The aim of this research proposal is to investigate the process whereby surgical alterations of the pancreas, including partial or total resection as well as removal and preservation of the pancreas (as for transplantation), result in abnormal regulation of glucose metabolism. These studies will test the hypotheses that alterations in glucose homeostasis are due, in part, to abnormalities in the neurohormonal control of pancreatic endocrine function, as well as specific deficiencies of islet hormones such as pancreatic polypeptides, or PP, which serve as specific deficiencies of islet hormones such as pancreatic polypeptide, or PP, which serve to mediate the effects of insulin on hepatic glucose metabolism. Animal studies of pancreatic disease (chronic pancreatitis) and pancreatic resection will examine whether the deficiency of PP associated with these states results in the persistence of inappropriately high levels of hepatic glucose production in spite of the presence of """"""""adequate"""""""" circulating levels of insulin and glucagon, and that this loss of regulation of endogenous glucose production contributes to overall glucose intolerance in these conditions. Further, it will be determined whether the abnormal glucose metabolism observed to result from the deficiency of pp is reversible by appropriate replacement administration of PP, in vitro and in vivo animal studies will be conducted to examine the chronic pancreatitis, pancreatic resection, and pancreatic autotranplantation will be examined to determine the extent to which these various alterations of the pancreas differ in terms of the control of islet hormone secretion, and the action of glucoregulatory hormones on their target tissues. The specific consequences of the interruption of cholinergic innervation of the pancreas will be studied to assess the secretory and metabolic consequences of neurotransmitter deficiencies in isolated (transplanted) pancreatic tissue. Finally, the secretory and negative feed-back responses of islet hormones will be examined through the use of the established isolated perfused human pancreas model to clarify the consequences of pancreatic denervation and/or (autotransplantation. Methodologic approaches will also utilize isolated rat liver preparations, and infusion techniques in dogs which employ the glucose clamp technique for the control of ambient glucose and hormone levels. Measurement of hepatic and peripheral glucose metabolism will be performed in vivo using tracer techniques which utilize 3-3H-glucose infusion. The observations drawn from previous studies of pancreatogenic diabetes, together with the planned studies on the mechanism of disordered hormone function, will be used to assess the pathophysiological consequences of surgical disorders and surgical manipulation of the pancreas.
