EFFECT OF METFORMIN ON INSULIN-STIMULATED GLUCOSE-TRANSPORT IN ISOLATED SKELETAL-MUSCLE OBTAINED FROM PATIENTS WITH NIDDM

Metformin has been demonstrated to lower blood glucose in vivo by a me chanism which increases peripheral glucose uptake. Furthermore, the th erapeutic concentration of metformin has been estimated to be in the o rder of 0.01 mmol/l. We investigated the effect of metformin on insuli n-stimulated 3-O-methylglucose transport in isolated skeletal muscle o btained from seven patients with non-insulin-dependent diabetes mellit us (NIDDM) and from eight healthy subjects. Whole body insulin-mediate d glucose utilization was decreased by 45 % (p < 0.05) in the diabetic subjects when studied at 8 mmol/l glucose, compared to the healthy su bjects studied at 5 mmol/l glucose. Metformin, at concentrations of 0. 1 and 0.01 mmol/l, had no effect on basal or insulin-stimulated (100 m u U/ml) glucose transport in muscle strips from either of the groups. However, the two control subjects and three patients with NIDDM which displayed a low rate of insulin-mediated glucose utilization (< 20 mu mol.kg(-1).min(-1)), as well as in vitro insulin resistance, demonstra ted increased insulin-stimulated glucose transport in the presence of metformin at 0.1 mmol/l (p < 0.05). In conclusion, the concentration o f metformin resulting in a potentiating effect on insulin-stimulated g lucose transport in insulin-resistant human skeletal muscle is 10-fold higher than the therapeutic concentrations administered to patients w ith NIDDM. Thus, it is conceivable that the hypoglycaemic effect of me tformin in vivo may be due to an accumulation of the drug in the extra cellular space of skeletal muscle, or to an effect of the drug distal to the glucose transport step.