Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects.

BACKGROUND Insulin resistance in the offspring of parents with non-insulin-dependent diabetes mellitus (NIDDM) is the best predictor of development of the disease and probably plays an important part in its pathogenesis. We studied the mechanism and degree to which exercise training improves insulin sensitivity in these subjects. METHODS Ten adult children of parents with NIDDM and eight normal subjects were studied before starting an aerobic exercise-training program, after one session of exercise, and after six weeks of exercise. Insulin sensitivity was measured by the hyperglycemic-hyperinsulinemic clamp technique combined with indirect calorimetry, and the rate of glycogen synthesis in muscle and the intramuscular glucose-6-phosphate concentration were measured by carbon-13 and phosphorus-31 nuclear magnetic resonance spectroscopy, respectively. RESULTS During the base-line study, the mean (+/-SE) rate of muscle glycogen synthesis was 63 +/- 9 percent lower in the offspring of diabetic parents than in the normal subjects (P < 0.001). The mean value increased 69 +/- 10 percent (P = 0.04) and 62 +/- 11 percent (P = 0.04) after the first exercise session and 102 +/- 11 percent (P = 0.02) and 97 +/- 9 percent (P = 0.008) after six weeks of exercise training in the offspring and the normal subjects, respectively. The increment in glucose-6-phosphate during hyperglycemic-hyperinsulinemic clamping was lower in the offspring than in the normal subjects (0.039 +/- 0.013 vs. 0.089 +/- 0.009 mmol per liter, P = 0.005), reflecting reduced glucose transport-phosphorylation, but this increment was normal in the offspring after the first exercise session and after exercise training. Basal and stimulated insulin secretion was higher in the offspring than the normal subjects and was not altered by the exercise training program. CONCLUSIONS Exercise increases insulin sensitivity in both normal subjects and the insulin-resistant offspring of diabetic parents because of a twofold increase in insulin-stimulated glycogen synthesis in muscle, due to an increase in insulin-stimulated glucose transport-phosphorylation.

[1]  H. Galbo,et al.  Effects of acute exercise and detraining on insulin action in trained men. , 1989, Journal of applied physiology.

[2]  R. DeFronzo,et al.  Effect of Physical Training on Insulin Action in Obesity , 1987, Diabetes.

[3]  R. Paffenbarger,et al.  Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. , 1991, The New England journal of medicine.

[4]  L. Groop,et al.  Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. , 1989, The New England journal of medicine.

[5]  D. Wasserman,et al.  Rat skeletal muscle hexokinase II mRNA and activity are increased by a single bout of acute exercise. , 1994, The American journal of physiology.

[6]  E. Horton,et al.  Glucose Transporter Number, Function, and Subcellular Distribution in Rat Skeletal Muscle After Exercise Training , 1992, Diabetes.

[7]  P. Neufer,et al.  Elevated skeletal muscle glucose transporter levels in exercise-trained middle-aged men. , 1991, The American journal of physiology.

[8]  E. A. Sims,et al.  Effects of Physical Training and Diet Therapy on Carbohydrate Metabolism in Patients with Glucose Intolerance and Non-insulin-dependent Diabetes Mellitus , 1984, Diabetes.

[9]  B. Gu,et al.  Estimate of the escape time of resonant tunneling electrons from a quantum well in double‐barrier heterostructures , 1989 .

[10]  G. Lusk,et al.  ANIMAL CALORIMETRY Twenty-Fourth Paper. ANALYSIS OF THE OXIDATION OF MIXTURES OF CARBOHYDRATE AND FAT , 1924 .

[11]  R P Tonino,et al.  Effect of physical training on the insulin resistance of aging. , 1989, The American journal of physiology.

[12]  L. Groop,et al.  Metformin Normalizes Nonoxidative Glucose Metabolism in Insulin-Resistant Normoglycemic First-Degree Relatives of Patients With NIDDM , 1992, Diabetes.

[13]  A. Vaag,et al.  Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus. , 1992, The Journal of clinical investigation.

[14]  E. Horton,et al.  Enhanced Peripheral and Splanchnic Insulin Sensitivity in NIDDM Men After Single Bout of Exercise , 1987, Diabetes.

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

[16]  E. Horton,et al.  Skeletal muscle plasma membrane glucose transport and glucose transporters after exercise. , 1990, Journal of applied physiology.

[17]  J. Henriksson,et al.  Capillary supply of the quadriceps femoris muscle of man: adaptive response to exercise , 1977, The Journal of physiology.

[18]  L. Groop,et al.  Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. , 1994, The Journal of clinical investigation.

[19]  R. Shulman,et al.  31P nuclear magnetic resonance measurements of muscle glucose-6-phosphate. Evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin-dependent diabetes mellitus. , 1992, The Journal of clinical investigation.

[20]  L. Groop,et al.  Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity. , 1993, The Journal of clinical investigation.

[21]  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.

[22]  A. Klip,et al.  Exercise modulates the insulin‐induced translocation of glucose transporters in rat skeletal muscle , 1990, FEBS letters.

[23]  B. Ludvik,et al.  Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. , 1994, The New England journal of medicine.

[24]  R. Shulman,et al.  Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Albu,et al.  Effect of exercise training on insulin sensitivity and glucose metabolism in lean, obese, and diabetic men. , 1991, Journal of applied physiology.

[26]  L. Groop,et al.  Impaired Activation of Glycogen Synthase in People at Increased Risk for Developing NIDDM , 1992, Diabetes.

[27]  Y. Oshida,et al.  Long-term mild jogging increases insulin action despite no influence on body mass index or VO2 max. , 1989, Journal of applied physiology.

[28]  J E Frijters,et al.  A short questionnaire for the measurement of habitual physical activity in epidemiological studies. , 1982, The American journal of clinical nutrition.

[29]  H. Beck-Nielsen,et al.  Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. , 1989, Acta endocrinologica.

[30]  A. Krolewski,et al.  Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. , 1990, Annals of internal medicine.

[31]  K. Ramkumar,et al.  Breakdown in p‐n junction diodes made on polycrystalline silicon of large grain size , 1989 .

[32]  E. Ravussin,et al.  Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. , 1993, The New England journal of medicine.