The proposed studies intend to explore indepth provocative new findings in obesity, namely, that with adipocyte enlargement a major shift occurs in the fat cells toward nonoxidative glucose metabolism and enhanced production of lactate, a water-soluble substrate easily exported from the fat cells and potentially capable of influencing hepatic glucose production and peripheral utilization of glucose. The applicant proposes to investigate the magnitude, regulation, and significance of lactate overproduction by adipocytes from progressively obese animals and humans, and to explore the mechanisms by which lactate overproduction may contribute to the carbohydrate intolerance, hyperinsulinemia and insulin resistance associated with the development of obesity and obesity-related non-insulin-dependent (Type II) diabetes mellitus. The investigation will include following objectives: a) To evaluate the relative and absolute production of lactate from glucose by adipocytes from different adipose regions in the rabbit and in the human, in relation to the degree of adiposity, and cell size and number. Adipocyte cellular enzymatic mechanisms and the experimental conditions which regulate fluxes of glucose into its major metabolic products (CO2, glyceride-fatty acids, glyceride-glycerol and lactate) will be studied in the rat. b) To determine, by studies with perfused adipose tissue of rats and rabbits in vivo, the quantitative contribution of adipose tissue to lactate economy, in relation to the animals's degree of adiposity, and glucose and insulin concentrations in the perfusing medium. c) To determine, in vivo in rats and in human volunteers, the effects of gradual elevation of circulating lactate levels on hepatic glucose production, peripheral utilization of glucose, plasma insulin levels, and degree of insulin resistance, by euglycemic clamp techniques. Obesity is a major health hazard in the western world due to its association with hypertension, hyperlipidemia, and diabetes. The health relatedness of this proposal resides in the elucidation of novel pathophysiologic and metabolic events accompanying the development of obesity and possibly contributing to the carbohydrate intolerance and insulin resistance of Type II diabetes.
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