LOW-DOSE ORAL GLYBURIDE REDUCES FASTING FLOOD GLUCOSE BY DECREASING HEPATIC GLUCOSE-PRODUCTION IN HEALTHY-VOLUNTEERS WITHOUT INCREASING CARBOHYDRATE OXIDATION

Glyburide is an effective hypoglycemic agent in patients with type II diabetes even after the loss of its ability to increase insulin secret ion. The exact mechanism is unknown. In an attempt to describe the dir ect effect of glyburide on glucose metabolism, a very low dose of glyb uride (20 mu g/kg body weight) was given orally to 12 healthy voluntee rs in an attempt to increase blood concentrations of the drug without causing a marked increase in insulin secretion. Fasting hepatic glucos e production (HGP), carbohydrate oxidation (GO), leucine appearance, l eucine oxidation, and fat oxidation were determined between hours 3 an d 4 and hours 7 and 8. The changes seen in the glyburide-treated volun teers were compared with the changes seen in 5 non-treated, healthy vo lunteers during the same 8-hour period. Mean blood glucose decreased g reater in the glyburide-treated volunteers (20 +/- 2% vs 5 +/- 2%, P < 0.01), Insulin and C-peptide concentrations after glyburide administr ation (hour 7 to 8) did not differ significantly from baseline (hour 3 to 4) values (insulin 53 +/- 9 pmol/L vs 52 +/- 9 pmol/L; C-peptide: 0.34 +/- 0.06 ng/mL vs 0.39 +/- 0.07 ng/mL). This low dose of glyburid e resulted in a significantly greater decrease in HGP (16 +/- 2%; P < 0.001) than seen with fasting alone (8 +/- 4%; P < 0.05). Carbohydrate oxidation significantly decreased in the glyburide treated group (11. 3 +/- 0.7 mu mol/kg/m to 9.1 +/- 0.3 mu mol/kg/m; P < 0.001) but was u nchanged in the healthy fasted volunteers (10.5 +/- 0.5 mu mol/kg/m to 10.5 +/- 1.7 mu mol/kg/m). Fat oxidation increased in the glyburide t reated group (0.19 +/- 0.03 mg/kg/m to 0.33 +/- 0.01 mg/kg/m, P < 0.00 1), but failed to significantly increase in the fasting group (0.23 +/ - 0.07 mg/kg/m vs 0.40 +/- 0.06 mg/kg/m), Changes in plasma leucine ap pearance and leucine oxidation were not different. Insulin stimulates CO in healthy volunteers, so that a failure to increase CO after a low dose of glyburide suggests that the majority of the fall in glucose c oncentrations was due to changes in HGP and not in oxidative glucose u tilization, In conclusion, low-dose glyburide enhances insulin effecti veness to reduce HGP without increasing CO.