ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/063/SRR23649163/SRR23649163_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/071/SRR23649171/SRR23649171_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/067/SRR23649167/SRR23649167_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/057/SRR23649157/SRR23649157_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/072/SRR23649172/SRR23649172_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/068/SRR23649168/SRR23649168_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/069/SRR23649169/SRR23649169_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/059/SRR23649159/SRR23649159_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/060/SRR23649160/SRR23649160_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/060/SRR23649160/SRR23649160_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/066/SRR23649166/SRR23649166_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/072/SRR23649172/SRR23649172_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/070/SRR23649170/SRR23649170_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/061/SRR23649161/SRR23649161_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/064/SRR23649164/SRR23649164_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/058/SRR23649158/SRR23649158_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/061/SRR23649161/SRR23649161_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/057/SRR23649157/SRR23649157_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/067/SRR23649167/SRR23649167_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/069/SRR23649169/SRR23649169_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/059/SRR23649159/SRR23649159_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/066/SRR23649166/SRR23649166_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/065/SRR23649165/SRR23649165_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/062/SRR23649162/SRR23649162_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/063/SRR23649163/SRR23649163_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/070/SRR23649170/SRR23649170_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/064/SRR23649164/SRR23649164_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/068/SRR23649168/SRR23649168_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/058/SRR23649158/SRR23649158_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/062/SRR23649162/SRR23649162_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/071/SRR23649171/SRR23649171_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR236/065/SRR23649165/SRR23649165_2.fastq.gzprimaryOK200GenomicsInstitute of Diabetes and Regeneration Research, Helmholtz Zentrum München German Research Center for Environmental Healthhttps://www.ebi.ac.uk/ena/browser/view/PRJNA939837Homo sapiensBlunted first-phase insulin secretion and insulin deficiency are indicators of β-cell dysfunction and diabetes manifestation. Thus, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore β-cell function. Here, we identify the insulin inhibitory receptor (short: inceptor encoded by the gene IIR) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (iPSC)-derived islets, we show that IIR knockout (KO) results in enhanced stem cell (SC)-β-cell differentiation and survival. Strikingly, extended in vitro culture of IIR KO SC-β-cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find that inceptor localises to clathrin-coated vesicles (CCVs) close to the plasma membrane (PM) and in the trans-Golgi network (TGN), as well as in secretory granules (SGs), where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody (mAB) increases proinsulin and insulin content and improves SC-β-cell GSIS. Overall design: Stage 6 iPSC derived islet-like clusters (SC-islets) from IIR KO and WT cell lines were analyzed by scRNA-seqxref:PubMed:39587340ENAfalseInceptor binds to and directs insulin towards lysosomal degradation in beta-cellsInceptor binds to and directs insulin towards lysosomal degradation in beta-cells2025-09-242024-09-18PRJNA939837GSE226346960639587340