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Siehler, J. ; Bilekova, S. ; Chapouton, P. ; Dema, A. ; Albanese, P.* ; Tamara, S.* ; Jain, C. ; Sterr, M. ; Enos, S.J. ; Chen, C. ; Malhotra, C. ; Villalba, A.* ; Schomann, L. ; Bhattacharya, S. ; Feng, J. ; Akgün, M. ; Ribaudo, F. ; Ansarullah ; Burtscher, I. ; Ahlbrecht, C. ; Plettenburg, O. ; Kurth, T.* ; Scharfmann, R.* ; Speier, S. ; Scheltema, R.A.* ; Lickert, H.

Inceptor binds to and directs insulin towards lysosomal degradation in β cells.

Nat. Metab. 6, 2374–2390 (2024)
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Blunted first-phase insulin secretion and insulin deficiency are indicators of β cell dysfunction and diabetes manifestation. Therefore, 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 (inceptor; encoded by the gene IIR/ELAPOR1) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (SC)-derived islets, we show that IIR knockout (KO) results in enhanced 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 localizes to clathrin-coated vesicles close to the plasma membrane and in the trans-Golgi network as well as in secretory granules, where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody increases proinsulin and insulin content and improves SC β cell GSIS. Altogether, our findings reveal the basic mechanisms of β cell insulin turnover and identify inceptor as an insulin degradation receptor.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mannose 6-phosphate Receptors; Regulated Secretory Pathway; Carboxypeptidase E; Autophagy; Proinsulin; Granules; Identification
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Journal Nature metabolism
Quellenangaben Volume: 6, Issue: 12, Pages: 2374–2390 Article Number: , Supplement: ,
Publisher Springer
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Regeneration Research (IDR)
Institute of Pancreatic Islet Research (IPI)
Institute of Medicinal Chemistry (IMC)
POF-Topic(s) 30201 - Metabolic Health
90000 - German Center for Diabetes Research
30203 - Molecular Targets and Therapies
Research field(s) Helmholtz Diabetes Center
Enabling and Novel Technologies
PSP Element(s) G-502300-001
G-501900-231
G-502301-001
G-502600-005
G-506300-001
Grants Marie Curie Actions (MSCA)
Helmholtz Future Topic 'Aging and Metabolic programming' (AMPro)
Helmholtz Society
Helmholtz Portfolio Theme 'Metabolic Dysfunction and Common Disease'
German Research Foundation
German Center for Diabetes Research (DZD)
European Research Council
NWO TA grant
European Union Horizon 2020 programme INFRAIA project Epic-XS
Helmholtz Zentrum Munchen Deutsches Forschungszentrum fur Gesundheit und Umwelt (GmbH)
European Union
DOI 10.1038/s42255-024-01164-y
WOS ID 001414003500001
Scopus ID 85210440923
PubMed ID 39587340
Erfassungsdatum 2024-12-03
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