Exp Clin Endocrinol Diabetes 2013; 121 - OP4_24
DOI: 10.1055/s-0033-1336632

Intracellular p8 mediates potent protection of insulin secretory function during inflammatory beta cell stress

AE Mehana 1, 2, I Pilz 1, B Dufner 1, C Jäger 1, S Sojka 1, J Baumann 1, M Alt 1, J Seufert 1, G Päth 1
  • 1University Hospital of Freiburg, Department of Internal Medicine II, Freiburg, Germany
  • 2University of Freiburg, Institute of Biology II, Faculty of Biology, Freiburg, Germany

Introduction: High caloric malnutrition promotes local cellular proinflammatory activation leading to insulin resistance in peripheral tissues, insulin secretory dysfunction and loss, and finally type 2 diabetes. The intracellular protein p8 has been shown to reduce exocrine tissue damage during pancreatitis. To investigate its role in the endocrine pancreas we generated transgenic mice with beta cell-specific p8 overexpression. p8 mice demonstrate substantially improved glucose tolerance during high fat diet (HFD) and/or insulitis. Since both p8 and wild type (Wt) mice demonstrate similar beta cell loss, we here characterise p8-mediated protection of insulin secretion during inflammatory beta cell stress.

Methods: Insulitis was induced by multiple low-dose STZ injections. Glucose tolerance was evaluated by non-fasting blood glucose and over night-fasted ipGTT. State of islet inflammation was characterised by numbers of infiltrating CD45+ lymphocytes and NF-kB activation (Western blot). Islet insulin secretion and content was measured by ELISA after 24h exposure to 10 ng/ml IL-1beta or 0.33 mM STZ.

Results: Upon insulitis, p8 mice exhibit significantly better glucose tolerance. This was accompanied by decreased lymphocyte infiltration and reduced NF-kB activation thereby demonstrating reduced inflammation. In vitro, insulin secretion and content was significantly enhanced in p8 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. Only after STZ we observed significant depletion of stored insulin but remaining insulin content was still comparable to untreated Wt islets.

Conclusions: p8 exhibits potent protection of insulin secretion and content during cell stress by reducing proinflammatory activation of NF-kB. Hence, p8 may be an important mediator in the stress defence system of beta cells.