NUPR1 preserves insulin secretion of pancreatic β-cells during inflammatory stress by multiple low-dose streptozotocin and high-fat diet

Obesity is associated with dyslipidemia and subclinical inflammation that promotes metabolic disturbances including insulin resistance and pancreatic beta-cell dysfunction. The nuclear protein, transcriptional regulator 1 (NUPR1) responds to cellular stresses and features tissue protective properties. To characterize the role of NUPR1 in endocrine pancreatic islets during inflammatory stress, we generated transgenic mice with beta-cell-specific Nupr1 overexpression (beta NUPR1). Under normal conditions. beta NUPR1 mice did not differ from wild type (WT) littermates and display normal glucose homeostasis and beta-cell mass. For induction of inflammatory conditions, mice were treated with multiple low-dose streptozotocin (mld-STZ) and/or fed a high-fat diet (HFD). All treatments significantly worsened glycaemia in WT mice, while beta NUPR1 mice substantially preserved insulin secretion and glucose tolerance. HFD increased beta-cell mass in all animals, with beta NUPR I mice tending to show higher values. The improved outcome of beta NUPR1 mice was accompanied by decreased NF-kappa B activation and lymphocyte infiltration in response to mld-STZ. In vitro, isolated beta NUPR1 islets preserved insulin secretion and content with insignificantly low apoptosis during culture stress and IL-1 beta exposure. These findings suggest that NUPR1 plays a vital role in the protection of beta-cells from apoptosis, related degradation of insulin storages and subsequent secretion during inflammatory and obesity-related tissue stress.