Details
| Original language | English |
|---|---|
| Number of pages | 31 |
| Journal | Nature Metabolism |
| Volume | 6 |
| Publication status | Published - 25 Nov 2024 |
Abstract
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.
ASJC Scopus subject areas
- Medicine(all)
- Internal Medicine
- Medicine(all)
- Endocrinology, Diabetes and Metabolism
- Medicine(all)
- Physiology (medical)
- Biochemistry, Genetics and Molecular Biology(all)
- Cell Biology
Sustainable Development Goals
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In: Nature Metabolism, Vol. 6, 25.11.2024.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Inceptor binds to and directs insulin towards lysosomal degradation in β cells
AU - Siehler, Johanna
AU - Bilekova, Sara
AU - Chapouton, Prisca
AU - Dema, Alessandro
AU - Albanese, Pascal
AU - Tamara, Sem
AU - Jain, Chirag
AU - Sterr, Michael
AU - Enos, Stephen J.
AU - Chen, Chunguang
AU - Malhotra, Chetna
AU - Villalba, Adrian
AU - Schomann, Leopold
AU - Bhattacharya, Sreya
AU - Feng, Jin
AU - Akgün Canan, Melis
AU - Ribaudo, Federico
AU - Ansarullah,
AU - Burtscher, Ingo
AU - Ahlbrecht, Christin
AU - Plettenburg, Oliver
AU - Kurth, Thomas
AU - Scharfmann, Raphael
AU - Speier, Stephan
AU - Scheltema, Richard A.
AU - Lickert, Heiko
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024/11/25
Y1 - 2024/11/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85210440923&partnerID=8YFLogxK
U2 - 10.1038/s42255-024-01164-y
DO - 10.1038/s42255-024-01164-y
M3 - Article
AN - SCOPUS:85210440923
VL - 6
JO - Nature Metabolism
JF - Nature Metabolism
ER -