title: Postreceptor effects of sulfonylurea on skeletal muscle glycogen synthase activity in type II diabetic patients.
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.kg-1.min-1 at in vivo plasma insulin levels of approximately 75 and approximately 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 (approximately 320 mU/L) before and after treatment. Insulin receptors purified with wheatgerm 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 less than .04.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: University Clinic of Endocrinology and Internal Medicine, Arhus Amtssygehus, Denmark.
authors.forename: J F
authors.initials: JF
authors.lastname: Bak
authors.forename: O
authors.initials: O
authors.lastname: Schmitz
authors.forename: N S
authors.initials: NS
authors.lastname: Sørensen
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D018528:ATP-Binding Cassette Transporters; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D005907:Gliclazide / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008875:Middle Aged; D009132:Muscles / Q000201:enzymology*; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000502:physiology; D011955:Receptors, Drug / Q000502:physiology*; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D006006:Glycogen Synthase; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D005907:Gliclazide; D005947:Glucose