Role of Lipid Oxidation in Pathogenesis of Insulin Resistance of Obesity and Type II Diabetes

Increased lipid oxidation is generally observed in subjects with obesity and diabetes and has been suggested to be responsible for the insulin resistance associated with these conditions. We measured, by continuous indirect calorimetry, lipid and glucose oxidation and nonoxidative glucose disposal in 82 obese subjects during a 100-g oral glucose tolerance test (OGTT) and in 26 during a euglycemic insulin (40 mU · min−1 · m−2) clamp. The obese subjects were subdivided into those with normal glucose tolerance (group A), those with impaired glucose tolerance (group B), and those with overt diabetes (group C). Forty-five healthy nonobese subjects were subdivided into a young and an older control group, which were age-matched to the nondiabetic obese (groups A and B) and diabetic obese (group C) subjects, respectively. In the postabsorptive state, as well as in response to insulin stimulation (both OGTT and insulin clamp), lipid oxidation was significantly increased in all three obese groups in comparison with either young or older controls. Basal glucose oxidation was significantly decreased in obese nondiabetic and obese glucose— intolerant subjects (groups A and B) compared with age-matched controls. During the OGTT and during the insulin clamp, insulin-stimulated glucose oxidation was decreased in all three obese groups. In contrast, nonoxidative glucose disposal was markedly inhibited in nondiabetic and diabetic obese patients during the euglycemic insulin clamp but not during the OGTT. After glucose ingestion, nonoxidative glucose uptake was normal in nondiabetic obese and glucoseintolerant obese subjects and decreased in diabetic obese subjects. Statistical analysis revealed that lipid and glucose oxidation were strongly and inversely related in the basal state, during euglycemic insulin clamp, and during OGTT. The negative correlation between lipid oxidation and nonoxidative glucose uptake, although significant, was much weaker. Fasting and post-OGTT hyperglycemia were the strongest (negative) correlates of nonoxidative glucose disposal in both single and multiple regresson models. We conclude that 7) reduced glucose oxidation and reduced nonoxidative glucose disposal partake of the insulin resistance of nondiabetic obese and diabetic obese individuals; 2) hyperglycemia provides a compensatory mechanism for the defect in nonoxidative glucose disposal in nondiabetic obese subjects; however, this compensation is characteristically lost when overt diabetes ensues; and 3) increased lipid oxidation may contribute, in part, to the defects in glucose oxidation and nonoxidative glucose uptake in obesity.

[1]  W. Shreeve,et al.  C14 studies in carbohydrate metabolism. I. The oxidation of glucose in normal human subjects. , 1954, The Journal of biological chemistry.

[2]  K. Zierler,et al.  The quantitatively minor role of carbohydrate in oxidative metabolism by skeletal muscle in intact man in the basal state; measurements of oxygen and glucose uptake and carbon dioxide and lactate production in the forearm. , 1956, The Journal of clinical investigation.

[3]  R. Steele,et al.  Measurement of size and turnover rate of body glucose pool by the isotope dilution method. , 1956, The American journal of physiology.

[4]  V. Dole,et al.  Microdetermination of long-chain fatty acids in plasma and tissues. , 1960, The Journal of biological chemistry.

[5]  S. Weinhouse,et al.  Blood glucose replacement rates in normal and diabetic humans. , 1961, Journal of applied physiology.

[6]  P. J. Randle,et al.  Regulation of Glucose Uptake by Muscle , 1962 .

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

[8]  E. Newsholme,et al.  Regulation of glucose uptake by muscle. 8. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscles. , 1964, The Biochemical journal.

[9]  A. Vannotti,et al.  EFFECTS OF FAT INFUSION ON GLUCOSE TOLERANCE AND INSULIN PLASMA LEVELS. , 1964, Medicina experimentalis : International journal of experimental medicine.

[10]  V. Herbert,et al.  Coated charcoal immunoassay of insulin. , 1965, The Journal of clinical endocrinology and metabolism.

[11]  R Hume,et al.  Prediction of lean body mass from height and weight , 1966, Journal of clinical pathology.

[12]  D. Kipnis,et al.  Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects. , 1967, The Journal of clinical investigation.

[13]  J. Flatt.  Role of the increased adipose tissue mass in the apparent insulin insensitivity of obesity. , 1972, The American journal of clinical nutrition.

[14]  S. Cushman,et al.  Cell-associated fatty acid levels and energy-requiring processes in mouse adipocytes. , 1974, The American journal of physiology.

[15]  G. Searle.  The use of isotope turnover techniques in the study of carbohydrate metabolism in man. , 1976, Clinics in endocrinology and metabolism.

[16]  K. Kim,et al.  Mechanism of palmityl coenzyme A inhibition of liver glycogen synthase. , 1977, The Journal of biological chemistry.

[17]  T. McDonald,et al.  Initial splanchnic extraction of ingested glucose in normal man. , 1978, Metabolism: clinical and experimental.

[18]  R. DeFronzo.  Glucose Intolerance and Aging: Evidence for Tissue Insensitivity to Insulin , 1979, Diabetes.

[19]  Classification and Diagnosis of Diabetes Mellitus and Other Categories of Glucose Intolerance , 1979, Diabetes.

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

[21]  E. Jéquier,et al.  Modifications of Glucose Storage and Oxidation in Nonobese Diabetics, Measured by Continuous Indirect Calorimetry , 1980, Diabetes.

[22]  R. DeFronzo,et al.  Synergistic interaction between exercise and insulin on peripheral glucose uptake. , 1981, The Journal of clinical investigation.

[23]  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.

[24]  R. DeFronzo,et al.  The effect of hyperglycemia, hyperinsulinemia, and route of glucose administration on glucose oxidation and glucose storage. , 1982, Metabolism: clinical and experimental.

[25]  R. DeFronzo.  Insulin secretion, insulin resistance, and obesity. , 1982, International journal of obesity.

[26]  R. DeFronzo,et al.  Effect of long chain triglyceride infusion on glucose metabolism in man. , 1982, Metabolism: clinical and experimental.

[27]  E. Jéquier,et al.  Relationship between glucose oxidation and glucose tolerance in man. , 1982, Metabolism: clinical and experimental.

[28]  R. DeFronzo,et al.  Splanchnic and Peripheral Disposal of Oral Glucose in Man , 1983, Diabetes.

[29]  R. DeFronzo,et al.  Effect of fatty acids on glucose production and utilization in man. , 1983, The Journal of clinical investigation.

[30]  R. Unger,et al.  Hyperinsulinemia in obesity: lack of relation to gastric emptying of glucose solution or to plasma somatostatin levels. , 1983, Metabolism: clinical and experimental.

[31]  O. Owen,et al.  Carbohydrate Oxidation and Storage in Obese Non-insulin-dependent Diabetic Patients: Effects of Improving Glycemic Control , 1983, Diabetes.

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

[33]  E. Jéquier,et al.  Decreased Thermogenic Response to an Oral Glucose Load in Older Subjects , 1983, Journal of the American Geriatrics Society.

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

[35]  A. Kissebah,et al.  Relationship between skeletal muscle insulin resistance, insulin-mediated glucose disposal, and insulin binding. Effects of obesity and body fat topography. , 1984, The Journal of clinical investigation.

[36]  E. Jéquier,et al.  Study on lipid metabolism in obesity diabetes. , 1984, Metabolism: clinical and experimental.

[37]  S. Lillioja,et al.  Relationship between insulin-mediated glucose disposal and lipid metabolism in man. , 1985, The Journal of clinical investigation.

[38]  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.