This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The common varieties of type 2 diabetes are characterized by both insulin resistance and disordered -cell function, most notably a defect in glucose-stimulated insulin-secretion. Multiple lines of recent evidence in rodents and cultured cells indicate that insulin receptors and insulin signaling proteins are found within the -cells themselves and that the insulin/IGF-1 signaling pathway is functionally important for glucose sensing. However, the physiologic and pathophysiological role of insulin signaling in normal and diabetic human -cells is largely unknown. In preliminary studies, we have demonstrated that in healthy humans elevated circulating levels of insulin can potentiate the insulin secretory response of the -cell to glucose. Therefore, in this study we will perform additional investigations to support our hypothesis that the -cell is an insulin sensitive tissue in healthy humans. We further hypothesize that dysfunctional insulin signaling at the level of the -cell may be one mechanism underlying blunted insulin secretion in insulin resistant persons with type 2 diabetes, and that -cells in persons with type 2 diabetes and insulin resistant syndromes will have reduced insulin augmentation of glucose induced insulin secretion.
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