The overall goal of the work described in this proposal is to increase our understanding of the metabolic consequences of successful pancreas and islet transplantation in Type I diabetic patients, and to ascertain the long term metabolic consequences of hemi-pancreatectomy in healthy human donors. Special emphasis will be given to our long term follow up of recipients of successful pancreas transplantation and of hemi- pancreatectomized donors and to gaining critically needed insights into the reasons why islet transplantation usually falls, despite the use of the identical immunosuppressive drug regimen used for successful pancreas transplantation.
The specific aims are: l) To provide serial, long term, cross-sectional and time-related prospective assessments of pancreatic islet alpha and beta cell function, regulation of glycemia, and counterregulation of hypoglycemia in Type I diabetic recipients of successful pancreas transplantation. We hypothesize that pancreas transplantation will provide long-term and stable normalization of glycemia. 2) To determine the long term metabolic consequences of hemipancreatectomy on insulin secretory reserve, insulin-mediated glucose disposal, and glucose-mediated glucose disposal in healthy human donors with normal glucose tolerance. We hypothesize that decreased insulin secretory reserve in donors is adjusted for by compensatory increases in insulin and/or glucose sensitivity in peripheral and/or hepatic tissues. 3) To determine whether failure of allografted pancreatic islet beta cell function occurs early post-transplantation during the engraftment period before classic immunologic rejection is likely, or later when immunorejection of a vascularized graft is the likely explanation for islet failure. We hypothesize that failure of initial engraftment is a major and previously under-recognized part of the explanation for islet failure. 4) To provide long term metabolic assessments of normoglycemic and insulin-independent recipients of islet autografts in chronic pancreatitis patients and islet allografts in Type I diabetic patients. We hypothesize that once islet transplantation has proven successful for over one year, long-term and stable normalization of glycemia will ensue. The research design and methods for achieving these goals will include a variety of metabolic measurements including glucose and hemoglobin A1C levels; measurements of insulin, C-peptide, and glucagon secretion; radioisotopic meal studies; hypoglycemic, hyperinsulinemic clamp studies; studies of glucose potentiation of arginine-induced insulin secretion; euglycemic, hyperinsulineniic clamp studies with and without concurrent somatostatin infusion; and muscle levels of GLUT-4 transporter. We anticipate these studies will provide an in-depth metabolic assessment of glucose metabolism and counterregulation of hypoglycemia in successful recipients of pancreas transplantation and hemi-pancreatectomized donors and will provide new insights into the mechanisms of islet allograft failure.
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