The proposed project is designed to examine the role of anti-insulin hormone actions and interactions in the pathogenesis of stress-induced changes in glucose and protein regulation in normal man and diabetic ketoacidosis. Recent studies from our laboratory have demonstrated that physiologic increments in glucagon, epinephrine and cortisol interact synergistically in the normal dog so as to produce marked hyperglycemia. The synergistic nature of the hormone interactions suggests that stress hyperglycemia cannot be ascribed to a single hormone, but is a consequence of the combined elevations of several hormones. In this project we will extend these observations by examining whether hormonal synergism can account for: 1) stress-hyperglycemia in normal man; 2) excessive protein wasting and gluconeogenesis in severe illness; 3) counterregulation of insulin hypoglycemia and 4) decompensation of glucose and ketone regulation in diabetes mellitus. Intravenous infusion of anti-insulin hormones (glucagon, epinephrine, cortisol and growth hormone) will be administered in doses designed to stimulate changes observed in severe stress or diabetic ketoacidosis. A radioactive glucose tracer will be infused to quantitate hepatic glucose production and glucose production and glucose uptake by peripheral tissues (e.g. muscle). The metabolic response to individual hormones will be compared to those observed when these hormones are given in combination. The influence of diabetes and insulin treatment (short and long-term) on the action of anti-insulin hormones will be determined. In additional studies we will examine the factors influencing the hepatic response to glucagon and epinephrine, the effect of small changes in blood epinephrine concentration on glucose tolerance, the effect of cortisol on gluconeogenesis, the insulin antagonistic effects of epinephrine on peripheral tissues, and the effect of somatostatin on hepatic sensitivity to glucagon and on protein absorption. This project will thus provide data regarding the hormonal basis of stress- and diabetes-induced alterations in glucose, fat and protein metabolsim. Such data of particular importance in the treatment of diabetes and protein-wasting conditions.
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