Numerous recent studies link development of type 2 diabetes (T2D) to endoplasmic reticulum (ER) stress, a condition that occurs whenever protein-folding requirements overwhelm protein-folding capacity in the secretory pathway. Notably, there is mounting evidence that ER stress contributes to diminished glucose-responsive insulin secretion in ?- cells, to?-cell apoptosis, and to generalperipheral insulin resistance, all hallmarks of T2D. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionallyupregulates genes that enhance ER protein-folding capabilities. If homeostasis is not restored through these outputs, the UPR triggers apoptosis instead. We hypothesize that key component of the UPR, act as a toggling switches between homeostatic and apoptotic outputs, ultimately controlling ?-cell fate. Our project goal is to study these switches at the molecular level using interventional approaches.
Type 2 diabetes mellitus (T2D) affects 18 million Americans, with national healthcare and lost productivity costs exceeding $100 billion per year. T2D begins as a state of compensated insulin resistance;frank disease develops when approximately 50% of insulin-producing pancreatic islet ?-cellsof affected individuals undergo cell death. A detailed understanding of how ?-cells die is necessary to rationally mount an assault on T2D. We hypothesize that the stress from having to overwork may be responsible for ?-cell death in T2D. In this proposal we are testing this concept using molecular and cellular approaches.
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