Preserved insulin response of Nupr1-transgenic islets during diabetogenic injury is correlated with reduced secretion of IL-1beta and enhanced secretion of IL-1 receptor antagonist

Introduction: We previously demonstrated that transgenic mice with beta cell-specific overexpression of Nupr1 (Nupr1-Tg) are resistant to multiple low-dose streptozotocin (STZ) and/or high fat diet (HFD). Preserved insulin secretion of Nupr-Tg islets in vivo was associated with reduced NF-kB activation and less lymphocyte infiltration. The pro-inflammatory cytokine IL-1beta is well known to promote beta cell apoptosis and to inhibit insulin secretion via activation of NF-kB. Therefore, we investigated the response of IL-1beta and its physiologic receptor antagonist IL-1RA in WT and Nupr1-Tg islets during diabetogenic stress in vitro.

Methods: Islets were isolated from normal- and 20 weeks HFD-fed mice. Islets were cultured in inserts and exposed for 24h to 0.33 mM STZ or 10 ng/ml IL-1beta. Glucose-induced insulin secretion and apoptotic cleavage of the DNA repair enzyme PARP was measured after 24h. For IL-1beta and IL-1RA, stress medium was exchanged after 24h to normal culture medium and supernatants were collected after another 24h.

Results: Time in culture, STZ and IL-1beta significantly inhibited insulin secretion and upregulated apoptotic PARP cleavage in WT islets while Nupr1-Tg islets were not much affected. This resistance of Nupr1-Tg islets was associated with reduced secretion of IL-1beta and significant upregulation of IL-1RA. Similarly, WT and Nupr1-Tg islets from HFD-fed mice demonstrate significant upregulation of IL-1beta while only Nupr1-Tg islets signficantly upregulated secretion of IL-1RA.

Conclusion: Diabetogenic stress increases the local production of IL-1beta in islets. Nupr1 overexpression counterregulates the detrimental effects of IL-1beta by substantial upregulation of IL-1RA.