p8 is a novel intracellular mediator of pancreatic β-cell protection that preserves insulin secretory function during inflammatory cell stress in vivo

Introduction: A current hypothesis considers type 2 diabetes a result of over nutrition-induced local inflammation leading to insulin resistance, insulin secretory dysfunction and pancreatic β-cell loss. The intracellular protein p8 has been shown to reduce tissue damage during acute pancreatitis. To investigate its role in the endocrine pancreas we generated transgenic mice with β-cell-specific p8 overexpression (Tg).

Methods: Mice were fed a high fat diet (HFD), and insulitis was induced by multiple low-dose STZ injections. Glucose tolerance was evaluated by measuring non-fasting random blood glucose and intraperitoneal glucose tolerance test (ipGTT). β-cell mass was determined microscopically. Islet inflammation was quantified by numbers of infiltrating CD45+ lymphocytes & NF-kB activation. Cleaved PARP was analysed for apoptosis, islet insulin secretion and content was measured ex vivo after 24h exposure to 10 ng/ml IL-1β or 0.33mM STZ.

Results: Tg mice demonstrated improved glucose tolerance during HFD and/or insulitis as compared to wild type (Wt) controls. No differences of β-cell mass were detected between p8 and Wt mice, and insulin sensitivity was similar. However, upon insulitis, the better glucose tolerance of p8 mice was accompanied by decreased lymphocyte infiltration & reduced NF-kB activation. Ex vivo, β-cell apoptosis was greatly reduced while insulin secretion and content was significantly enhanced in isolated p8 Tg islets as compared to Wt islets. Importantly, there was no degradation of insulin secretion & content during 8 days of culture or in response to 24h exposure to IL-1β or STZ.

Conclusions: p8 exhibits potent protection of insulin biosynthesis, secretion and content during inflammatory pancreatic β-cell stress by reducing activation of NF-kB. p8 may be an important molecular mediator in the stress defence system of β-cells, and therefore represent a therapeutic target for protection of endogenous insulin biosynthesis in diabetes mellitus.