Pancreas and Islet Transplantation in Humans

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DESCRIPTION (provided by applicant): This project is based upon the premise that conventional use of the intrahepatic site for islet transplantation is a key factor in abnormal function of beta-cells and alpha-cells during hypoglycemia in transplant recipients. Our approach is to study intrahepatic islet function in patients with chronic pancreatitis who undergo total pancreatectomy and autoislet transplantation (TP/AIT) in both hepatic and nonhepatic sites. Use of autoislet recipients for metabolic studies carries the huge advantage of examining islet function in a setting without the confounding problems of immunosuppressive agents that are beta-cell toxic and the autoimmune state of type 1 diabetes. The specific aims of this project are: Specific Aim #1: To identify the mechanism(s) through which initially successful TP/AIT recipients develop decreased beta-cell function and hyperglycemia over time. We will study TP/AIT recipients who have successfully received autoislets in hepatic and non-hepatic sites through use of measures of islet secretion by stimulation of insulin, C-peptide, and glucagon responses to intravenous (IV) glucose and arginine; functional beta-cell mass by glucose potentiation of arginine-induced insulin secretion; and insulin sensitivity by euglycemic, hyperglycemic clamps. Specific Aim #2: To identify the mechanism(s) through which TP/AIT recipients have refractory alpha-cell function and deficient counter-regulation of hypoglycemia. We will study counter-regulatory hormonal responses in TP/AIT recipients using the radio-labeled (3H)-hypoglycemic clamps with glucagon flush to document glycogen depletion after 72 hr. fasts; meal-induced hypoglycemia with and without somatostatin infusion; and exercise- induced hypoglycemia with bicycle at 40% of peak Vo2. We envision the results will provide novel insights that will pertain not only to improving outcomes in TP/AIT recipients but also insights that will improve outcomes in alloislet transplantation for type 1 diabetic patients.