Postreceptor effects of sulfonylurea on skeletal muscle glycogen synthase activity in type II diabetic patients

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Abstract
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 glycemic control and enhanced pancreatic .beta.-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 .cntdot. kg-1 .cntdot. min-1 at in vivo plasma insulin levels of .apprx.75 and .apprx.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 (.apprx.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 (A0.5) was identical before and after therapy (0.54 .+-. 0.05 vs. 0.54 .+-. 0.05 mM, respectively, NS). However, in biopsies obtained at hyperinsulinemia, A0.5 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.