Reduced nephrin tyrosine phosphorylation enhances insulin secretion and increases glucose tolerance with age.
Endocrinology
; 2024 Jul 02.
Article
in En
| MEDLINE
| ID: mdl-38954536
ABSTRACT
BACKGROUND:
Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic ß cells are implicated in diabetes. Nephrin signaling is mediated in part through its three cytoplasmic YDxV motifs, which can be tyrosine phosphorylated by high glucose and ß cell injuries. Although in vitro studies demonstrate these phosphorylated motifs can regulate ß 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 ß 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 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 ß cell function.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Endocrinology
Year:
2024
Document type:
Article
Affiliation country: