The overall goal of this project is to define the molecular defects associated with the beta cell dysfunction in diabetes using techniques of molecular biology combined with whole organ and cellular physiology. Studies will be conducted with the isolated perfused pancreas to define the regulation of oscillatory insulin secretion using pharmacologic agents which affect specific sites in the insulin secretory pathway including the ATP-sensitive K+ channel and the L-type Ca2+ channel. The results will be compared with amino acid induced insulin secretion. Alterations in the secretory oscillations and their response to these secretagogues will be determined in pancreata from animals with diabetes due either to autoimmune beta cell destruction (DP BB/Wor rat) or reduced beta cell mass (the GK rat) and animals infused with large amounts of glucose to induce beta cell dysfunction. These experiments will enable us to test the hypothesis that states of beta cell dysfunction are associated with low amplitude, irregular secretory oscillations. In addition we propose to examine alterations in expression of the genes which encode for glucokinase, and two proteins which play a key role in the regulation of intracellular Ca2+ signalling, i.e., the voltage dependent Ca2+-channel and the IP3 receptor. The results will be compared with alterations in expression of the GLUT2 gene. These studies will allow us to test the hypothesis that diabetes causes abnormalities in either GLUT2, glucokinase or the ATP-sensitive K+ channel with relative sparing of the voltage dependent Ca2+ channel and IP3 receptor. Finally, experiments will be performed to determine if the pattern of oscillatory insulin secretion present in normal islets persists in islets isolated from diabetic rats, dispersed islets and in insulin secreting cell lines. A model beta cell line, the betaTC3 cell line has been demonstrated to increase its responsiveness to insulin after incubation in low glucose when compared to high glucose. The molecular mechanisms underlying this effect of high glucose will be studied following incubation of these cells in high and low glucose. The role of voltage dependent Ca2+ and K+ channels and the IP3 receptor in the regulation of insulin secretion in this cell line will be studied by transfecting normal and mutant forms of these genes and characterizing the effects on insulin secretory output. These studies will increase our understanding of normal beta cell physiology and pathophysiology in IDDM and will facilitate the development of novel pharmacologic and other therapeutic approaches to maximize our ability to preserve and maintain beta cell function in patients with early IDDM and in islet cell transplant recipients.

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