ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/093/SRR31314293/SRR31314293_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/001/SRR31314301/SRR31314301_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/095/SRR31314295/SRR31314295_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/001/SRR31314301/SRR31314301_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/097/SRR31314297/SRR31314297_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/091/SRR31314291/SRR31314291_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/096/SRR31314296/SRR31314296_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/091/SRR31314291/SRR31314291_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/094/SRR31314294/SRR31314294_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/097/SRR31314297/SRR31314297_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/098/SRR31314298/SRR31314298_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/092/SRR31314292/SRR31314292_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/090/SRR31314290/SRR31314290_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/096/SRR31314296/SRR31314296_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/099/SRR31314299/SRR31314299_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/090/SRR31314290/SRR31314290_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/000/SRR31314300/SRR31314300_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/093/SRR31314293/SRR31314293_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/094/SRR31314294/SRR31314294_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/092/SRR31314292/SRR31314292_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/000/SRR31314300/SRR31314300_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/095/SRR31314295/SRR31314295_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/098/SRR31314298/SRR31314298_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR313/099/SRR31314299/SRR31314299_2.fastq.gzprimaryOK200GenomicsShanghai Diabetes Institute, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicinehttps://www.ebi.ac.uk/ena/browser/view/PRJNA1185158Mus musculusImpaired β-cell function is a hallmark of type 2 diabetes (T2D), whereas, the underlying cellular signaling machineries that regulate β-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 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 islets isolated from 6-week HFD-fed Ins2Cre mice and Il22ra1βKO micexref:PubMed:39675006ENAT2DM - Type 2 Diabetes mellitus, Adult-Onset Diabetes Mellitus, Diabetes Type 2, type 2, alpha-Ada, d230, anon-EST:fe2E2, BamF, interleukin-22 receptor type 2, l(3)alpha-Spec, interleukin-22 receptor type 1, BamC, AP-2, Noninsulin Dependent, alpha-Spect, alpha-Spe, dTAFII250, Type 2 Diabetes Mellitus, DIABETES MELLITUS TYPE 02, EfW1, alpha-Spc, CG31654, diabetes mellitus type 2, l(2)SH2 0460, Maturity-onset diabetes, fs(3)neo61, IL-22R1, dmTAF[[II]]230, IL-22R2, alpha subunits, CG10422, rat, l(3)04276, alpha-ada, dmTAF1, Taf230, interleukin-22, Non-Insulin-Dependent, klo, Non-Insulin Dependent Diabetes Mellitus, alpha-adaptin, Maturity Onset Diabetes, alpha-Sp, non-insulin-dependent diabetes mellitus, DmelCG10422, CG1977, Slow Onset, alpha-spec, Maturity-Onset Diabetes, TAF250, T2DM, Taf200, dTAF[[II]]250, TFIID TAF250, Il22ra1 protein, CG4260, IL-22R alpha chain, cel, IL-22RA2, cell, Non-Insulin-Dependent Diabetes Mellitus, dre3, alpha 2 chain, Taf1p, Maturity Onset Diabetes Mellitus, Alpha-Adaptin, adult-onset, alpha-spectrin, Ketosis-Resistant Diabetes Mellitus, NIDDM, 1.6.2.2, dTAF250, Noninsulin-Dependent, alpha 1 subunit, Diabetes mellitus, Maturity-onset diabetes mellitus, Noninsulin Dependent Diabetes Mellitus, Stable, MODY (Maturity-onset diabetes of the young), Diabetes Mellitus, IL22RA2 protein, Ketosis-Resistant, TAF, Non Insulin Dependent, Diabetes, NADH-cytochrome b5 reductase 3 membrane-bound form, alpha chains, l(3)dre3, Adult Onset, Type 2 diabetes, IL-22BP protein, dTAF[[II]]230, TAF[[II]]250, alpha-Spectrin, IL-22 receptor-alpha 2, alpha 1 protein, 3A9, Adult-onset diabetes, Type 2 diabetes mellitus, DmelCG1977, Adult-onset diabetes mellitus, alpha 1 chain, mouse, B5R., TAF200, interleukin 22 receptor, MODY, l(3)84Ab, ham, BG:DS00004.13, interleukin-22 receptor alpha-chain, TAFII-250, TAF250/230, Cell, Noninsulin-dependent diabetes mellitus, ada, dTAF230, Adult-Onset, alphaSpec, Diaphorase-1, TAFII250, D-Ada, T2D, Adult-Onset Diabetes, p230, alpha 2 subunit, IL22RA1 protein, cg4260, Slow-Onset Diabetes Mellitus, Maturity-Onset, TAF[[II]]250/230, TFIID, MENE(2L)-A, dAP-2a, Type 2 Diabetes Mellitus Non-Insulin Dependent, Ketosis Resistant, alphaSp, spectrin, Maturity-Onset Diabetes Mellitus, IL-22R, Taf[[II]]250, l(2)06694, MENE (2L)-A, NADH-cytochrome b5 reductase 3 soluble form, Type 2 Diabetes, TAF[[II]]230, D-alphaAda, mating_type_alpha, IL-22 receptor, FCP-B, Type II Diabetes, TAF[II]250, alpha, AP-2alpha, Type 2, CG17603, Cytochrome b5 reductase, TAF[[II]], human, DmelCG4260, Noninsulin-Dependent Diabetes Mellitus, AP2, type II, DmelCG17603, non-insulin-dependent, Non-Insulin Dependent Diabetes, Taf250, l(3)62Bd, SR3-5, Bam-C, BAM, Bam, alpha mating type (yeast), l(2)SH0460, alfa-Spec, receptor, Type II, Slow-Onset, Stable Diabetes Mellitus, Spec, Maturity Onset, TAF230, TAF1T2DM - Type 2 Diabetes mellitus, Adult-Onset Diabetes Mellitus, Diabetes Type 2, type 2, alpha-Ada, d230, anon-EST:fe2E2, BamF, interleukin-22 receptor type 2, l(3)alpha-Spec, interleukin-22 receptor type 1, BamC, AP-2, Noninsulin Dependent, alpha-Spect, alpha-Spe, dTAFII250, Type 2 Diabetes Mellitus, DIABETES MELLITUS TYPE 02, EfW1, alpha-Spc, CG31654, diabetes mellitus type 2, l(2)SH2 0460, Maturity-onset diabetes, fs(3)neo61, IL-22R1, dmTAF[[II]]230, IL-22R2, alpha subunits, CG10422, rat, l(3)04276, alpha-ada, dmTAF1, Taf230, interleukin-22, Non-Insulin-Dependent, klo, Non-Insulin Dependent Diabetes Mellitus, alpha-adaptin, Maturity Onset Diabetes, alpha-Sp, non-insulin-dependent diabetes mellitus, DmelCG10422, CG1977, Slow Onset, alpha-spec, Maturity-Onset Diabetes, TAF250, T2DM, Taf200, dTAF[[II]]250, TFIID TAF250, Il22ra1 protein, CG4260, IL-22R alpha chain, cel, IL-22RA2, cell, Non-Insulin-Dependent Diabetes Mellitus, dre3, alpha 2 chain, Taf1p, Maturity Onset Diabetes Mellitus, Alpha-Adaptin, adult-onset, alpha-spectrin, Ketosis-Resistant Diabetes Mellitus, NIDDM, 1.6.2.2, dTAF250, Noninsulin-Dependent, alpha 1 subunit, Diabetes mellitus, Maturity-onset diabetes mellitus, Noninsulin Dependent Diabetes Mellitus, Stable, MODY (Maturity-onset diabetes of the young), Diabetes Mellitus, IL22RA2 protein, Ketosis-Resistant, TAF, Non Insulin Dependent, Diabetes, NADH-cytochrome b5 reductase 3 membrane-bound form, alpha chains, l(3)dre3, Adult Onset, Type 2 diabetes, IL-22BP protein, dTAF[[II]]230, TAF[[II]]250, alpha-Spectrin, IL-22 receptor-alpha 2, alpha 1 protein, 3A9, Adult-onset diabetes, Type 2 diabetes mellitus, DmelCG1977, Adult-onset diabetes mellitus, alpha 1 chain, mouse, B5R., TAF200, interleukin 22 receptor, MODY, l(3)84Ab, ham, BG:DS00004.13, interleukin-22 receptor alpha-chain, TAFII-250, TAF250/230, Cell, Noninsulin-dependent diabetes mellitus, ada, dTAF230, Adult-Onset, alphaSpec, Diaphorase-1, TAFII250, D-Ada, T2D, Adult-Onset Diabetes, p230, alpha 2 subunit, IL22RA1 protein, cg4260, Slow-Onset Diabetes Mellitus, Maturity-Onset, TAF[[II]]250/230, TFIID, MENE(2L)-A, dAP-2a, Type 2 Diabetes Mellitus Non-Insulin Dependent, Ketosis Resistant, alphaSp, spectrin, Maturity-Onset Diabetes Mellitus, IL-22R, Taf[[II]]250, l(2)06694, MENE (2L)-A, NADH-cytochrome b5 reductase 3 soluble form, Type 2 Diabetes, TAF[[II]]230, D-alphaAda, mating_type_alpha, IL-22 receptor, FCP-B, Type II Diabetes, TAF[II]250, alpha, AP-2alpha, Type 2, CG17603, Cytochrome b5 reductase, TAF[[II]], human, DmelCG4260, Noninsulin-Dependent Diabetes Mellitus, AP2, type II, DmelCG17603, non-insulin-dependent, Non-Insulin Dependent Diabetes, Taf250, l(3)62Bd, SR3-5, Bam-C, BAM, Bam, alpha mating type (yeast), l(2)SH0460, alfa-Spec, receptor, Type II, Slow-Onset, Stable Diabetes Mellitus, Spec, Maturity Onset, TAF230, TAF1falsePancreatic β-cell interleukin-22 receptor subunit alpha 1 deficiency impairs β-cell function in type 2 diabetes via cytochrome b5 reductase 3 [BKO]Pancreatic β-cell interleukin-22 receptor subunit alpha 1 deficiency impairs β-cell function in type 2 diabetes via cytochrome b5 reductase 3 [BKO]2025-09-242024-11-14PRJNA1185158GSE2816511009039675006