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p85α deficiency protects β-cells from endoplasmic reticulum stress-induced apoptosis.
Proc. Natl. Acad. Sci. U.S.A..Jan 21, 2014;111(3):1192-7.
Winnay JN, Dirice E, Liew CW, Kulkarni RN, Kahn CR.
Section on Integrative Physiology and Metabolism and Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215.
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 p85α 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 p85α expression in β-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 β-cell mass and function. These data demonstrate that modulation of p85α can protect pancreatic β-cells from ER stress, pointing to a potentially therapeutic target in diabetic states.