Metformin and Muscle in Insulin-resistant Older Veterans

The proposed study utilizes clinical and translational research approaches to study
sarcopenia. Sarcopenia is common in older adults and is associated with decreased strength,
increased disability, falls and fractures. There are currently few interventions to prevent
or treat sarcopenia and a poor understanding of the mechanisms for sarcopenia. Given the
growing number of Veterans over the age of 65, studies to prevent sarcopenia and resulting
disability are important for the health, independence and well-being of this population. The
investigators' preliminary studies have shown that older adults with diabetes have an
accelerated loss in muscle mass and gait speed, except when treated with metformin. Older
adults with prediabetes also have a greater decline in muscle mass and higher incidence of
disability. Therefore, this study further investigates these findings by addressing the
following aims: (1) to determine whether metformin can prevent the loss in muscle mass and
physical performance and (2) to examine changes in muscle histologic characteristics
associated with metformin treatment in older adults with prediabetes.

Inclusion Criteria:

- The investigators will enroll 120 sedentary, weight-stable, ambulatory Veterans aged
65 years and older with prediabetes identified with fasting glucose values 100 mg/dL
or greater but under 126 mg/dL with no use of diabetes medications.

- Participants must demonstrate that they are able to ambulate 400 meters without
assistance.

Exclusion Criteria:

- Chronic medical conditions affecting muscle mass or function like active non-skin
cancer and hypogonadism

- Medications affecting muscle mass or function like glucocorticoids and
androgen/antiandrogens

- Contraindications to metformin such as renal dysfunction defined as creatinine >= 1.5
mg/dL for men or >=1.4 mg/dL for women or eGFR<60 mL/min; liver dysfunction defined as
ALT>48 U/L, AST>41 U/L or AlkPhos>141U/L; B12 deficiency defined as B12 level <180
pg/dL; congestive heart failure; known hypersensitivity to metformin; excessive
alcohol intake (average of 2 or more alcoholic beverages/day over a month)

For the muscle biopsy substudy, additional exclusion criteria include:

- Conditions that include bleeding risk such as the use of warfarin,
clopidogrel/ticlopidine, aggrenox, dabigatran or anagrelide; laboratory results
showing platelets<150 billion/L or INR>1.2 or aPTT>36 seconds

- Allergy to lidocaine