| First Author | Yu F | Year | 2024 |
| Journal | Cell Rep | Volume | 43 |
| Issue | 12 | Pages | 115057 |
| PubMed ID | 39675006 | Mgi Jnum | J:361082 |
| Mgi Id | MGI:7852017 | Doi | 10.1016/j.celrep.2024.115057 |
| Citation | Yu F, et al. (2024) Pancreatic beta cell interleukin-22 receptor subunit alpha 1 deficiency impairs beta cell function in type 2 diabetes via cytochrome b5 reductase 3. Cell Rep 43(12):115057 |
| abstractText | Impaired beta cell function is a hallmark of type 2 diabetes (T2D), but the underlying cellular signaling machineries that regulate beta cell function remain unknown. Here, we identify that the interleukin-22 receptor subunit alpha 1 (IL-22RA1), known as a co-receptor for IL-22, is downregulated in human and mouse T2D beta cells. Mice with beta cell Il22ra1 knockout (Il22ra1betaKO) exhibit defective insulin secretion and impaired glucose tolerance after being fed a high-fat diet (HFD) or an HFD/low dose of streptozotocin (STZ). Mechanistically, beta cell IL-22RA1 deficiency inhibits cytochrome b5 reductase 3 (CYB5R3) expression via the IL-22RA1/signal transducer and activator of the transcription 3 (STAT3)/c-Jun axis, thereby impairing mitochondrial function and reducing beta cell identity. Overexpression of CYB5R3 reinstates mitochondrial function, beta cell identity, and insulin secretion in Il22ra1betaKO mice. Moreover, the pharmacological activation of CYB5R3 with tetrahydroindenoindole restores insulin secretion in Il22ra1betaKO mice, IL-22RA1-knockdown human islets, and Min6 cells. In conclusion, these findings suggest an important role of IL-22RA1 in preserving beta cell function in T2D, which offers a potential therapeutic target for treating diabetes. |
