Metformin's Effect on Glucagon-induced Glucose Production and Protein Metabolism.

It is believed that Metformin antagonizes the action of glucagon through different pathways.
In mice, Metformin leads to inhibition of adenylate cyclase, reduction of levels of cyclic
AMP and protein kinase A (PKA) activity, therefore blocking glucagon-dependent glucose output
form hepatocytes. Glucagon plays an important role in the increased catabolic state seen in
insulin deficiency. Hyperglucagonaemia states have been shown to accelerate proteolysis and
leucine oxidation in insulin-deficient humans. Patients with insulin resistance and increased
levels of glucagon have an increased in energy expenditure which may contribute to the
catabolic state associated with this condition. We hypothesized that treatment with Metformin
for 2 weeks will significantly inhibit glucagon-induced endogenous glucose production in
insulin resistant individuals. We also hypothesized that glucagon-induced alterations in
whole body protein metabolism and the increases in O2 consumption associated with
hyperglucagonaemia states will be significantly inhibited by Metformin in these individuals.
This would open the door for the development of other antidiabetic drugs with antagonism of
glucagon as their principal mechanism of action.

Inclusion Criteria:

- 35-65 years of age

- Fasting blood glucose >100 mg/dl

- BMI 27-36 kg/m2

- Waist Circumference: Men ≥ 104 cm; women ≥ 88 cm

- If previously on anti-diabetic medication, should be off for at least 1 month

Exclusion Criteria:

- Active use of hypoglycemic agents (< 1 month)

- Renal failure, creatinine ≥ 1.5 mg/dL in men or ≥ 1.4 mg/dL in women

- Alanine aminotransferase levels exceed 135 IU/L or aspartate aminotransferase levels
exceed 129 IU/L (3 x the upper limit of normal)

- Congestive Heart Failure (EF < 40 %)

- Active coronary artery disease

- Recent (less than 6 weeks) or planned imaging study requiring IV contrast

- Participation in structured exercise (> 2 hr per week)

- Recent change in dietary habits or weight

- Tobacco use

- Use of systemic glucocorticoids

- Anti-coagulant therapy (warfarin/heparin)

- Pregnancy or breastfeeding

- Alcohol consumption greater than 2 drinks/day

- Uncontrolled Hypothyroidism, abnormal thyroid stimulating hormone levels

- Metformin Allergy