Dual Role of Neuroplastin in Pancreatic ß 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 ß 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 ß cells remain unclear. In this study, we generated ß cell-specific Nptn knockout (KO) mice and conducted metabolic characterization. NPTN deficiency improved glucose tolerance by increasing insulin secretion and ß cell mass in the pancreas. Moreover, proliferation and mitochondrial numbers in ß 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-?B axis in ß cells. Additionally, NPTN deficiency conferred resistance to STZ-induced diabetic phenotypes. Finally, exogenous MANF treatment in islets or ß 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 ß cell functions in diabetes mellitus. Overall design: To better understand the impact of Nptn knockout in b cells, bulk RNA-sequencing (RNA-seq) with islets isolated from Nptnf/f and Nptnf/f; Ins1Cre mice at 7 weeks old was performed.