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 (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.
Postreceptor Effects of Sulfonylurea on Skeletal Muscle Glycogen Synthase Activity in Type II Diabetic Patients
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Jens Friis, Ole Schmitz, Niels Schwartz Sørensen, Oluf Pedersen; Postreceptor Effects of Sulfonylurea on Skeletal Muscle Glycogen Synthase Activity in Type II Diabetic Patients. Diabetes 1 November 1989; 38 (11): 1343–1350. https://doi.org/10.2337/diab.38.11.1343
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