The combined effects of metformin and exercise on AMPK activation, insulin action, and substrate metabolism in insulin resistant individuals

The results from the Diabetes Prevention Program highlight the effectiveness of metformin and regular physical activity in the prevention of Type 2 diabetes. The mechanism by which these treatments prevent diabetes is by improving insulin sensitivity. Metformin and exercise independently increase insulin sensitivity; however, the combined effects have not been studied. To assess the combined effects, we studied 2 groups of insulin resistant subjects matched for age (33±10 vs. 32±10 yrs), weight (87±16 vs. 91±23 kg), body fat (41±7 vs. 36.4±6%), fitness (27±6 vs. 29±6 ml/kg/min) and degree of insulin resistance (composite insulin sensitivity index 2.8±1 vs. 2.2±1). The 1st group (n=9:6W,3M) was studied before treatment (B), after 2-3 weeks of 2000 mg/day metformin (MET), and after metformin plus 40min of exercise at 65%VO2peak (MET+Ex). The 2nd group (n=7:5W,3M) was studied at baseline and after an acute bout of exercise at 65%VO2peak (Ex). Biopsies of the vastus lateralis were taken at B, after MET, immediately after MET+Ex (group 1) or immediately after Ex only (group 2), and used to measure AMPK alpha 2 activity and muscle glycogen. Insulin sensitivity was assessed 3 hrs post-exercise with a euglycemic hyperinsulinemic (40 mU/m2/min) clamp enriched with [6,62H]glucose. Data were compared using ANOVA with repeated measures. Exercise alone increased insulin sensitivity by 54% (p\u3c0.01); however, there was no increase in insulin sensitivity with MET+Ex. Muscle glycogen was reduced by ∼50% with both Ex and MET+Ex suggesting that differences in muscle glycogen concentrations are not responsible for the differences in post-exercise insulin sensitivity. Skeletal muscle AMPK 2 activity was increased by 3-fold (p\u3c0.01) with Ex alone but did not increase with MET+Ex. Circulating plasma free fatty acids increased with metformin + exercise compared to baseline and exercise alone. There was a positive significant correlation between free fatty acid concentrations and insulin sensitivity. In addition, metformin + exercise significantly increased basal hepatic glucose production and lactate concentrations more so than exercise alone. These surprising findings suggest that adding short-term metformin treatment to an acute bout of exercise does not enhance insulin sensitivity and may actually attenuate the well documented effects of exercise. These results highlight the importance of future studies designed to examine the effects of long-term metformin treatment combined with exercise training on whole-body insulin sensitivity.