Combining short-term metformin treatment and one bout of exercise does not increase insulin action in insulin-resistant individuals

Abstract

Results from the Diabetes Prevention Program highlight the effectiveness of metformin or regular physical activity in the prevention of type 2 diabetes. Independently, metformin and exercise increase insulin sensitivity, but they have not been studied in combination. To assess the combined effects, insulin-resistant subjects (n = 9) matched for weight, body fat, and aerobic fitness were studied before any treatment (B), after 2-3 wk of 2,000 mg/day metformin (MET), and after metformin plus 40 min of exercise at 65% Vo(2peak) (MET + Ex). A second group (n = 7) was studied at baseline and after an identical bout of exercise with no metformin (Ex). Biopsies of the vastus lateralis were taken at B, after MET, immediately after MET + Ex (group 1), or immediately after Ex (group 2). Insulin sensitivity was assessed 4 h postexercise with a euglycemic hyperinsulinemic (40 mU.m(2).min(-1)) clamp enriched with [6,6-(2)H]glucose. Insulin sensitivity was 54% higher after Ex (P < 0.01), but there was no change with Met + Ex. Skeletal muscle AMPKalpha2 activity was elevated threefold (P < 0.01) after Ex, but there was no increase with MET + Ex. These findings suggest that the combination of short-term metformin treatment and an acute bout of exercise does not enhance insulin sensitivity, and the addition of metformin may attenuate the well-documented effects of exercise alone.

Fig. 1.

Effect of metformin + exercise on whole body insulin sensitivity. Insulin sensitivity was measured during the last 30 min of the euglycemic hyperinsulinemic clamp and is defined as the rate of disappearance of glucose per steady-state plasma insulin. Open bars, baseline; hatched bar, exercise only; black bar, metformin; gray bar, metformin + exercise. *Significantly different from placebo baseline (P < 0.05). R_d/I, rate of blood glucose uptake per unit plasma insulin concentration.

Fig. 2.

Effect of metformin + exercise on basal and insulin-stimulated free fatty acid (FFA) concentrations (A) and suppression of FFA during the last 30 min of a euglycemic hyperinsulinemic clamp (B). Open bars, baseline; hatched bar, exercise only; black bar, metformin; gray bar, metformin + exercise. *Significantly different from placebo baseline (P < 0.05).

Fig. 3.

Basal whole body substrate oxidation after exercise. Substrate oxidation was measured 30 min after exercise using indirect calorimetry. *Significantly different from metformin baseline (P < 0.05). CHO, carbohydrate.

Fig. 4.

Skeletal muscle AMP-activated protein kinase (AMPK)α2 activity (A) and muscle glycogen concentrations (B) measured in skeletal muscle biopsies taken immediately after exercise or rest. Open bars, baseline; hatched bar, exercise only; black bars, metformin; gray bar, metformin + exercise. *Significantly different from placebo baseline (P < 0.0001); $significantly different from metformin + exercise (P < 0.0001). AU, arbitrary units.

Fig. 5.

Basal rate of glucose appearance (R_a). R_a was measured in the 2-h period after exercise. Open bars, baseline; hatched bar, exercise only; black bar, metformin; gray bar, metformin + exercise. $Significantly different from metformin + exercise (P < 0.005); *significantly different from metformin baseline and metformin only (P < 0.05).