The research described in this proposal involves clinical investigation into abnormal physiologic regulation of endocrine pancreatic function and glucose homeostasis in Type I diabetic patients who have undergone allograft pancreas transplantation. Since the allograft pancreas has no neural connections after transplantation, this operative procedure provides a unique opportunity to investigate the importance of neuroregulation of the endocrine pancreas. Moreover, since this operative procedure results in an ectopically situated allograft pancreas whose venous outflow returns to the systemic rather than the portal circulation, it is important to fully understand the metabolic consequences of this abnormal circuitry. The experiments involve evaluation of insulin and C-peptide secretion in response to various agonists without and with glucose potentiation; adrenergic agonist and blockade studies; and studies of insulin resistance using both euglycemic hyperinsulinemia and hyperglycemia clamps. The experiments also involve assessments of glucagon responses to arginine and hypoglycemia as well as pancreatic polypeptide responses to secretin and hypoglycemia. Catecholamine secretion will also be assessed during the adrenergic blockage and hypoglycemia studies. We also propose to evaluate the long-term consequences of hemi-pancreatectomy in a group of non- diabetic subjects who donated half of their pancreases to Type I diabetic recipients. These studies are designed to assess whether already known metabolic abnormalities in donors are at their peak or whether continued deterioration in glucose homeostasis will be greater than age-matched controls. At the conclusion of this work, it is anticipated that we will be able to provide a unique assessment of the importance of neuroregualtion of the endocrine pancreas as well as a better understanding of the abnormal metabolic consequences of transplanting a denervated, ectopically located allograft pancreas in Type I diabetic patients.
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