p85α deficiency protects β-cells from endoplasmic reticulum stress-induced apoptosis

In insulin resistant states such as type 2 diabetes, there is a high demand on the beta-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 p85 alpha 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 beta-cells can markedly delay the onset and severity of the diabetic phenotype observed in Akita(+/-) 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 beta-cell mass and function. These data demonstrate that modulation of p85 alpha can protect pancreatic beta-cells from ER stress, pointing to a potentially therapeutic target in diabetic states.