Aging is the number one risk factor for the majority of chronic diseases. There are no pharmaceutical treatments to slow aging and prolong healthspan. The anti-diabetic drug metformin is considered a likely pharmaceutical candidate to slow aging. In this study, the investigators hypothesize that 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. Further, the investigators hypothesize that 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. The investigators will use a dual-site, 12- week drug intervention trial performed in a double-blind, placebo-controlled manner on 148 subjects recruited from two separate sites (Oklahoma Medical Research Foundation (OMRF) and University of Wisconsin-Madison (UWM)). After consent and initial subject screening for chronic disease, subjects will be stratified to insulin sensitive (IS) or insulin resistant (IR) groups. Over a 12- week intervention, half of each group will take metformin and half will take a placebo. Pre- and post--intervention, subjects will complete a series of procedures to assess insulin sensitivity, glucose regulation, and biomarkers of aging. The same subjects will provide a skeletal muscle biopsy pre-- and post-intervention to assess the change in mitochondrial function and mitochondrial remodeling with and without metformin treatment. By completion of this project, the investigators expect to provide evidence that helps further delineate who may benefit from metformin treatment to slow aging.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
166
Metformin (Hunter Pharmacy) following a "ramp up" dosing protocol with a targeted dose of 1500 mg/day for 12 weeks.
Silicified microcrystalline cellulose, Micosolle®, K30 povidone, sodium starch glycolate, and magnesium stearate
University of Oklahoma Health Sciences Center, Oklahoma Shared Clinical and Translational Resources
Oklahoma City, Oklahoma, United States
University of Wisconsin-Madison
Madison, Wisconsin, United States
Mean Change in Insulin Sensitivity Index
Insulin Sensitivity Index = M / I x 1000. M = Glucose disposal rate (mg/min), normalized to fat-free mass (kg). I = insulin concentration (mU/L) during steady state of the clamp (based on glucose infusion rate). We rely on the delta (post-pre) of the insulin sensitivity index as our primary outcome. Positive delta values indicate improved insulin sensitivity (a positive outcome), while negative delta values indicate lower insulin sensitivity (a negative outcome). Insulin sensitivity cannot be physiologically zero or negative. Maximum negative change insulin sensitivity index = -52.31 mg/kg FFM/min/mU/L. Maximum positive insulin sensitivity index = 42.32 mg/kg FFM/min/mU/L.
Time frame: Change from baseline to 12 weeks
Mean Change in Mitochondrial Function of the Electron Transport System Measured by Complex I Activity
Mitochondrial respiration was measured using permeabilized muscle fibers from the vastus lateralis using high-resolution respirometry. We rely on the delta (change from post-pre) of the Complex I mitochondrial respiratory capacity. Positive values indicate an increase in mitochondrial respiratory capacity and improved outcomes, while negative values indicate a reduction in mitochondrial respiratory capacity and a negative outcome. There is no minimum or maximum reported for mitochondrial respiratory capacity of CI, but mitochondrial respiratory capacity of CI cannot physiologically be zero or negative. We and others have previously reported maximal complex I linked oxidative phosphorylation at approximately 250 pmol/mg of tissue/s in ultra-endurance athletes.
Time frame: Change from baseline to 12 weeks
Mean Change in Daily Average Glucose Measure
5-day continuous glucose monitoring
Time frame: Change from baseline to 12 weeks
Mean Change in Blood-based Biomarker Measures of Aging
This blood-based biomarker panel, developed by LeBrasseur and colleagues, measures changes in senescence-associated secretory phenotype proteins. This panel is associated with chronological age, biological age, and adverse clinical outcomes. Changes in the protein levels of biomarkers reflect changes in biological age. A greater abundance in these biomarkers is associated with greater frailty or biological aging. We rely on the delta (change from post-pre) of the biological markers. A positive value is associated with a negative outcome, while a negative value is associated with a positive outcome.
Time frame: Change from baseline to 12 weeks
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