EFFECTS OF METFORMIN ON THE PATHWAYS OF GLUCOSE-UTILIZATION AFTER ORAL GLUCOSE IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS PATIENTS

To analyze the effects of metformin (M) on the kinetics and pathways o f glucose utilization after glucose ingestion, nine non-insulin-depend ent diabetes mellitus (NIDDM) patients underwent two ii-hour oral gluc ose tolerance tests (OGTTs) preceded in random order by a 3-week treat ment with either M (850 mg twice per day) or placebo. Each test includ ed intravenous infusion of 3-H-3-glucose and labeling of the oral dose (75 g) with 1-C-14-glucose, with measurements of glucose kinetics, gl ycolytic flux ((H2O)-H-3 production), and glucose oxidation (indirect calorimetry and expired (CO2)-C-14). Basal glycemia was decreased by M (6.6 v 8.2 mmol/L, P < .01) with no changes in insulin levels, with t he hypoglycemic effect correlating strongly (P < .001) with a decrease in glucose production. Mean 0- to 5-hour postprandial glycemia was al so decreased by the drug (9.9 v 12.2 mmol/L, P < .04), lactate concent ration was increased (1.79 v 1.44 mmol/L, P < .01), and absolute insul in levels were increased, but not to a significant extent. The rates o f appearance (Ra) of exogenous and endogenous glucose were not modifie d, and the hypoglycemic effect of M in the postprandial state was enti rely related to an increase in systemic glucose disposal (85.1 v 77.5 g/5 h, P < .001). Carbohydrate oxidation was unchanged, and glycolytic flux and nonoxidative glycolysis were increased by approximately 13 g /5 h (P < .01), with the excess lactate produced probably being conver ted to glycogen in the liver. Whole-body glycogen synthesis through th e direct pathway tended to be reduced (-8 g/5 h, P > .05). Thus, M dec reases postprandial glycemia by increasing glucose disposal and stimul ates lactate production. The data also suggest that the drug increases the proportions of glycogen deposited through the indirect rather tha n the direct pathway. Copyright (C) 1997 by W.B. Saunders Company.