GLUCOSE HOMEOSTASIS IN THE SURGICALLY ALTERED PANCREAS

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Surgical alterations of the pancreas have been used as treatment for various disease processes. However, understanding of how anatomic alterations of the pancreas can change postoperative regulation of carbohydrate metabolism is unclear. Recently, pancreas transplantation has been employed for Type I diabetes, yet very little understanding of post- transplant insulin secretion exists. This application seeks continuation of our efforts using three surgical models which are relevant to understanding postoperative changes in glucose homeostasis and insulin secretion. Distinct changes in insulin secretion appear to result because of one of three anatomic alterations relevant to transplantation: 1. reduction of beta cell mass, 2. systemic release of insulin in pancreatic venous effluent, and 3. denervation (autotransplantation). Our canine surgical models have been evaluated using intravenous (IVGTT) and oral (OGTT) glucose challenge. Studies using euglycemic hyperinsulinemic and hyperglycemic clamps have been performed. Our preliminary findings have suggested that alteration in disposal of glucose exists over a varying range of endogenous insulin levels. Systemic drainage of the pancreas restores "normal" levels of insulin in the periphery, yet alterations in peripheral glucose levels persist. Clamp studies suggest that sensitivity to endogenous insulin is decreased. Studies to evaluate peripheral sensitivity to exogenously infused insulin and hepatic glucose output have not explained why these alterations exist. Additional studies have suggested that factors other than insulin levels (insulin-independent glucose disposal) and, possibly, the deficiency of an enteric hormone, GIP (glucose-dependent insulinotropic polypeptide), or pancreatic polypeptide (PP) may explain our findings. We propose to continue our efforts in three areas. First, we wish to continue evaluating insulin response to glucose challenge and examine more thoroughly enteric hormone deficiencies. Second, we propose to evaluate the pulsatile pattern of insulin release, and whether changes in normal secretory patterns by surgical interventions would explain altered peripheral glucose levels. Third, we propose studies to evaluate the immunosuppressive agent, cyclosporine, and its effect on the surgical alterations relevant to pancreas transplantation using our autotransplant model. These studies will allow basic observations about physiologic glucoregulation of insulin release. The studies on pulsatile release of insulin and cyclosporine effects offer unique opportunities to evaluate postsurgical (transplant) effects on glucose homeostasis.