title: p85α deficiency protects β-cells from endoplasmic reticulum stress-induced apoptosis.
abstract: 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.
authors.affiliation: Section on Integrative Physiology and Metabolism and Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215.
authors.forename: Jonathon N
authors.initials: JN
authors.lastname: Winnay
authors.forename: Ercument
authors.initials: E
authors.lastname: Dirice
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000172:deficiency*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D018384:Oxidative Stress; D010179:Pancreas / Q000502:physiology; D010641:Phenotype; D011489:Protein Denaturation; D017510:Protein Folding; D013997:Time Factors
chemical_list: D007328:Insulin; D058543:Class Ia Phosphatidylinositol 3-Kinase; D005947:Glucose