Diabetes is a world-wide major cause of morbidity and mortality that is associated with disturbances in ? cell function that result in the loss of glucose-stimulated insulin secretion for control of blood glucose. Recent studies demonstrated an association between ? cell function and/or survival with an intracellular signaling pathway termed the unfolded protein response (UPR). Upon accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER), three UPR signal transduction subpathways are activated to increase the protein folding capacity and increase the protein degradative machinery. Protein synthesis is transiently attenuated through PERK-mediated phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (elF2a), one subpathway of the UPR. Recently, we discovered that PERK/elFa signaling is required to preserve the environment of the ER to support high-level insulin production in response to increases in blood glucose. Our discoveries support the hypothesis that increases in insulin production exceed the protein-folding capacity of the ER. Under these conditions, the PERK/elF2a subpathway is activated transiently to prevent oxidative stress, and when perpetually activated, induces a cell death response through induction of the transcription factor CHOP. We propose that reducing oxidative stress or preventing CHOP expression will improve ? cell function and survival in response to insulin resistance. Given the significance of the PERK/elF2a UPR subpathway in ? cell function, is it likely that IRE1 and ATF6 UPR subpathways are also essential for ? cell function. The studies proposed will elucidate the requirements of PERK/elF2a, IRE1, and ATF6 signaling using novel genetic mouse models in which UPR sensor genes can be turned 'on'or 'off'in a temporal- and/or tissue-specific manner. These in vivo models will be used to elucidate novel insights into ? cell failure and to evaluate novel modalities for therapeutic intervention. Diabetes is a multifactorial disease that stems largely from an inability of pancreatic ? cells to produce adequate amounts of insulin for control of blood glucose levels. Excessive insulin synthesis can lead to accumulation of unfolded protein within the ? cell. The study of cell signaling pathways activated by unfolded protein will lead to insights and new treatments for this disease.
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