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.
The studies proposed in this competitive renewal focus on identifying mechanisms that are responsible for b- cell and a-cell fates after intrahepatic transplantation in humans. These putative mechanisms primarily involve inappropriate b-cell and a-cell secretory responses during hypoglycemia that occur because the cells are exposed to increased intrahepatic glycogenolysis and consequent increased interstitial glucose flux. Establishment of these mechanisms will provide convincing arguments that inclusion of non-hepatic sites will improve metabolic outcomes of autoislet, and by extension, alloislet, transplantation.
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