The anti-inflammatory protein NUPR1 protects pancreatic islets from diabetogenic lipotoxic injury ex vivo

Background and aim: According to the so-called “nutrition overflow hypothesis”, type 2 diabetes results from nutrition-induced local tissue inflammation leading to insulin resistance, insulin secretory dysfunction and finally pancreatic β-cell loss. Free fatty acids (FFA) acting through toll-like receptors are key mediators of this lipotoxic inflammatory response. We previously demonstrated that the intracellular protein NUPR1 (p8) exerts potent anti-inflammatory and anti-diabetogenic effects in β-cells in vivo. Here we investigated the anti-lipotoxic potential of NUPR1 ex vivo in pancreatic islets of transgenic mice with β-cell-specific Nupr1 overexpression under the control of the rat insulin 1 promoter (Nupr1-Tg).

Materials and methods: Islets were obtained from Nupr1-Tg mice or syngeneic Wt mice for control. Palmitate was employed as a model for FFA-induced lipotoxicity. In INS-1E β-cells we established a LD50 of 0.15 mM palmitate, which was used for 24h treatment of islets. Cell viability was assessed by MTS assay and insulin secretion was analysed by ELISA.

Results: Untreated Nupr1-Tg islets demonstrated increased baseline viability as compared to Wt islets. Palmitate exposure induced the loss of viability of both Nupr1-Tg and Wt islets, which was substantially more pronounced in Wt islets. Moreover, the preserved viability of Nupr1-Tg islets was associated with in parallel enhanced insulin secretion as compared to Wt controls.

Conclusions: β-cell-overexpression of Nupr1 in transgenic pancreatic islets preserves viability and insulin secretory capacity in response to lipotoxic injury by palmitate ex vivo. These results suggest that NUPR1 bears potent anti-inflammatory capacity to protect insulin biosynthesis in nutrition-induced lipotoxic type 2 diabetes.