Metformin Effect on Brain Function in Insulin Resistant Elderly People

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: 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. 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. 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.

Participants in placebo group will receive Placebo Oral Tablets identical to the metformin tablets for 10 months.

Participants in placebo group will receive an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months.

Change from baseline in brain ATP production as measured by phosphorus Magnetic Spectroscopy (31P-MRS) after 10 months of metformin administration

Multivoxel chemical shift imaging (dual-tuned proton (Helmholtz pair)/phosphorus (loop) flex coil will be applied such that the phosphorus loop overlies the right DLPFC, WIP 1071, axial 1.5 cm slice prescribed to encompass the right dorsolateral prefrontal cortex, 12x12 matrix reconstructed to 16x16 matrix, 1.5 cm nominal isotropic voxels, TR=1500) will be used to acquire phosphorus metabolite information from the right DLPFC

Change from baseline in brain structure as measured by functional MRI (fMRI) after 10 months of metformin administration

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.

Change from baseline in cognitive function as measured by NIH Toolbox Cognitive Battery after 10 months of metformin administration

Oxygen flux in isolated muscle mitochondria will be measured using a titrated substrate protocol on an Oroboros oximetry instrument.

Change from baseline in brain blood flow as measured by functional MRI after 10 months of metformin administration

To measure global brain blood flow information: An axial 3D pseudo-continuous arterial spin labelling (pCASL) sequence (WIP 818) with 4mm isotropic voxels (TI1=1800, TI2=3600, iPat ≤ 2) will be used to acquire quantitative blood flow measurements (flow in ml/100g/min) throughout the brain.

Inclusion Criteria: Age >/= 65 years Abdominal girth > 102 cm in men and > 88 cm in women- Fasting glucose >/= 100-140 mg/dL Non-smoker English language proficiency Exclusion Criteria: Coronary artery disease or heart failure A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples: Inpatient psychiatric treatment in the past 6 months Presence of a known adrenal disorder Abnormal liver function test results (Transaminase >2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function Abnormal renal function tests results (calculated GFR <60 mL/min/1.73m2); testing required for subjects with diabetes duration of greater than 5 years post onset of puberty Active gastroparesis If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of stability on the medication for the past 2 months prior to enrollment in the study Uncontrolled thyroid disease (TSH undetectable or >10 mlU/L): testing required within here months prior to admission for subjects with a goiter, positive antibodies, or who are on thyroid hormone replacement, and within one year otherwise Abuse of alcohol or recreational drugs Infectious process not anticipated to resolve prior to study procedures (e.g. meningitis, pneumonia, osteomyelitis) Uncontrolled arterial hypertension (Resting diastolic blood pressure >90 mmHg and/or systolic blood pressure >160 mmHg) at the time of screening Oral steroids A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol Any metal in the body that could interfere with magnetic resonance imaging (MRI) including pacemaker or implanted defibrillator, neurostimulators, ear implants, metal fragments within the body, metal joints, rods, pins, plates or screws Medications that may impact study end points such as mitochondrial biology eg. beta blockers Anti-hyperglycemic drugs including metformin Any other medication that the investigator believes is a contraindication to the subject's participation