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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 β-cells. Mice with β-cell Il22ra1 knockout (Il22ra1βKO) exhibit defective insulin secretion and impaired glucose tolerance after a high-fat diet (HFD) or HFD/low-dose streptozotocin (STZ). Mechanistically, β-cell IL22RA1 deficiency inhibits cytochrome b5 reductase 3 (CYB5R3) expression via the IL22RA1/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, pharmacological activation of CYB5R3 with tetrahydroindenoindole restores insulin secretion in Il22ra1βKO mice, IL22RA1 knockdown human islets and Min6 cells. In conclusion, these findings suggest an important role of IL22RA1 in preserving β-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 β-cell function via IL22RA1 signaling, we performed RNA-sequencing (RNA-seq) on Min6 cells infected with adenovirus sh-ctrl versus those infected with sh-Il22ra1 after PA treatment"],"repository":["ENA"],"description_synonyms":["Adult-Onset Diabetes Mellitus, Diabetes Type 2, type 2, BamF, interleukin-22 receptor type 2, interleukin-22 receptor type 1, BamC, AP-2, Small Hairpin, alpha-Spe, Type 2 Diabetes Mellitus, alpha-Spc, CG31654, diabetes mellitus type 2, dmTAF[[II]]230, Repeat Associated siRNA, Small, rat, l(3)04276, Trans Acting, interleukin-22, Non-Insulin Dependent Diabetes Mellitus, alpha-adaptin, Maturity Onset Diabetes, DmelCG10422, Slow Onset, alpha-spec, TFIID TAF250, CG4260, IL-22R alpha chain, cel, alpha-spectrin, Ketosis-Resistant Diabetes Mellitus, NIDDM, 1.6.2.2, Noninsulin-Dependent, alpha 1 subunit, Diabetes mellitus, Repeat-Associated, MODY (Maturity-onset diabetes of the young), Non Insulin Dependent, alpha chains, B5R, Interfering RNA, dTAF[[II]]230, Trans-Acting siRNA, IL-22 receptor-alpha 2, Adult-onset diabetes mellitus, mouse, TAF200, ham, TAFII-250, TAF250/230, Noninsulin-dependent diabetes mellitus, Short, ada, Adult-Onset, alphaSpec, TAFII250, D-Ada, Adult-Onset Diabetes, Small Scan, alpha 2 subunit, IL22RA1 protein, cg4260, dAP-2a, Ketosis Resistant, Short Interfering RNA, spectrin, Hairpin RNA, Scan, Maturity-Onset Diabetes Mellitus, IL-22R, l(2)06694, MENE (2L)-A, NADH-cytochrome b5 reductase 3 soluble form, IL-22 receptor, Type II Diabetes, alpha, AP-2alpha, Type 2, Repeat Associated, CG17603, TAF[[II]], human, DmelCG4260, Noninsulin-Dependent Diabetes Mellitus, type II, non-insulin-dependent, Non-Insulin Dependent Diabetes, Taf250, SR3-5, Slow-Onset, TAF230, T2DM - Type 2 Diabetes mellitus, alpha-Ada, d230, anon-EST:fe2E2, l(3)alpha-Spec, Noninsulin Dependent, alpha-Spect, dTAFII250, DIABETES MELLITUS TYPE 02, EfW1, l(2)SH2 0460, Maturity-onset diabetes, fs(3)neo61, IL-22R1, IL-22R2, alpha subunits, CG10422, alpha-ada, Short Hairpin RNA, dmTAF1, Taf230, Scan RNA, Non-Insulin-Dependent, Small Scan RNA, klo, alpha-Sp, non-insulin-dependent diabetes mellitus, CG1977, Maturity-Onset Diabetes, TAF250, T2DM, Taf200, scnRNA, dTAF[[II]]250, Il22ra1 protein, IL-22RA2, cell, Non-Insulin-Dependent Diabetes Mellitus, dre3, alpha 2 chain, Taf1p, Maturity Onset Diabetes Mellitus, Alpha-Adaptin, adult-onset, Short Hairpin, dTAF250, Maturity-onset diabetes mellitus, Noninsulin Dependent Diabetes Mellitus, Stable, Diabetes Mellitus, Trans Acting siRNA, IL22RA2 protein, Ketosis-Resistant, TAF, Diabetes, NADH-cytochrome b5 reductase 3 membrane-bound form, tasiRNA, l(3)dre3, Adult Onset, Type 2 diabetes, IL-22BP protein, RNA, Trans-Acting, TAF[[II]]250, alpha-Spectrin, alpha 1 protein, 3A9, Adult-onset diabetes, Type 2 diabetes mellitus, DmelCG1977, alpha 1 chain, interleukin 22 receptor, MODY, l(3)84Ab, shRNA, BG:DS00004.13, interleukin-22 receptor alpha-chain, Cell, Repeat-Associated siRNA., Small Hairpin RNA, dTAF230, Short Interfering, Diaphorase-1, T2D, p230, Slow-Onset Diabetes Mellitus, Maturity-Onset, TAF[[II]]250/230, TFIID, MENE(2L)-A, Type 2 Diabetes Mellitus Non-Insulin Dependent, alphaSp, Taf[[II]]250, Type 2 Diabetes, Small Interfering RNA, TAF[[II]]230, D-alphaAda, mating_type_alpha, FCP-B, TAF[II]250, Cytochrome b5 reductase, AP2, DmelCG17603, l(3)62Bd, siRNA, Bam-C, BAM, Bam, alpha mating type (yeast), l(2)SH0460, alfa-Spec, receptor, Type II, Stable Diabetes Mellitus, Spec, Maturity Onset, TAF1"],"name_synonyms":["Adult-Onset Diabetes Mellitus, Diabetes Type 2, type 2, BamF, interleukin-22 receptor type 2, interleukin-22 receptor type 1, BamC, AP-2, Small Hairpin, alpha-Spe, Type 2 Diabetes Mellitus, alpha-Spc, CG31654, diabetes mellitus type 2, dmTAF[[II]]230, Repeat Associated siRNA, Small, rat, l(3)04276, Trans Acting, interleukin-22, Non-Insulin Dependent Diabetes Mellitus, alpha-adaptin, Maturity Onset Diabetes, DmelCG10422, Slow Onset, alpha-spec, TFIID TAF250, CG4260, IL-22R alpha chain, cel, alpha-spectrin, Ketosis-Resistant Diabetes Mellitus, NIDDM, 1.6.2.2, Noninsulin-Dependent, alpha 1 subunit, Diabetes mellitus, Repeat-Associated, MODY (Maturity-onset diabetes of the young), Non Insulin Dependent, alpha chains, B5R, Interfering RNA, dTAF[[II]]230, Trans-Acting siRNA, IL-22 receptor-alpha 2, Adult-onset diabetes mellitus, mouse, TAF200, ham, TAFII-250, TAF250/230, Noninsulin-dependent diabetes mellitus, Short, ada, Adult-Onset, alphaSpec, TAFII250, D-Ada, Adult-Onset Diabetes, Small Scan, alpha 2 subunit, IL22RA1 protein, cg4260, dAP-2a, Ketosis Resistant, Short Interfering RNA, spectrin, Hairpin RNA, Scan, Maturity-Onset Diabetes Mellitus, IL-22R, l(2)06694, MENE (2L)-A, NADH-cytochrome b5 reductase 3 soluble form, IL-22 receptor, Type II Diabetes, alpha, AP-2alpha, Type 2, Repeat Associated, CG17603, TAF[[II]], human, DmelCG4260, Noninsulin-Dependent Diabetes Mellitus, type II, non-insulin-dependent, Non-Insulin Dependent Diabetes, Taf250, SR3-5, Slow-Onset, TAF230, T2DM - Type 2 Diabetes mellitus, alpha-Ada, d230, anon-EST:fe2E2, l(3)alpha-Spec, Noninsulin Dependent, alpha-Spect, dTAFII250, DIABETES MELLITUS TYPE 02, EfW1, l(2)SH2 0460, Maturity-onset diabetes, fs(3)neo61, IL-22R1, IL-22R2, alpha subunits, CG10422, alpha-ada, Short Hairpin RNA, dmTAF1, Taf230, Scan RNA, Non-Insulin-Dependent, Small Scan RNA, klo, alpha-Sp, non-insulin-dependent diabetes mellitus, CG1977, Maturity-Onset Diabetes, TAF250, T2DM, Taf200, scnRNA, dTAF[[II]]250, Il22ra1 protein, IL-22RA2, cell, Non-Insulin-Dependent Diabetes Mellitus, dre3, alpha 2 chain, Taf1p, Maturity Onset Diabetes Mellitus, Alpha-Adaptin, adult-onset, Short Hairpin, dTAF250, Maturity-onset diabetes mellitus, Noninsulin Dependent Diabetes Mellitus, Stable, Diabetes Mellitus, Trans Acting siRNA, IL22RA2 protein, Ketosis-Resistant, TAF, Diabetes, NADH-cytochrome b5 reductase 3 membrane-bound form, tasiRNA, l(3)dre3, Adult Onset, Type 2 diabetes, IL-22BP protein, RNA, Trans-Acting, TAF[[II]]250, alpha-Spectrin, alpha 1 protein, 3A9, Adult-onset diabetes, Type 2 diabetes mellitus, DmelCG1977, alpha 1 chain, interleukin 22 receptor, MODY, l(3)84Ab, shRNA, BG:DS00004.13, interleukin-22 receptor alpha-chain, Cell, Repeat-Associated siRNA., Small Hairpin RNA, dTAF230, Short Interfering, Diaphorase-1, T2D, p230, Slow-Onset Diabetes Mellitus, Maturity-Onset, TAF[[II]]250/230, TFIID, MENE(2L)-A, Type 2 Diabetes Mellitus Non-Insulin Dependent, alphaSp, Taf[[II]]250, Type 2 Diabetes, Small Interfering RNA, TAF[[II]]230, D-alphaAda, mating_type_alpha, FCP-B, TAF[II]250, Cytochrome b5 reductase, AP2, DmelCG17603, l(3)62Bd, siRNA, Bam-C, BAM, Bam, alpha mating type (yeast), l(2)SH0460, alfa-Spec, receptor, Type II, Stable Diabetes Mellitus, Spec, Maturity Onset, TAF1"],"additional_accession":[]},"is_claimable":false,"name":"Pancreatic β-cell interleukin-22 receptor subunit alpha 1 deficiency impairs β-cell function in type 2 diabetes via cytochrome b5 reductase 3 [shRNA]","description":"Pancreatic β-cell interleukin-22 receptor subunit alpha 1 deficiency impairs β-cell function in type 2 diabetes via cytochrome b5 reductase 3 [shRNA]","dates":{"last_updated":"2025-09-24","first_public":"2024-11-14"},"accession":"PRJNA1185161","cross_references":{"GEO":["GSE281652"],"taxon":["10090"],"PubMed":["39675006"]}}