| First Author | Kitamura RA | Year | 2024 |
| Journal | Proc Natl Acad Sci U S A | Volume | 121 |
| Issue | 33 | Pages | e2411234121 |
| PubMed ID | 39666939 | Mgi Jnum | J:360638 |
| Mgi Id | MGI:7790442 | Doi | 10.1073/pnas.2411234121 |
| Citation | Kitamura RA, et al. (2024) Dual role of neuroplastin in pancreatic beta cells: Regulating insulin secretion and promoting islet inflammation. Proc Natl Acad Sci U S A 121(33):e2411234121 |
| abstractText | 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 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 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 Ca(2+) levels and subsequent activation of downstream molecules. Simultaneously, we demonstrated that NPTN induces the expression of proinflammatory cytokines via the TRAF6-NF-kappaB axis in beta cells. Additionally, NPTN deficiency conferred resistance to streptozotocin-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 proinflammatory 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 DM. |
