Metabolic Changes Following a 1-Year Diet and Exercise Intervention in Patients With Type 2 Diabetes

OBJECTIVE To characterize the relationships among long-term improvements in peripheral insulin sensitivity (glucose disposal rate [GDR]), fasting glucose, and free fatty acids (FFAs) and concomitant changes in weight and adipose tissue mass and distribution induced by lifestyle intervention in obese individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS We measured GDR, fasting glucose, and FFAs during a euglycemic clamp and adipose tissue mass and distribution, organ fat, and adipocyte size by dual-energy X-ray absorptiometry, CT scan, and adipose tissue biopsy in 26 men and 32 women in the Look-AHEAD trial before and after 1 year of diet and exercise aimed at weight loss. RESULTS Weight and fasting glucose decreased significantly (P < 0.0001) and significantly more in men than in women (−12 vs. −8% and −16 vs. −7%, respectively; P < 0.05), while FFAs during hyperinsulinemia decreased and GDR increased significantly (P < 0.00001) and similarly in both sexes (−53 vs. −41% and 63 vs. 43%; P = NS). Men achieved a more favorable fat distribution by losing more from upper compared with lower and from deeper compared with superficial adipose tissue depots (P < 0.01). Decreases in weight and adipose tissue mass predicted improvements in GDR but not in fasting glucose or fasting FFAs; however, decreases in FFAs during hyperinsulinemia significantly determined GDR improvements. Hepatic fat was the only regional fat measure whose change contributed independently to changes in metabolic variables. CONCLUSIONS Patients with type 2 diabetes undergoing a 1-year lifestyle intervention had significant improvements in GDR, fasting glucose, FFAs and adipose tissue distribution. However, changes in overall weight (adipose tissue mass) and hepatic fat were the most important determinants of metabolic improvements.

[1]  A. Sherman,et al.  Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis , 2007, Diabetologia.

[2]  E. Ravussin,et al.  Metabolic Flexibility in Response to Glucose Is Not Impaired in People With Type 2 Diabetes After Controlling for Glucose Disposal Rate , 2008, Diabetes.

[3]  R. Wing,et al.  The effect of weight loss on change in waist-to-hip ratio in patients with type II diabetes. , 1992, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[4]  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.

[5]  Karen C Johnson,et al.  Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. , 2003, Controlled clinical trials.

[6]  A. Golay,et al.  Pathways from obesity to diabetes , 2002, International Journal of Obesity.

[7]  L. Kuller,et al.  Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. , 2003, American journal of physiology. Endocrinology and metabolism.

[8]  R. Lehmann,et al.  Loss of abdominal fat and improvement of the cardiovascular risk profile by regular moderate exercise training in patients with NIDDM , 1995, Diabetologia.

[9]  T. A. Hughes,et al.  Effects of caloric restriction and weight loss on glycemic control, insulin release and resistance, and atherosclerotic risk in obese patients with type II diabetes mellitus. , 1984, The American journal of medicine.

[10]  G. Boden.  Role of Fatty Acids in the Pathogenesis of Insulin Resistance and NIDDM , 1997, Diabetes.

[11]  B. Goodpaster,et al.  Subcutaneous Abdominal Fat and Thigh Muscle Composition Predict Insulin Sensitivity Independently of Visceral Fat , 1997, Diabetes.

[12]  A. Häkkinen,et al.  Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. , 2000, Diabetes.

[13]  E. Ravussin,et al.  Decreased Expression of Adipogenic Genes in Obese Subjects with Type 2 Diabetes , 2006, Obesity.

[14]  B. S. Mohammed,et al.  Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity , 2009, Proceedings of the National Academy of Sciences.

[15]  L. Kuller,et al.  Effects of moderate weight loss and orlistat on insulin resistance, regional adiposity, and fatty acids in type 2 diabetes. , 2004, Diabetes care.

[16]  E. Ravussin,et al.  Differential Effect of Weight Loss on Adipocyte Size Subfractions in Patients With t ype 2 , 2009 .

[17]  F. Toledo,et al.  Effects of Physical Activity and Weight Loss on Skeletal Muscle Mitochondria and Relationship With Glucose Control in Type 2 Diabetes , 2007, Diabetes.

[18]  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.

[19]  T. Wadden,et al.  The Look AHEAD Study: A Description of the Lifestyle Intervention and the Evidence Supporting It , 2006, Obesity.

[20]  Y. Tamura,et al.  Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. , 2005, The Journal of clinical endocrinology and metabolism.

[21]  Alessandra Bertoldo,et al.  Weight loss-induced plasticity of glucose transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes. , 2003, Diabetes.

[22]  Mark A Pereira,et al.  Effect of a Lifestyle Intervention on Change in Cardiorespiratory Fitness in Adults with Type 2 Diabetes: Results from the Look AHEAD Study , 2008, International Journal of Obesity.

[23]  R. Henry,et al.  Secretion and hepatic extraction of insulin after weight loss in obese noninsulin-dependent diabetes mellitus. , 1988, The Journal of clinical endocrinology and metabolism.

[24]  C. Bogardus,et al.  Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts Type II diabetes independent of insulin resistance , 2000, Diabetologia.

[25]  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.

[26]  F. Renström,et al.  Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’ , 2007, Diabetologia.

[27]  B. Goodpaster,et al.  Enhanced fat oxidation through physical activity is associated with improvements in insulin sensitivity in obesity. , 2003, Diabetes.

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

[29]  B. Goodpaster,et al.  Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. , 2000, The American journal of clinical nutrition.

[30]  J. Price,et al.  Plasma fatty acids, adiposity, and variance of skeletal muscle insulin resistance in type 2 diabetes mellitus. , 2001, The Journal of clinical endocrinology and metabolism.

[31]  E. Ravussin,et al.  Adipose tissue distribution in relation to insulin resistance in type 2 diabetes mellitus. , 2007, American journal of physiology. Endocrinology and metabolism.

[32]  F Vinicor,et al.  The continuing epidemics of obesity and diabetes in the United States. , 2001, JAMA.

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

[34]  D. Kelley,et al.  Metabolic consequences of weight loss on glucose metabolism and insulin action in type 2 diabetes , 2000, Diabetes, obesity & metabolism.

[35]  B. Goodpaster,et al.  Subdivisions of subcutaneous abdominal adipose tissue and insulin resistance. , 2000, American journal of physiology. Endocrinology and metabolism.

[36]  E. Ravussin,et al.  Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. , 2006, Diabetes care.

[37]  R. Schwartz,et al.  Diet-induced weight loss is associated with an improvement in beta-cell function in older men. , 2004, The Journal of clinical endocrinology and metabolism.

[38]  R R Wing,et al.  Long-term effects of modest weight loss in type II diabetic patients. , 1987, Archives of internal medicine.

[39]  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.

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

[41]  T. Wadden,et al.  One‐year Weight Losses in the Look AHEAD Study: Factors Associated With Success , 2009, Obesity.

[42]  A. Bigard,et al.  Mobilization of Visceral Adipose Tissue Related to the Improvement in Insulin Sensitivity in Response to Physical Training in NIDDM: Effects of branched-chain amino acid supplements , 1997, Diabetes Care.

[43]  E. Ravussin,et al.  Differential Effect of Weight Loss on Adipocyte Size Subfractions in Patients With Type 2 Diabetes , 2009, Obesity.