Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction.

BACKGROUND & AIMS We determined the effects of acute and chronic calorie restriction with either a low-fat, high-carbohydrate (HC) diet or a low-carbohydrate (LC) diet on hepatic and skeletal muscle insulin sensitivity. METHODS Twenty-two obese subjects (body mass index, 36.5 +/- 0.8 kg/m2) were randomized to an HC (>180 g/day) or LC (<50 g/day) energy-deficit diet. A euglycemic-hyperinsulinemic clamp, muscle biopsy specimens, and magnetic resonance spectroscopy were used to determine insulin action, cellular insulin signaling, and intrahepatic triglyceride (IHTG) content before, after 48 hours, and after approximately 11 weeks (7% weight loss) of diet therapy. RESULTS At 48 hours, IHTG content decreased more in the LC than the HC diet group (29.6% +/- 4.8% vs 8.9% +/- 1.4%; P < .05) but was similar in both groups after 7% weight loss (LC diet, 38.0% +/- 4.5%; HC diet, 44.5% +/- 13.5%). Basal glucose production rate decreased more in the LC than the HC diet group at 48 hours (23.4% +/- 2.2% vs 7.2% +/- 1.4%; P < .05) and after 7% weight loss (20.0% +/- 2.4% vs 7.9% +/- 1.2%; P < .05). Insulin-mediated glucose uptake did not change at 48 hours but increased similarly in both groups after 7% weight loss (48.4% +/- 14.3%; P < .05). In both groups, insulin-stimulated phosphorylation of c-Jun-N-terminal kinase decreased by 29% +/- 13% and phosphorylation of Akt and insulin receptor substrate 1 increased by 35% +/- 9% and 36% +/- 9%, respectively, after 7% weight loss (all P < .05). CONCLUSIONS Moderate calorie restriction causes temporal changes in liver and skeletal muscle metabolism; 48 hours of calorie restriction affects the liver (IHTG content, hepatic insulin sensitivity, and glucose production), whereas moderate weight loss affects muscle (insulin-mediated glucose uptake and insulin signaling).

[1]  L. N. Valenti,et al.  Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: A role for insulin resistance and diabetes , 2008, Hepatology.

[2]  B. S. Mohammed,et al.  Nonalcoholic fatty liver disease is associated with hepatic and skeletal muscle insulin resistance in overweight adolescents. , 2008, The American journal of clinical nutrition.

[3]  B. S. Mohammed,et al.  Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. , 2008, Gastroenterology.

[4]  M. Milburn,et al.  Analysis of the adult human plasma metabolome. , 2008, Pharmacogenomics.

[5]  F. Yao.  Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels : a role for insulin resistance and diabetes , 2008 .

[6]  D. Bohning,et al.  Effects of short-term very low-calorie diet on intramyocellular lipid and insulin sensitivity in nondiabetic and type 2 diabetic subjects. , 2008, Metabolism: clinical and experimental.

[7]  P. Zimmet,et al.  Diagnosis and classification of diabetes mellitus , 2002 .

[8]  B. Bergman,et al.  Effects of fasting on insulin action and glucose kinetics in lean and obese men and women. , 2007, American journal of physiology. Endocrinology and metabolism.

[9]  G. Bray,et al.  Epidemiology, trends, and morbidities of obesity and the metabolic syndrome , 2006, Endocrine.

[10]  J. Marescaux,et al.  The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes , 2006, Annals of surgery.

[11]  I. Macdonald,et al.  Effects of acute starvation on insulin resistance in obese patients with and without type 2 diabetes mellitus. , 2005, Clinical nutrition.

[12]  H. Pijl,et al.  Effect of a 2-day very low-energy diet on skeletal muscle insulin sensitivity in obese type 2 diabetic patients on insulin therapy. , 2005, Metabolism: clinical and experimental.

[13]  S. Sanderson,et al.  The natural history of nonalcoholic fatty liver disease: a population-based cohort study. , 2005, Gastroenterology.

[14]  H. Pijl,et al.  Two days of a very low calorie diet reduces endogenous glucose production in obese type 2 diabetic patients despite the withdrawal of blood glucose-lowering therapies including insulin. , 2005, Metabolism: clinical and experimental.

[15]  R. Stubbs,et al.  Loss of Insulin Resistance after Roux-en-Y Gastric Bypass Surgery: a Time Course Study , 2005, Obesity surgery.

[16]  K. Petersen,et al.  Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. , 2005, Diabetes.

[17]  S. Grundy,et al.  Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. , 2005, American journal of physiology. Endocrinology and metabolism.

[18]  Y. Miyazaki,et al.  Separate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis. , 2004, The Journal of clinical endocrinology and metabolism.

[19]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[20]  A. Häkkinen,et al.  Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. , 2003, Diabetes.

[21]  J. Nygren,et al.  Effects of 3 days of "postoperative" low caloric feeding with or without bed rest on insulin sensitivity in healthy subjects. , 2003, Clinical nutrition.

[22]  M. Mozzoli,et al.  FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. , 2002, American journal of physiology. Endocrinology and metabolism.

[23]  G. Shulman,et al.  Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and β‐cell dysfunction , 2002, European journal of clinical investigation.

[24]  Claude Pichard,et al.  Dual-energy X-ray absorptiometry and body composition: differences between devices and comparison with reference methods. , 2002, Nutrition.

[25]  M. Hellerstein,et al.  Effect of dietary energy restriction on glucose production and substrate utilization in type 2 diabetes. , 2000, Diabetes.

[26]  R. Bergman,et al.  Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin. , 2000, American journal of physiology. Endocrinology and metabolism.

[27]  Roger Davis,et al.  The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 * , 2000, The Journal of Biological Chemistry.

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

[29]  B. Patterson.  Use of stable isotopically labeled tracers for studies of metabolic kinetics: an overview. , 1997, Metabolism: clinical and experimental.

[30]  K. Petersen,et al.  Mechanism of free fatty acid-induced insulin resistance in humans. , 1996, The Journal of clinical investigation.

[31]  D. Kelly,et al.  Activation of a novel metabolic gene regulatory pathway by chronic stimulation of skeletal muscle. , 1996, The American journal of physiology.

[32]  W. Pories,et al.  Who Would Have Thought It? An Operation Proves to Be the Most Effective Therapy for Adult‐Onset Diabetes Mellitus , 1995, Annals of surgery.

[33]  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.

[34]  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.

[35]  Goldstein Dj.  Beneficial health effects of modest weight loss , 1992 .

[36]  B. Goldstein,et al.  Beneficial health effects of modest weight loss. , 1992, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[37]  R. Wolfe,et al.  Carbohydrate restriction regulates the adaptive response to fasting. , 1992, The American journal of physiology.

[38]  R. Henry,et al.  Benefits and Limitations of Very-Low-Calorie Diet Therapy in Obese NIDDM , 1991, Diabetes Care.

[39]  M. Jensen,et al.  Heated hand vein blood is satisfactory for measurements during free fatty acid kinetic studies. , 1991, Metabolism: clinical and experimental.

[40]  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.

[41]  R N Bergman,et al.  Estimation of Endogenous Glucose Production During Hyperinsulinemic-Euglycemic Glucose Clamps: Comparison of Unlabeled and Labeled Exogenous Glucose Infusates , 1987, Diabetes.

[42]  M. Jensen,et al.  Lipolysis during fasting. Decreased suppression by insulin and increased stimulation by epinephrine. , 1987, The Journal of clinical investigation.

[43]  M. Selzer.  The Michigan alcoholism screening test: the quest for a new diagnostic instrument. , 1971, The American journal of psychiatry.

[44]  G. H. Greenbaum.  An evaluation of niacinamide in the treatment of childhood schizophrenia. , 1970, The American journal of psychiatry.

[45]  R. Steele,et al.  INFLUENCES OF GLUCOSE LOADING AND OF INJECTED INSULIN ON HEPATIC GLUCOSE OUTPUT * , 1959, Annals of the New York Academy of Sciences.

[46]  Rosaura Sánchez,et al.  Who Would Have Thought It , 1872 .