Pancreatic β cell interleukin-22 receptor subunit alpha 1 deficiency impairs β cell function in type 2 diabetes via cytochrome b5 reductase 3


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Human pancreatic beta cells, interleukin 1 receptor type ii, pancreatic β cell, growing β cells in pancreatic islets, interleukin 22 protein receptor, anti pancreatic islet cells test, pancreatic islet cell antibodies test, interleukin 22 receptor subunit alpha 1.

Pancreatic β cell interleukin-22 receptor subunit alpha 1 deficiency impairs β cell function in type 2 diabetes via cytochrome b5 reductase 3

Impaired β cell function is a hallmark of type 2 diabetes (T2D), but the underlying cellular signaling machineries that regulate β 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 β cells. Mice with β cell Il22ra1 knockout (Il22ra1βKO) 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, β 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 β cell identity. Overexpression of CYB5R3 reinstates mitochondrial function, β cell identity, and insulin secretion in Il22ra1βKO mice. Moreover, the pharmacological activation of CYB5R3 with tetrahydroindenoindole re stores insulin secretion in Il22ra1βKO mice, IL-22RA1-knockdown human islets, and Min6 cells. In conclusion, these findings suggest an important role of IL-22RA1 in preserving β cell function in T2D, which offers a potential therapeutic target for treating diabetes. © 2024 The Authors

Authors : Yu F.; Xie S.; Wang T.; Huang Y.; Zhang H.; Peng D.; Feng Y.; Yang Y.; Zhang Z.; Zhu Y.; Meng Z.; Zhang R.; Li X.; Yin H.; Xu J.; Hu C.

Source : Elsevier B.V.

Article Information

Year 2024
Type Article
DOI 10.1016/j.celrep.2024.115057
ISSN 26391856
Volume 43

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