Fasting hyperglycemia normalizes oxidative and nonoxidative pathways of insulin-stimulated glucose metabolism in noninsulin-dependent diabetes mellitus.

The present studies were undertaken to determine whether fasting hyperglycemia can compensate for decreased insulin-stimulated glucose disposal, oxidation, and storage in noninsulin-dependent diabetes mellitus (NIDDM) as well as to determine whether hyperglycemia normalizes insulin-stimulated skeletal muscle glycogen synthase and pyruvate dehydrogenase (PDH) activities. To accomplish this, we used the glucose clamp technique with isotopic determination of glucose disposal and indirect calorimetry for measuring the pathways of glucose metabolism, and vastus lateralis muscle biopsies to determine the effects of insulin on glycogen synthase and PDH activities. Nine patients with NIDDM and eight matched non-diabetic subjects were infused with insulin (40 mU/m2.min) while plasma glucose was maintained at the prevailing fasting concentration. During insulin infusion, rates of glucose disposal, storage, and oxidation were the same in the two groups. Insulin infusion significantly activated glycogen synthase fractional velocity to the same extent in NIDDM (0.210 +/- 0.056 vs. 0.332 +/- 0.079) and controls (0.192 +/- 0.036 vs. 0.294 +/- 0.050). Insulin infusion increased PDH fractional velocity in controls (from 0.281 +/- 0.022 to 0.404 +/- 0.038), but not in NIDDM (from 0.356 +/- 0.043 to 0.436 +/- 0.060), although the activity of PDH during insulin infusion did not differ between the groups. We conclude that prevailing fasting hyperglycemia normalizes the nonoxidative and oxidative pathways of insulin-stimulated glucose in metabolism in NIDDM and may act as a homeostatic mechanism to normalize muscle glucose metabolism.

[1]  L. Mandarino,et al.  Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase. Evidence for their role in oxidative and nonoxidative glucose metabolism. , 1987, The Journal of clinical investigation.

[2]  L. Disilvio,et al.  Impact of glucose ingestion on hepatic and peripheral glucose metabolism in man: an analysis based on simultaneous use of the forearm and double isotope techniques. , 1986, The Journal of clinical endocrinology and metabolism.

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

[4]  R. DeFronzo,et al.  Hepatic and extrahepatic splanchnic glucose metabolism in the postabsorptive and glucose fed dog. , 1985, Metabolism: clinical and experimental.

[5]  R. Rizza,et al.  Underestimation of Glucose Turnover Measured With [6-3H]- and [6,6-2 H2]- but not [6-14C]glucose During Hyperinsulinemia in Humans , 1989, Diabetes.

[6]  V. Herbert,et al.  Coated charcoal immunoassay of insulin. , 1965, The Journal of clinical endocrinology and metabolism.

[7]  M. Entman,et al.  Differential effects of oral, peripheral intravenous, and intraportal glucose on hepatic glucose uptake and insulin and glucagon extraction in conscious dogs. , 1983, The Journal of clinical investigation.

[8]  R. DeFronzo,et al.  Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[9]  L. Mandarino,et al.  Decreased Activation of Skeletal Muscle Glycogen Synthase by Mixed-Meal Ingestion in NIDDM , 1988, Diabetes.

[10]  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.

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

[12]  R G Shulman,et al.  Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. , 1990, The New England journal of medicine.

[13]  R. DeFronzo,et al.  Insulin sensitivity and insulin binding to monocytes in maturity-onset diabetes. , 1979, The Journal of clinical investigation.

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

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

[16]  W. C. Owen,et al.  Alanine and gluconeogenesis in man: effect of ethanol. , 1972, The Journal of clinical endocrinology and metabolism.

[17]  R. DeFronzo,et al.  Regulation of Splanchnic and Peripheral Glucose Uptake by Insulin and Hyperglycemia in Man , 1983, Diabetes.

[18]  A. Cherrington,et al.  Insulin as a mediator of hepatic glucose uptake in the conscious dog. , 1982, The American journal of physiology.

[19]  J. Olefsky,et al.  Influence of hyperglycemia on insulin's in vivo effects in type II diabetes. , 1984, The Journal of clinical investigation.

[20]  R. Bergman,et al.  Intraportal Glucose Infusion Matched to Oral Glucose Absorption: Lack of Evidence for “Gut Factor” Involvement in Hepatic Glucose Storage , 1982, Diabetes.

[21]  A. Consoli,et al.  Mechanism for Underestimation of Isotopically Determined Glucose Disposal , 1989, Diabetes.

[22]  A. Cherrington,et al.  Interaction Between Insulin and Glucose-Delivery Route in Regulation of Net Hepatic Glucose Uptake in Conscious Dogs , 1990, Diabetes.

[23]  R. DeFronzo,et al.  Role of Lipid Oxidation in Pathogenesis of Insulin Resistance of Obesity and Type II Diabetes , 1987, Diabetes.

[24]  L. Mandarino,et al.  Mechanism and Significance of Insulin Resistance in Non-insulin-dependent Diabetes Mellitus , 1981, Diabetes.

[25]  H. Yki-Järvinen,et al.  Kinetics of glucose disposal in whole body and across the forearm in man. , 1987, The Journal of clinical investigation.

[26]  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.

[27]  R. Henry,et al.  Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake. , 1990, The Journal of clinical investigation.

[28]  B. Trimarco,et al.  Differential effects of insulin on splanchnic and peripheral glucose disposal after an intravenous glucose load in man. , 1982, The Journal of clinical investigation.

[29]  A. Cherrington,et al.  Effect of a mixed meal on hepatic lactate and gluconeogenic precursor metabolism in dogs. , 1984, The American journal of physiology.

[30]  Hans Ulrich Bergmeyer,et al.  Methods of Enzymatic Analysis , 2019 .