL/min)
• B12 lab values outside of normal range (<193 or >982 pg/mL)
• Alzheimer's (history)
• Chronic kidney disease (history, abnormal blood kidney panel including serum creatinine > 1.4)
• Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy)
• Those on glucose lowering drugs
• Those planning to have imaging that requires intravenous contrast dye (within 6 weeks) or are on any of the following medications since they are contraindicated with the use of metformin: Dofetilide, Lamotrigine, Pegvisomant, Somatropin, Trimethoprim, Trospium, Gatifloxacin, Cephalexin, Cimetidine, Dalfampridine
• Tobacco use
• Allergies to lidocaine or metformin