| Iatrogenic hypoglycemia is the number one short-term complication for diabetic patients striving to maintain strict glycemic control. In these patients, hyperinsulinemia associated with physical activity is a major cause of hypoglycemia. The current cure for insulin-dependent diabetic patients is islet cell transplantation, although implanting an artificial insulin delivery system is another future possibility. However, the various sites and mechanisms of hyperinsulinemic modulations of glycemia and the body's ability to compensate for these are not completely understood. Therefore, the purpose of this dissertation was to determine actions of insulin on specific sites of the body, and in turn, how the body can compensate in the setting of increased glucose utilization (Rd). In vivo experiments were conducted in chronically instrumented, conscious, unstressed dogs. The contributions of portal versus peripheral venous hyperinsulinemia in mediating the suppression of endogenous glucose production (Ra) during exercise were investigated. It was shown that suppression of Ra during exercise by mild hyperinsulinemia is predominantly determined by portal venous insulin. Next, it was demonstrated that portal venous hyperinsulinemia does not stimulate gut glucose absorption, neither its transporter-mediated or passive components. Compensation for increased Rd (i.e. hypoglycemia) occurs via neural, hormonal, and autoregulatory responses. A novel method to increase Rd independent of insulin was developed (using a bilateral renal arterial phloridzin infusion) to investigate hepatic autoregulation of Ra during rest. It was shown that during rest, an autoregulatory suppression of Ra is more sensitive to an increment in glycemia, than stimulation of Ra is to a reduction in glycemia. Finally, we investigated whether increasing concentrations of the adenosine 5'-monophosphate analogue, 5-aminoimidazole-4-carboxamide-1-beta-D-ribosyl-5-monphospate (ZMP), in the liver (via an intraportal 5-aminoimidazole-4-carboxamide-ribofuranoside infusion) would create a metabolic response consistent with an increase in whole body metabolic need during the metabolic stress of insulin-induced hypoglycemia. It was shown that in the presence of basal glucagon and high physiological insulin, increasing hepatic ZMP levels stimulates Ra via an increase in glycogenolysis during euglycemia, and that this glycogenolytic effect is potentiated by hypoglycemia. The findings of the research in this dissertation have important implications for developing strategies for islet implantation and use of insulin delivery systems in people with diabetes. Second, impaired suppression of Ra in the setting of a small increase in glucose may be a cause of the hyperglycemia that occurs in insulin resistant states. Third, mechanisms to increase hepatic purine nucleotide concentrations could effectively be exploited to combat insulin-induced hypoglycemia, the single most frequently occurring complication in diabetes. |
