Combined effects of Metformin and Exercise on AMPK á2 Activity and Insulin

Activation of AMP-activated protein kinase stimulates skeletal muscle glucose transport via insulin-independent mechanisms. Both moderate-intensity exercise and anti-hyperglycemic drugs increase skeletal muscle AMPK á2 activity and glucose uptake in individuals with type 2 diabetes. To assess the combined effect of metformin and moderate-intensity exercise on AMPK á2 activity and whole-body and hepatic insulin action in insulin resistant subjects, muscle AMPKá2 activity and insulin sensitivity were 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 MET + 40min of exercise. 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. Related outcomes were glucose rate of disappearance/mean plasma insulin (Rd/I) measured after the first and second hour of the clamp, metabolic clearance rate (MCR), and % suppression of basal hepatic glucose production. With MET, there was no change in AMPK á2 activity or MCR. There was a 12% increase in Rd/I at 0-60 min. With MET+Ex, there was a 46% increase in AMPK á2 activity and 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.