| First Author | Williamson CR | Year | 2024 |
| Journal | Endocrinology | Volume | 165 |
| Issue | 8 | PubMed ID | 38954536 |
| Mgi Jnum | J:360205 | Mgi Id | MGI:7705465 |
| Doi | 10.1210/endocr/bqae078 | Citation | Williamson CR, et al. (2024) Reduced Nephrin Tyrosine Phosphorylation Enhances Insulin Secretion and Increases Glucose Tolerance With Age. Endocrinology 165(8) |
| abstractText | BACKGROUND: Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic beta cells are implicated in diabetes. Nephrin signaling is mediated in part through its 3 cytoplasmic YDxV motifs, which can be tyrosine phosphorylated by high glucose and beta cell injuries. Although in vitro studies demonstrate these phosphorylated motifs can regulate beta cell vesicle trafficking and insulin release, in vivo evidence of their role in this cell type remains to be determined. METHODS: To further explore the role of nephrin YDxV phosphorylation in beta cells, we used a mouse line with tyrosine to phenylalanine substitutions at each YDxV motif (nephrin-Y3F) to inhibit phosphorylation. We assessed islet function via primary islet glucose-stimulated insulin secretion assays and oral glucose tolerance tests. RESULTS: Nephrin-Y3F mice successfully developed pancreatic endocrine and exocrine tissues with minimal structural differences. Unexpectedly, male and female nephrin-Y3F mice showed elevated insulin secretion, with a stronger increase observed in male mice. At 8 months of age, no differences in glucose tolerance were observed between wild-type (WT) and nephrin-Y3F mice. However, aged nephrin-Y3F mice (16 months of age) demonstrated more rapid glucose clearance compared to WT controls. CONCLUSION: Taken together, loss of nephrin YDxV phosphorylation does not alter baseline islet function. Instead, our data suggest a mechanism linking impaired nephrin YDxV phosphorylation to improved islet secretory ability with age. Targeting nephrin phosphorylation could provide novel therapeutic opportunities to improve beta cell function. |
