GLUCOSE HOMEOSTASIS AND THE SURGICALLY ALTERED PANCREAS

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Glucoregulation of insulin release is poorly understood both in normal intact organisms as well as those altered by disease processes. Chronic studies of models of the surgically altered pancreas allow understanding of certain disease processes (reduced beta cell mass - diabetes) as well as applicability of surgery in treatment (pancreas transplantation). Our preliminary findings have documented the important consequences of portal to systemic release of insulin as well as "insulin-independent" effects on peripheral glucose disposal. These observations have relevance in evaluating three surgical alterations of the pancreas which have pathophysiologic consequence - reduced beta cell mass (80% pancreatectomy), systemic release of insulin (spleno-caval diversion) and denervation (autotransplantation). This proposal intends to expand our preliminary findings by continued observations of intravenous and oral glucose challenge on chronic models of the surgically altered pancreas. Additionally, we propose further studies that allow more sophisticated analysis of hepatic glucose output after "de-insulination" of the portal vein. The response of decreased beta cell mass to sulfonylurea treatment will be studied. Studies employing "steady state" hyperglycemic glucose infusions will be done to study the modulating effects of peptides which suppress (somatostatin) or stimulate (GIP) insulin secretion. Finally, continued studies on "insulin-independent" glucose disposal will allow further understanding of what appears to be a large fraction of glucose handling in the periphery which occurs in the absence of the hormone. We will determine whether this explains the effects of surgery on already documented changes in glucose disposal post- operatively. This studies will allow basic observations about physiologic glucoregulation of insulin release as well as the consequences of surgical alterations of the pancreas which might be employed for treatment of disease processes.