p85[alpha] deficiency protects [Beta]-cells from endoplasmic reticulum stress-induced apoptosis

In insulin resistant states such as type 2 diabetes, there is a high demand on the β-cell to synthesize and secrete insulin, which challenges the ability of the endoplasmic reticulum (ER) to synthesize and fold nascent proteins. This creates a state of ER stress that triggers a coordinated program referred to as the unfolded protein response (UPR) that attempts to restore ER homeostasis. We identified a role for the p85a regulatory subunit of PI3K to modulate the UPR by promoting the nuclear localization of X-box binding protein 1, a transcription factor central to the UPR. In the present study we demonstrate that reducing p85a expression in β-cells can markedly delay the onset and severity of the diabetic phenotype observed in ... mice, which express a mutant insulin molecule. This is due to a decrease in activation of ER stress-dependent apoptotic pathways and a preservation of β-cell mass and function. These data demonstrate that modulation of p85a can protect pancreatic β-cells from ER stress, pointing to a potentially therapeutic target in diabetic states. (ProQuest: ... denotes formulae/symbols omitted.)