Dual Role of Neuroplastin in Pancreatic Beta 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 {beta} 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 MANFs 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 {beta} cells remain unclear. In this study, we generated {beta} cell-specific Nptn knockout (KO) mice and conducted metabolic characterization. NPTN deficiency improved glucose tolerance by increasing insulin secretion and {beta} cell mass in the pancreas. Moreover, proliferation and mitochondrial numbers in {beta} 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-{kappa}B axis in {beta} cells. Additionally, NPTN deficiency conferred resistance to STZ-induced diabetic phenotypes. Finally, exogenous MANF treatment in islets or {beta} 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 pro-inflammatory responses, which are antagonized by MANF treatment. Thus, targeting the MANF-NPTN interaction may lead to a novel treatment for improving {beta} cell functions in diabetes mellitus. Significance statementMesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident small secretory protein that has the potential as therapeutic agent for various diseases related to inflammation and ER stress, such as Type 1 diabetes mellitus. Our work shed light on the roles of a binding partner protein of MANF, Neuroplastin (NPTN), in pancreatic {beta} cells. We demonstrated NPTN regulates Ca2+ dynamics as well as inflammation in pancreatic {beta} cells. NPTN deficiency caused improved insulin secretion as well as the resistance to Type 1 diabetic phenotypes. We also found out that MANF treatment leads to similar phenotypes observed in NPTN deficient models through antagonizing NPTNs functions. Overall, our results provide a new insight into treatment for improving {beta} cell functions in diabetes mellitus.