Diabetologie und Stoffwechsel 2013; 8 - FV52
DOI: 10.1055/s-0033-1341712

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

AE Mehana 1, 2, I Pilz 1, B Dufner 1, C Jäger 1, S Sojka 1, J Baumann 1, M Alt 1, C Liu 1, N Perakakis 1, K Laubner 1, G Päth 1, J Seufert 1
  • 1University Hospital of Freiburg, Freiburg, Germany
  • 2University of Freiburg, Freiburg, Germany

Introduction: A current hypothesis considers type 2 diabetes as a result of over nutrition-induced local inflammation leading to insulin resistance, insulin secretory dysfunction and finally pancreatic beta 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 beta cell-specific p8 overexpression (Tg).

Methods: Mice were fed a high fat diet, 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). Beta cell mass was determined microscopically. Islet inflammation was quantified by numbers of infiltrating CD45+ lymphocytes and NF-kB activation (Western blot). Islet insulin secretion and content was measured ex vivo by ELISA after 24h exposure to 10 ng/ml IL-1beta or 0.33 mM STZ.

Results: Tg mice demonstrated substantially improved glucose tolerance during high fat diet (HFD) and/or insulitis as compared to wild type (Wt) controls. Both, p8 and Wt mice display the same degree of beta cell loss. However, upon insulitis, the better glucose tolerance of p8 mice was accompanied by decreased lymphocyte infiltration and reduced NF-kB activation, i.e. reduced inflammation. Ex vivo, insulin secretion and content was significantly enhanced in isolated p8Tg islets compared to Wt islets. Importantly, there was no degradation of insulin secretion and content during 8 days of culture or in response to 24h exposure to IL-1beta or STZ.

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