Alzheimer's disease (AD) and other forms of dementia are rapidly increasing with the aging of the population, and show a clear preponderance among people with insulin resistance. Metformin, an insulin sensitizer, is being examined in clinical trials as an anti-aging drug. However, very little objective data is available regarding metformin's effect on the brain, a major organ affected by aging.
Insulin resistance is highly prevalent with advancing age. Metformin is an insulin sensitizer and is currently being extensively investigated for its potential anti-aging effect. However, only very limited information is available on metformin effect on brain, which is a major organ affected by aging. With appropriate experimental design, the investigators are attempting to understand the mechanism of metformin treatment on the physiology of the brain as well as cognitive effects. These studies may uncover relationships that could be favorably manipulated to decrease health risks associated with insulin sensitivity and the effect on the brain. The study results may lead to a breakthrough in providing either definitive data or sufficiently strong preliminary data regarding metformin's effect on elderly people with insulin resistance, on whether the drug enhances brain mitochondrial function in conjunction with improvement of brain functional network and cognitive function. The overall hypothesis is that metformin administration to elderly people with insulin resistance enhances brain mitochondrial function in conjunction with improvement of brain function. To test this hypothesis, the investigators will address the following Specific Aims: 1. Determine whether 40 weeks of metformin administration in elderly people (\> 65 years) with insulin resistance enhances brain mitochondrial ATP production. The investigators will measure brain ATP production by 31P-MRS. 2. Determine the effect of 40 weeks of metformin administration in elderly people (\> 65 years) with insulin resistance on blood flow and functional network in different areas of brain. As a secondary outcome, the investigators will measure structural changes in white and grey matter areas of brain to determine whether metformin has any effect on brain structure. 3. Determine the effect of 40 weeks of metformin administration in elderly people (\> 65 years) with insulin resistance on cognitive function. The investigators will utilize the computerized NIH Toolbox to measure cognitive outcomes. The investigators will also associate outcomes from our specific aims with improvements in whole-body insulin sensitivity and skeletal muscle mitochondrial function. The investigators propose to complete 40 weeks of study in 40 elderly (\> 65 years) participants with fasting glucose between 100 to 140 mg/dl and abdominal girth of \>102 cm in men and \> 88 cm in women. All participants will be those who are not oral hypoglycemic agents including metformin. In this double-blind placebo trial, the investigators will randomly assign the participants to placebo or metformin in an escalated dose to reach a maximum of 2500 mg per day.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
40
Metformin treatment of 2500mg for 10 months in the Metformin group
Placebo treatment of identical tablets to metformin group
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Change From Baseline in Brain PCr/ATP Ratio as Measured by Phosphorus Magnetic Spectroscopy (31P-MRS) After 10 Months of Metformin Administration
Multivoxel spectroscopic imaging of the brain will be performed using our dual-tuned single-channel-proton eight-channel-phosphorus head coil. A single 2.5 cm thick slice will be prescribed to encompass the temporal and occipital lobes, and weighted MRSI will be performed using a 16x16 matrix to acquire nominal 2.5 cm3 voxels. Multivoxel phosphorus magnetic resonance spectroscopic imaging data were reconstructed and quantified using jMRUI 6.0. Spectra were preprocessed by (a) truncating the data to 768 points, then 0-filling to 1024 points; (b) apodizing with a 5 Hz Lorenzian; and (c) aligning the data such that the PCr peak was set to 0 Hz. Next, 2 voxels from occipital lobe were selected, extracted, and averaged together into a single free induction decay in order to reduce noise. The outcome measure PCr/ATP ratio is a marker of ATP resynthesis potential and is reported as a change from pre- to post-treatment.
Time frame: Baseline, 10 months
Change From Baseline in Cognitive Function as Measured by NIH Toolbox After 10 Months of Metformin Administration
The NIH Toolbox will be utilized to measure cognitive outcomes. The NIH Toolbox-Cognition Battery is composed of 7 tests (\~30 minutes) and our primary outcome measure will be the Total Cognition Composite score comprised from these 7 tests. Results are presented as a fully-adjusted T-score. For a single timepoint, T-scores are expected to have a population mean of 50, standard deviation of 10. For a single timepoint, higher T-scores indicate better cognitive test performance. An increase in T-score over time is considered a better outcome. At the individual level, a T-score \< 40 is considered low test performance. There were no clear clinically relevant thresholds for a change in T-score over 10 months at the start of this study. Comparison of the mean change in T-score over time in the Metformin treatment group to placebo is our analysis of interest
Time frame: Baseline, 10 months
Change From Baseline in Brain Structure as Measured by MRI After 10 Months of Metformin Administration
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AA sagittal 3D MPRAGE sequence with 0.7mm isotropic voxels (TR=2400, TE=2.57, TI=1100, FA=8) will be used to acquire high-resolution structural data for volumetric analysis of brain region changes related to metformin. To measure white matter information: An axial 2D symmetric multi-slice (SMS) diffusion tensor imaging (DTI) sequence with 60 diffusion directions, 5 B0 acquisitions and 2mm isotropic voxels (TR=3000, TE=73, FA=90, ETL 43, both A-P and P-A phase encoding for B0 images) will be used to acquire white matter integrity data related to metformin.
Time frame: Baseline, 10 months
Change From Baseline in Muscle Mitochondrial Respiration as Measured by High-resolution Respirometry Following 10 Months of Metformin Administration
High-resolution respirometry will be used to analyze oxygen consumption in isolated mitochondria from skeletal muscle biopsy samples while simultaneously quantifying reactive oxygen species (ROS) production using amplex red. An increase in mitochondrial respiration is indicative of increased mitochondrial function which is a positive outcome.
Time frame: Baseline, 10 months
Change From Baseline in Muscle Mitochondrial ATP Production as Measured by Fluorometry Following 10 Months of Metformin Administration
Concurrent to mitochondrial respiration, muscle mitochondrial ATP production will be measured using high-sensitivity fluorometry. An increase in mitochondrial ATP production shows increase mitochondrial efficiency which is a positive outcome.
Time frame: Baseline, 10 months