The projects in this application deal with the mechanisms by which beta-cells are impaired or destroyed in diabetic syndromes. An underlying premise in several of the projects is that the early loss of glucose-stimulated-insulin secretion in both forms of diabetes points to an early lesion in a specific glucose-sensing 'apparatus'. For this reason a variety of parameters will be examined during the development of the nonautoimmune disease in the hope of bracketing the site of an intrinsic defect. Similarly in autoimmune diabetes the hypothesis that an exoplasmic component of the same beta-cell """"""""apparatus"""""""" is a target of immunologic attack will be tested. The role of the glucose transporter (GT) and glucokinase (GK) as components of the glucose-sensing """"""""apparatus"""""""" will be determined by analyzing expression patterns of the genes for these two proteins in glucose-responsive and nonresponsive beta-cell lines. At a more distal site in the putative glucose-sensing apparatus, the possibility that glucose, by elevating malonyl-CoA in beta-cells and diverting fatty acids from oxidation into the diacylglycerol pool, increases protein kinase C activity; if so, this may constitute possible locus of a defect in nonautoimmune diabetes. The role of amylin in the defective insulin response of nonautoimmune diabetes will also be scrutinized. Finally, the proximal events giving rise to autoimmune diabetes will be studied beginning with the concept that autoimmune diabetes is triggered by injury to beta-cells delivered by lymphokines released from macrophages during routine infections. Mechanisms of immune destruction of beta-cells will be addressed in studies of the antibodies and T cells that are directed at beta-cell antigens and the genetic predisposition to IDDM determined by HLA molecules will be analyzed.
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