Postreceptor Effects of Sulfonylurea on Skeletal Muscle Glycogen Synthase Activity in Type II Diabetic Patients

To elucidate the subcellular mechanism of action of sulfonylurea on glucose utilization of skeletal muscle, we studied nine newly diagnosed patients with type II (non-insulin-dependent) diabetes. Examinations were performed before and after 8 wk of gliclazide therapy. Gliclazide treatment was associated with improved glycemie control and enhanced pancreatic β-cell responses to meal stimulation. During euglycemic insulin clamps, insulin-inhibited endogenous glucose production was improved after gliclazide therapy. Moreover, mean (±SE) glucose disposal rate increased from 3.2 ± 0.7 to 4.8 ± 0.8 and from 7.9 ± 0.9 to 10.4 ± 0.9 mg · kg¹ · min⁻¹ at in vivo plasma insulin levels of ∼75 and ∼320 mU/L, respectively. In addition, insulin-receptor function and glycogen synthase activity were analyzed in skeletal muscle biopsies obtained in seven patients. The biopsies were obtained during basal insulinemia and hyperinsulinemia (∼320 mU/L) before and after treatment. Insulin receptors purified with wheat-germ agglutinin showed unchanged insulin-binding properties and unchanged receptor kinase function with respect to basal and insulin-stimulated phosphorylation of exogenous peptide poly(Glu⁸⁰Tyr²⁰). Gliclazide treatment had no effect on the maximal activities of glycogen synthase. Moreover, in biopsies obtained at basal insulinemia, the half-maximal activation constant for glucose 6-phosphate (A_0.5) was identical before and after therapy (0.54 ± 0.05 vs. 0.54 ± 0.05 mM, respectively, NS). However, in biopsies obtained at hyperinsulinemia, A_0.5 was 0.30 ± 0.05 vs. 0.20 ± 0.02 mM before and after gliclazide therapy, P < .04. In conclusion, this study indicates that gliclazide, in addition to its splanchnic effects, may enhance insulin-stimulated peripheral glucose metabolism through a potentiation of insulin action on skeletal muscle glycogen synthase by a mechanism distal to the insulin-receptor kinase.