Combined Effects of Metformin and Exercise on AMPK α2 Activity and Insulin Action in Insulin Resistant Individuals.

Sharoff, Carrie G.; Hagobian, Todd A.; Chipkin, Stuart R.; Yu, Haiyan; Hirshman, Michael F.; Goodyear, Laurie J.; Braun, Barry

Activation of AMP-activated protein kinase (AMPK) stimulates skeletal muscle glucose transport via insulin-independent mechanisms. Both moderate intensity exercise and the anti-hyperglycemic drug, metformin, increase skeletal muscle AMPK α2 activity and glucose uptake in individuals with type 2 diabetes. The combined impact of exercise and metformin has not been studied. To assess the combined effect of metformin and moderate-intensity exercise on AMPK α2 activity and insulin sensitivity in insulin resistant subjects, muscle AMPKα2 activity and whole-body and hepatic insulin action was measured in insulin-resistant men (n=4) and women (n=7) at 3 time points: pre-treatment baseline (B), after 2-3 weeks of metformin (2000 mg/day; MET), and after metformin plus one bout of exercise at 65%VO2peak (MET+Ex). To assess muscle AMPK activity, vastus lateralis biopsies were taken before treatment with metformin (B), after 2-3wks of metformin treatment (MET), and after 2-3wks metformin treatment + 40min of exercise (MET+Ex). Immediately after the muscle biopsy, [6,6-2H]-glucose was infused for 90min followed by a 2-hr euglycemic hyperinsulinemic (40 mU/m2/min) clamp enriched with 2% [6,62H]glucose. Outcomes related to insulin action were glucose rate of disappearance/mean plasma insulin (Rd/I) measured after the first and second hour of the clamp (0-60min and 60-120min respectively), metabolic clearance rate (MCR), and % suppression of basal hepatic glucose production. With MET, there was no change in AMPK α2 activity or MCR but there was a 12% increase in Rd/I at 0-60 min. With MET+Ex, there was a 46% increase in AMPK α2 activity and a 45% increased in Rd/I at 0-60min with no change in MCR. Rd/I was not different from B with MET or MET+Ex at 60-120min. % Hepatic suppression increased 75 and 99% with MET and MET+Ex respectively. Thus, it appears that both MET and MET+Ex increase hepatic insulin sensitivity while only MET+Ex increases AMPK α2 activity and whole-body insulin sensitivity. Ongoing studies are evaluating the independent effect of exercise on AMPK activity and insulin action. ADA-Funded Research

HYPOGLYCEMIC agents; EXERCISE physiology; PROTEIN kinases; ADENOSINE monophosphate; MECHANISM of action for insulin; INSULIN resistance; PEOPLE with diabetes

Diabetes, 2007, Vol 56, pA283

0012-1797

Academic Journal