Pancreatic ß-cell interleukin-22 receptor subunit alpha 1 deficiency impairs ß-cell function in type 2 diabetes via cytochrome b5 reductase 3 [BKO]
Impaired ß-cell function is a hallmark of type 2 diabetes (T2D), whereas, the underlying cellular signaling machineries that regulate ß-cell function remain unknown. Here, we identify that the interleukin-22 receptor subunit alpha 1 (IL22RA1), known as a co-receptor for IL-22, is downregulated in human and mouse T2D ß-cells. Mice with ß-cell Il22ra1 knockout (Il22ra1ßKO) exhibit defective insulin secretion and impaired glucose tolerance after a high-fat diet (HFD) or HFD/low-dose streptozotocin (STZ). Mechanistically, ß-cell IL22RA1 deficiency inhibits cytochrome b5 reductase 3 (CYB5R3) expression via the IL22RA1/STAT3/c-JUN axis, thereby impairing mitochondrial function and reducing ß-cell identity. Overexpression of CYB5R3 reinstates mitochondrial function, ß-cell identity and insulin secretion in Il22ra1ßKO mice. Moreover, pharmacological activation of CYB5R3 with tetrahydroindenoindole restores insulin secretion in Il22ra1ßKO mice, IL22RA1 knockdown human islets and Min6 cells. In conclusion, these findings suggest an important role of IL22RA1 in preserving ß-cell function in T2D, which offers a potential therapeutic target for treating diabetes. Overall design: To investigate the influence of changes in transcriptional patterns that modulate ß-cell function via IL22RA1 signaling, we performed RNA-sequencing (RNA-seq) on islets isolated from 6-week HFD-fed Ins2Cre mice and Il22ra1ßKO mice