title: Effects of hyperinsulinemia and hyperglycemia on insulin receptor function and glycogen synthase activation in skeletal muscle of normal man.
abstract: Insulin receptor function, glycogen synthase activity, and activation by phosphatases were studied in biopsies of human skeletal muscle under conditions of hyperglycemia and/or hyperinsulinemia for 150 minutes. Twenty-one healthy volunteers underwent either (A) a hyperinsulinemic, euglycemic clamp (serum insulin, 160.0 +/- 7.7 mU/L; plasma glucose, 4.9 +/- 0.1 mmol/L; n = 9), (B) a hyperglycemic clamp during normoinsulinemia (serum insulin, 18.1 +/- 3.3 mU/L; plasma glucose, 12.9 +/- 0.2 mmol/L; n = 6), or (C) a combined hyperinsulinemic, hyperglycemic clamp (serum insulin, 158.3 +/- 15.0 mU/L; plasma glucose, 11.4 +/- 0.8 mmol/L; n = 6). During all studies, the endogenous insulin secretion was inhibited with somatostatin. Insulin binding and kinase activity of insulin receptors solubilized from vastus lateralis muscle biopsies were unaffected by hyperglycemia and/or hyperinsulinemia. Hyperinsulinemia activated the muscle glycogen synthase with a decrease in the half-maximal activation constant (A0.5) for glucose-6-phosphate (G6P) from 0.53 +/- 0.04 to 0.21 +/- 0.02 mmol/L (study A, P less than .02) and from 0.53 +/- 0.06 to 0.19 +/- 0.05 mmol/L (study C, P less than .03). In addition, the rate of glycogen synthase activation by phosphatases increased from 0.078 +/- 0.017 to 0.134 +/- 0.029 U/min/mg protein (study A, P less than .03) and from 0.082 +/- 0.013 to 0.145 +/- 0.033 U/min/mg protein (study C, P = .05). Hyperglycemia during normoinsulinemia did not affect A0.5 or phosphatase activity. In conclusion, (1) hyperinsulinemia for 2 1/2 hours increases glycogen synthase activity and activation by phosphatases independently on the glycemia; and (2) insulin receptor binding and basal and insulin-stimulated receptor kinase activity are not modified during short-term hyperinsulinemia and/or hyperglycemia.
authors.affiliation: Medical Endocrinological Department, University Clinic of Internal Medicine, Aarhus Amtssygehus, Denmark.
authors.forename: J F
authors.initials: JF
authors.lastname: Bak
authors.forename: N
authors.initials: N
authors.lastname: Møller
authors.forename: O
authors.initials: O
authors.lastname: Schmitz
authors.forename: E A
authors.initials: EA
authors.lastname: Richter
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D019298:Glucose-6-Phosphate; D005958:Glucosephosphates / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000097:blood*; D009132:Muscles / Q000201:enzymology*; D009994:Osmolar Concentration; D011972:Receptor, Insulin / Q000378:metabolism*; D012016:Reference Values
chemical_list: D005958:Glucosephosphates; D007328:Insulin; D019298:Glucose-6-Phosphate; D006006:Glycogen Synthase; D011972:Receptor, Insulin; D005947:Glucose