Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase. Evidence for their role in oxidative and nonoxidative glucose metabolism.

To determine whether activation by insulin of glycogen synthase (GS), phosphofructokinase (PFK), or pyruvate dehydrogenase (PDH) in skeletal muscle regulates intracellular glucose metabolism, subjects were studied basally and during euglycemic insulin infusions of 12, 30, and 240 mU/m2 X min. Glucose disposal, oxidative and nonoxidative glucose metabolism were determined. GS, PFK, and PDH were assayed in skeletal muscle under each condition. Glucose disposal rates were 2.37 +/- 0.11, 3.15 +/- 0.19, 6.71 +/- 0.44, and 11.7 +/- 1.73 mg/kg X min; glucose oxidation rates were 1.96 +/- 0.18, 2.81 +/- 0.28, 4.43 +/- 0.32, and 5.22 +/- 0.52. Nonoxidative glucose metabolism was 0.39 +/- 0.13, 0.34 +/- 0.26, 2.28 +/- 0.40, and 6.52 +/- 1.21 mg/kg X min. Both the proportion of active GS and the proportion of active PDH were increased by hyperinsulinemia. PFK activity was unaffected. Activation of GS was correlated with nonoxidative glucose metabolism, while activation of PDH was correlated with glucose oxidation. Sensitivity to insulin of GS was similar to that of nonoxidative glucose metabolism, while the sensitivity to insulin of PDH was similar to that of glucose oxidation. Therefore, the activation of these enzymes in muscle may regulate nonoxidative and oxidative glucose metabolism.

[1]  P. Lönnroth,et al.  Insulin Binding and Responsiveness in Fat Cells from Patients with Reduced Glucose Tolerance and Type II Diabetes , 1983, Diabetes.

[2]  S. Lillioja,et al.  Correlation between muscle glycogen synthase activity and in vivo insulin action in man. , 1984, The Journal of clinical investigation.

[3]  E. Reimann,et al.  Modified assays to detect activation of glycogen synthase following exercise. , 1981, The American journal of physiology.

[4]  R. Steele,et al.  Measurement of size and turnover rate of body glucose pool by the isotope dilution method. , 1956, The American journal of physiology.

[5]  E. Hultman,et al.  Muscle glycogen and glycogen synthetase in normal subjects and in patients with diabetes mellitus. Effect of intravenous glucose and insulin administration. , 1972, Scandinavian journal of clinical and laboratory investigation.

[6]  L. Mandarino,et al.  Rates of noninsulin-mediated glucose uptake are elevated in type II diabetic subjects. , 1985, The Journal of clinical investigation.

[7]  J. A. Scarlett,et al.  Role of Glucose Transport in the Postreceptor Defect of Non-insulin-dependent Diabetes Mellitus , 1982, Diabetes.

[8]  J. Larner,et al.  Studies on UDPG-glycogen transglucosylase. I. Preparation and differentiation of two activities of UDPG-glycogen transglucosylase from rat skeletal muscle. , 1962, Biochemistry.

[9]  F. Nuttall,et al.  The glycogen synthase system in skeletal muscle of normal humans and patients with myotonic dystrophy: effect of glucose and insulin administration. , 1974, Metabolism: clinical and experimental.

[10]  P. J. Randle,et al.  Regulation of Glucose Uptake by Muscle , 1962 .

[11]  O. Pedersen,et al.  Insulin receptor binding and insulin action in human fat cells: effects of obesity and fasting. , 1982, Metabolism: clinical and experimental.

[12]  Classification and Diagnosis of Diabetes Mellitus and Other Categories of Glucose Intolerance , 1979, Diabetes.

[13]  O. Owen,et al.  Carbohydrate Oxidation and Storage in Obese Non-insulin-dependent Diabetic Patients: Effects of Improving Glycemic Control , 1983, Diabetes.

[14]  J. A. Scarlett,et al.  Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. , 1981, The Journal of clinical investigation.

[15]  L. Mandarino,et al.  Adipocyte glycogen synthase and pyruvate dehydrogenase in obese and type II diabetic subjects. , 1986, The American journal of physiology.

[16]  E. Newsholme,et al.  Regulation of glucose uptake by muscle. 8. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscles. , 1964, The Biochemical journal.

[17]  R. DeFronzo,et al.  The Effect of Graded Doses of Insulin on Total Glucose Uptake, Glucose Oxidation, and Glucose Storage in Man , 1982, Diabetes.

[18]  E. Horton,et al.  Effects of Prior High-Intensity Exercise on Glucose Metabolism in Normal and Insulin-resistant Men , 1985, Diabetes.

[19]  K. Frayn,et al.  Calculation of substrate oxidation rates in vivo from gaseous exchange. , 1983, Journal of applied physiology: respiratory, environmental and exercise physiology.

[20]  A. Kissebah,et al.  Relationship between skeletal muscle insulin resistance, insulin-mediated glucose disposal, and insulin binding. Effects of obesity and body fat topography. , 1984, The Journal of clinical investigation.

[21]  J. A. Thomas,et al.  A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. , 1968, Analytical biochemistry.

[22]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[23]  O. Wieland.  The mammalian pyruvate dehydrogenase complex: structure and regulation. , 1983, Reviews of physiology, biochemistry and pharmacology.

[24]  R. Eichner,et al.  Fasting and diabetes alter adipose tissue glycogen synthase. , 1984, The American journal of physiology.

[25]  J. Larner,et al.  STUDIES ON UDPG-ALPHA-GLUCAN TRANSGLUCOSYLASE. III. INTERCONVERSION OF TWO FORMS OF MUSCLE UDPG-ALPHA-GLUCAN TRANSGLUCOSYLASE BY A PHOSPHORYLATION-DEPHOSPHORYLATION REACTION SEQUENCE. , 1963, Biochemistry.

[26]  P. J. Randle,et al.  Regulation of glucose uptake by muscles. 10. Effects of alloxan-diabetes, starvation, hypophysectomy and adrenalectomy, and of fatty acids, ketone bodies and pyruvate, on the glycerol output and concentrations of free fatty acids, long-chain fatty acyl-coenzyme A, glycerol phosphate and citrate-cycl , 1964, The Biochemical journal.

[27]  E. Newsholme,et al.  The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. , 1963, Lancet.

[28]  Ernest Beutler,et al.  Red Cell Metabolism: A Manual of Biochemical Methods , 1975 .

[29]  O. Wieland,et al.  Control of pyruvate dehydrogenase interconversion in adipose tissue by insulin , 1971, FEBS letters.

[30]  S. Taylor,et al.  Glucose metabolism in perfused skeletal muscle. Pyruvate dehydrogenase activity in starvation, diabetes and exercise. , 1976, The Biochemical journal.

[31]  R. DeFronzo,et al.  The Effect of Insulin on the Disposal of Intravenous Glucose: Results from Indirect Calorimetry and Hepatic and Femoral Venous Catheterization , 1981, Diabetes.

[32]  E. Reimann,et al.  Glycogen synthase activation in human skeletal muscle: effects of diet and exercise. , 1979, The American journal of physiology.

[33]  J. Olefsky,et al.  Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. , 1980, The Journal of clinical investigation.

[34]  K. Itaya,et al.  COLORIMETRIC DETERMINATION OF FREE FATTY ACIDS IN BIOLOGICAL FLUIDS. , 1965, Journal of lipid research.

[35]  J. Blass,et al.  A defect in pyruvate decarboxylase in a child with an intermittent movement disorder. , 1970, The Journal of clinical investigation.

[36]  E. Newsholme,et al.  Regulation of glucose uptake by muscle. 9. Effects of fatty acids and ketone bodies, and of alloxan-diabetes and starvation, on pyruvate metabolism and on lactate-pyruvate and L-glycerol 3-phosphate-dihydroxyacetone phosphate concentration ratios in rat heart and rat diaphragm muscles. , 1964, The Biochemical journal.

[37]  C Verdonk,et al.  Insulin increases the maximum velocity for glucose uptake without altering the Michaelis constant in man. Evidence that insulin increases glucose uptake merely by providing additional transport sites. , 1982, The Journal of clinical investigation.

[38]  P. Arner,et al.  Postreceptor Defects Causing Insulin Resistance in Normoinsulinemic Non-insulin-dependent Diabetes Mellitus , 1982, Diabetes.