Dual role of neuroplastin in pancreatic β cells: Regulating insulin secretion and promoting islet inflammation.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident secretory protein that reduces inflammation and promotes proliferation in pancreatic β cells. Numerous studies have highlighted the potential of MANF as a therapeutic agent for diabetes mellitus (DM), making it essential to understand the mechanisms underlying MANF's functions. In our previous search for a molecule that mediates MANF signaling, we identified Neuroplastin (NPTN) as a binding partner of MANF that localizes on the cell surface. However, the roles of NPTN in pancreatic β cells remain unclear. In this study, we generated β cell-specific Nptn knockout (KO) mice and conducted metabolic characterization. NPTN deficiency improved glucose tolerance by increasing insulin secretion and β cell mass in the pancreas. Moreover, proliferation and mitochondrial numbers in β cells increased in Nptn KO islets. These phenotypes resulted from elevated cytosolic Ca2+ levels and subsequent activation of downstream molecules. Simultaneously, we demonstrated that NPTN induces the expression of proinflammatory cytokines via the TRAF6-NF-κB axis in β cells. Additionally, NPTN deficiency conferred resistance to streptozotocin-induced diabetic phenotypes. Finally, exogenous MANF treatment in islets or β cells led to similar phenotypes as those observed in NPTN-deficient models. These results indicate that NPTN plays important roles in the regulation of insulin secretion, proliferation, and mitochondrial quantity, as well as proinflammatory responses, which are antagonized by MANF treatment. Thus, targeting the MANF-NPTN interaction may lead to a novel treatment for improving β cell functions in DM.