期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：3
页码：1192-1197
DOI：10.1073/pnas.1322564111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 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 p85 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 can protect pancreatic {beta}-cells from ER stress, pointing to a potentially therapeutic target in diabetic states.
