Metformin Effect on Brain Function in Insulin Resistant Elderly People

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.

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