Effect of dietary energy restriction on glucose production and substrate utilization in type 2 diabetes.

A total of 8 obese subjects with type 2 diabetes were studied while on a eucaloric diet and after reduced energy intake (25 and then 75% of requirements for 10 days each). Weight loss was 2, 3, and 3 kg after 5, 10, and 20 days, respectively; all of the weight lost was body fat. Fasting blood glucose (FBG) levels fell from 11.9 +/- 1.4 at baseline to 8.9 +/- 1.6, 7.9 +/- 1.4, and 8.8 +/- 1.3 mmol/l at days 5, 10, and 20, respectively (P < 0.05, baseline vs. 5, 10, and 20 days). Endogenous glucose production (EGP) was 22 +/- 2, 18 +/- 2, 17 +/- 2, and 22 +/- 2 pmol x kg(-1) lean body mass (LBM) x min(-1) (P < 0.05, days 5 and 10 vs. baseline). Gluconeogenesis measured by mass isotopomer distribution analysis provided 31 +/- 4, 41 +/- 5, 40 +/- 4, and 33 +/- 4%, respectively, of the EGP (NS); absolute glycogenolytic contribution to the EGP was 15 +/- 2, 11 +/- 2, 11 +/- 2, and 15 +/- 2 pmol x kg(-1) LBM x min(-1), respectively (P < 0.001, baseline vs. days 5 and 10 and day 10 vs. day 20). The blood glucose clearance rate increased significantly at day 20 (P < 0.05). Neither lipolysis nor flux of plasma nonesterified fatty acids were altered compared with baseline. In conclusion, severe energy restriction per se independent of major changes in body composition reduces both FBG concentration and EGP in type 2 diabetes, the reduction in EGP results entirely from a reduction of glycogenolytic input into blood glucose, and the duration of reduced glycogenolysis is short-lived after relaxation of energy restriction even without weight gain, but effects on plasma glucose clearance persist and partially maintain the improvement in fasting glycemia.

[1]  N. Benowitz,et al.  Effects of cigarette smoking and its cessation on lipid metabolism and energy expenditure in heavy smokers. , 1994, The Journal of clinical investigation.

[2]  R. Wolfe,et al.  Concentration dependence of methyl palmitate isotope ratios by electron impact ionization gas chromatography/mass spectrometry. , 1993, Biological mass spectrometry.

[3]  H. Brunengraber,et al.  Limitations of the Mass Isotopomer Distribution Analysis of Glucose to Study Gluconeogenesis , 1995, The Journal of Biological Chemistry.

[4]  J. Olefsky,et al.  Effects of Weight Loss on Mechanisms of Hyperglycemia in Obese Non-Insulin-Dependent Diabetes Mellitus , 1986, Diabetes.

[5]  S. Turner,et al.  Hepatic gluconeogenic fluxes and glycogen turnover during fasting in humans. A stable isotope study. , 1997, The Journal of clinical investigation.

[6]  M. Laakso,et al.  Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycemia in obese non-insulin-dependent diabetic subjects. , 1988, Metabolism: clinical and experimental.

[7]  E. Jéquier,et al.  Effects of ingested fructose and infused glucagon on endogenous glucose production in obese NIDDM patients, obese non-diabetic subjects, and healthy subjects. , 1996 .

[8]  J. Olefsky,et al.  Glycemic effects of intensive caloric restriction and isocaloric refeeding in noninsulin-dependent diabetes mellitus. , 1985, The Journal of clinical endocrinology and metabolism.

[9]  E. Kraegen,et al.  The Determinants of Glycemic Responses to Diet Restriction and Weight Loss in Obesity and NIDDM , 1998, Diabetes Care.

[10]  M. Haymond,et al.  Gluconeogenesis in very low birth weight infants receiving total parenteral nutrition. , 1999, Diabetes.

[11]  Rena R Wing,et al.  Caloric Restriction Per Se Is a Significant Factor in Improvements in Glycemic Control and Insulin Sensitivity During Weight Loss in Obese NIDDM Patients , 1994, Diabetes Care.

[12]  E. Jéquier,et al.  Assessment of energy expenditure and fuel utilization in man. , 1987, Annual review of nutrition.

[13]  W. Sheu,et al.  Relationship Between Hepatic Glucose Production and Fasting Plasma Glucose Concentration in Patients With NIDDM , 1994, Diabetes.

[14]  T. Jenssen,et al.  Failure of substrate-induced gluconeogenesis to increase overall glucose appearance in normal humans. Demonstration of hepatic autoregulation without a change in plasma glucose concentration. , 1990, The Journal of clinical investigation.

[15]  J. Vazquez,et al.  Lipolysis and gluconeogenesis from glycerol during weight reduction with very-low-calorie diets. , 1994, Metabolism: clinical and experimental.

[16]  R. Shulman,et al.  Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. , 1992, The Journal of clinical investigation.

[17]  Molecular ion fragmentation and its effects on mass isotopomer abundances of fatty acid methyl esters ionized by electron impact , 1999, Journal of the American Society for Mass Spectrometry.

[18]  R. Wing,et al.  Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus. , 1993, The Journal of clinical endocrinology and metabolism.

[19]  E H STRISOWER,et al.  Conversion of fatty acids to carbohydrate; application of isotopes to this problem and role of the Krebs cycle as a synthetic pathway. , 1957, Physiological reviews.

[20]  F. Capani,et al.  Predominant Role of Gluconeogenesis in Increased Hepatic Glucose Production in NIDDM , 1989, Diabetes.

[21]  E. Barrett,et al.  Hepatic glucose metabolism and insulin resistance in NIDDM and obesity. , 1993, Bailliere's clinical endocrinology and metabolism.

[22]  M. Vranic,et al.  Mild type II diabetes markedly increases glucose cycling in the postabsorptive state and during glucose infusion irrespective of obesity. , 1988, The Journal of clinical investigation.

[23]  J. Wahren,et al.  A limitation in the use of mass isotopomer distributions to measure gluconeogenesis in fasting humans. , 1995, The American journal of physiology.

[24]  R. Wolfe,et al.  The relationship between gluconeogenic substrate supply and glucose production in humans. , 1990, The American journal of physiology.

[25]  M. Hellerstein.  Isotopic studies of carbohydrate metabolism in non-insulin-dependent diabetes mellitus , 1995 .

[26]  M. Hellerstein,et al.  Gluconeogenesis and Intrahepatic Triose Phosphate Flux in Response to Fasting or Substrate Loads. APPLICATION OF THE MASS ISOTOPOMER DISTRIBUTION ANALYSIS TECHNIQUE WITH TESTING OF ASSUMPTIONS AND POTENTIAL PROBLEMS (*) , 1995, The Journal of Biological Chemistry.

[27]  N. Barzilai,et al.  Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes. , 1993, The Journal of clinical investigation.

[28]  S. Turner,et al.  Measurement of hepatic Ra UDP-glucose in vivo in rats: relation to glycogen deposition and labeling patterns. , 1997, The American journal of physiology.

[29]  S. Turner,et al.  Short-term alterations in carbohydrate energy intake in humans. Striking effects on hepatic glucose production, de novo lipogenesis, lipolysis, and whole-body fuel selection. , 1995, The Journal of clinical investigation.

[30]  K. Marsh,et al.  Glucose homeostasis in children with falciparum malaria: precursor supply limits gluconeogenesis and glucose production. , 1997, The Journal of clinical endocrinology and metabolism.

[31]  M. Hellerstein,et al.  Rate of glucose entry into hepatic uridine diphosphoglucose by the direct pathway in fasted and fed states in normal humans. , 1995, Metabolism: clinical and experimental.

[32]  V. Large,et al.  Measuring gluconeogenesis with [2-13C]glycerol and mass isotopomer distribution analysis of glucose. , 1995, The American journal of physiology.

[33]  H. Yki-Järvinen,et al.  No Reduction in Total Hepatic Glucose Output by Inhibition of Gluconeogenesis With Ethanol in NIDDM Patients , 1991, Diabetes.

[34]  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.

[35]  E. Volpi,et al.  Evidence of Increased Systemic Glucose Production and Gluconeogenesis in an Early Stage of NIDDM , 1997, Diabetes.

[36]  T. Vary,et al.  Fraction of hepatic cytosolic acetyl-CoA derived from glucose in vivo: relation to PDH phosphorylation state. , 1991, The American journal of physiology.

[37]  S. Stanik,et al.  Insulin secretion improves following dietary control of plasma glucose in severely hyperglycemic obese patients. , 1980, Metabolism: clinical and experimental.