Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus.

Seven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.

[1]  M. Somogyi.  A METHOD FOR THE PREPARATION OF BLOOD FILTRATES FOR THE DETERMINATION OF SUGAR , 1930 .

[2]  P. Scheinberg,et al.  THE CEREBRAL BLOOD FLOW IN MALE SUBJECTS AS MEASURED BY THE NITROUS OXIDE TECHNIQUE. NORMAL VALUES FOR BLOOD FLOW, OXYGEN UTILIZATION, GLUCOSE UTILIZATION, AND PERIPHERAL RESISTANCE, WITH OBSERVATIONS ON THE EFFECT OF TILTING AND ANXIETY. , 1949, The Journal of clinical investigation.

[3]  G. Rowe,et al.  A study in man of cerebral blood flow and cerebral glucose, lactate and pyruvate metabolism before and after eating. , 1959, The Journal of clinical investigation.

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

[5]  L. Stimmler.  Immunoassay of insulin with insulin antibody precipitate. , 1963, Lancet.

[6]  H. Hohorst.  l-(+)-Lactate: Determination with Lactic Dehydrogenase and DPN , 1965 .

[7]  B. Landau,et al.  Estimation of the pentose cycle contribution to glucose metabolism in tissue in vivo. , 1967, Biochemistry.

[8]  G. Reaven,et al.  Demonstration of insulin resistance in untreated adult onset diabetic subjects with fasting hyperglycemia. , 1975, The Journal of clinical investigation.

[9]  R. DeFronzo,et al.  Glucose clamp technique: a method for quantifying insulin secretion and resistance. , 1979, The American journal of physiology.

[10]  J. Olefsky,et al.  Mechanisms of insulin resistance in obesity and noninsulin-dependent (type II) diabetes. , 1981, The American journal of medicine.

[11]  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.

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

[13]  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.

[14]  J. Aikens,et al.  A microfluorometric method for the determination of free fatty acids in plasma. , 1983, Journal of lipid research.

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

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

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

[18]  B V Howard,et al.  Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. , 1984, The Journal of clinical investigation.

[19]  B. Obermaier,et al.  Insulin receptor kinase in human skeletal muscle , 1985, FEBS letters.

[20]  R. DeFronzo,et al.  Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. , 1985, The Journal of clinical investigation.

[21]  S. Lillioja,et al.  Glucose storage is a major determinant of in vivo "insulin resistance" in subjects with normal glucose tolerance. , 1986, The Journal of clinical endocrinology and metabolism.

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

[23]  R. Rizza,et al.  Postprandial hyperglycemia in patients with noninsulin-dependent diabetes mellitus. Role of hepatic and extrahepatic tissues. , 1986, The Journal of clinical investigation.

[24]  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.

[25]  R. DeFronzo.  Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. , 1988, Diabetes.

[26]  J. Olefsky,et al.  Role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus. , 1988, The Journal of clinical investigation.

[27]  G. Dohm,et al.  An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects. , 1988, The Journal of clinical investigation.

[28]  E. Jéquier,et al.  Regulation of glucose storage in obesity and diabetes: metabolic aspects. , 1988, Diabetes/metabolism reviews.

[29]  C. Bogardus,et al.  Muscle Glycogen Synthesis and Disposition of Infused Glucose in Humans With Reduced Rates of Insulin-Mediated Carbohydrate Storage , 1988, Diabetes.

[30]  R. DeFronzo,et al.  The disposal of an oral glucose load in patients with non-insulin-dependent diabetes. , 1988, Metabolism: clinical and experimental.

[31]  R. DeFronzo,et al.  Metabolic basis of obesity and noninsulin-dependent diabetes mellitus. , 1988, Diabetes/metabolism reviews.

[32]  L. Groop,et al.  Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. , 1989, The Journal of clinical investigation.

[33]  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.

[34]  A comparison of brain glucose metabolism in diabetes as measured by positron emission tomography or by arteriovenous techniques. , 1990, Annals of medicine.

[35]  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.

[36]  M. Laakso,et al.  Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. , 1990, The Journal of clinical investigation.

[37]  L. Mandarino,et al.  Effects of insulin on skeletal muscle glucose storage, oxidation, and glycolysis in humans. , 1990, The American journal of physiology.

[38]  R. DeFronzo,et al.  Indirect calorimetry: methodological and interpretative problems. , 1990, The American journal of physiology.

[39]  L. Rossetti,et al.  Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake. A dose-response euglycemic clamp study in normal and diabetic rats. , 1990, The Journal of clinical investigation.

[40]  M. Laakso,et al.  Kinetics of Insulin-Mediated and Non-Insulin-Mediated Glucose Uptake in Humans , 1990, Diabetes.

[41]  L. Mandarino,et al.  Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. , 1990, The Journal of clinical investigation.

[42]  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.

[43]  R. Rizza,et al.  Effect of Insulin on Oxidation of Intracellularly and Extracellularly Derived Glucose in Patients With NIDDM: Evidence for Primary Defect in Glucose Transport and/or Phosphorylation but Not Oxidation , 1990, Diabetes.

[44]  M. Laakso,et al.  Reduced capacity and affinity of skeletal muscle for insulin-mediated glucose uptake in noninsulin-dependent diabetic subjects. Effects of insulin therapy. , 1991, The Journal of clinical investigation.

[45]  L. Groop,et al.  Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. , 1991, The Journal of clinical investigation.