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DOI: 10.1055/s-0034-1374962
The anti-inflammatory protein NUPR1 (p8) is a novel intracellular mediator of pancreatic β-cell protection during diabetogenic stress in vitro and in vivo
Introduction: The intracellular protein NUPR1 (alias p8) reduces tissue damage during acute pancreatitis, and its expression is enriched in pancreatic islets. Therefore, we hypothesized that NUPR1 may exert protective mechanisms in the endocrine pancreas under inflammatory diabetogenic stress. This was investigated in transgenic mice with β-cell-specific NUPR1 overexpression (Tg).
Methods: Mice were fed a high fat diet (HFD) and/or treated with multiple low-doses of streptozotocin (STZ). Glucose homeostasis was assessed by non-fasting blood glucose, ipGTT, ipITT, and serum insulin levels. β-cell mass was determined microscopically. Islet inflammation was quantified through infiltrating CD45+ lymphocytes and NF-kB activation. Islet function, β-cell apoptosis and proliferation were evaluated in isolated islets that were exposed for 24 hrs to 10 ng/ml IL-1β or 0.33 mM STZ.
Results: Tg-mice demonstrated substantially improved glucose tolerance, maintained insulin secretion and β-cell mass during HFD and/or insulitis compared to Wt controls. Tg islets showed reduced lymphocyte infiltration and NF-kB activation. Isolated Tg islets in response to 24hrs IL-1β or STZ exposure showed greatly reduced apoptosis and enhanced insulin secretion and content compared to Wt. Further, Tg islets showed no reduction in proliferation compared to significant reductions in Wt islets.
Conclusions: NUPR1 overexpression compensates for decreased β-cell mass by reducing apoptosis and enhancing proliferative capacity. This protects insulin biosynthesis, secretion and content during inflammatory diabetogenic pancreatic stress. NUPR1, therefore, represents a therapeutic target for endocrine pancreas protection and maintenance of transplanted islets.