The long-term objectives of this proposal are to determine whether defective epinephrine responses, abnormal thresholds for adrenergic symptoms and decline in cognitive function during hypoglycemia in insulin- dependent diabetes mellitus (IDDM) patients can be normalized by successful pancreas transplantation. In addition, these studies will examine the specific role of both hyper- and hypoglycemia in the blunting of the epinephrine response to hypoglycemia, and ascertain the optimal anatomic site for islet transplantation as it relates to providing normal glucagon secretion during hypoglycemia. The specific aims and experimental methods to achieve these objectives are: l) To determine if impaired catecholamine responses to hypoglycemia in IDDM are normalized following pancreas transplantation; 2) To ascertain whether impaired symptomatic responses to hypoglycemia, thresholds for hypoglycemic awareness and cognitive function during hypoglycemia are improved in IDDM patients following pancreas transplantation; 3) To determine whether repeated bouts of hypoglycemia and sustained hyperglycemia independently contribute to defective epinephrine responses in IDDM and; 4) To determine if the impaired glucagon response to hypoglycemia following intrahepatic islet transplantation can be avoided by transplanting islets in other anatomic sites. Prospective studies of pancreas transplant recipients and appropriate controls (Specific Aims 1-3) will be performed utilizing the hyperinsulinemic, stepped hypoglycemic clamp technique. The stepped hypoglycemic clamp is a more precise, sensitive and reproducible measurement of responsivity to hypoglycemia than the more conventional insulin tolerance test. In addition this test allows for determination of glycemic thresholds for each parameter measured. To specifically address the independent adverse effects of hypo- and hyperglycemia (Specific Aim 3), the stepped hypoglycemic clamp technique will again be employed. Pancreas transplant recipients, who have both normoglycemia and sustained avoidance of hypoglycemia, and IDDM patients who achieve strict avoidance of hypoglycemia but do not establish euglycema, will be studied and responses compared. Animal studies (Specific Aim 4) designed to determine the impact of anatomic site of islet transplantation on glucagon responses to hypoglycemia will utilize hyperinsulinemic, hypoglycemic clamp in dogs autotransplanted with islets in the intrahepatic, intrasplenic and intraperitoneal sites.