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 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)
Bak
J F
JF
University Clinic of Endocrinology and Internal Medicine, Arhus Amtssygehus, Denmark.
Schmitz
O
O
Sørensen
N S
NS
Pedersen
O
O
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
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