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Inceptor counteracts insulin signalling in β-cells to control glycaemia.

Nature 590, 326–331 (2021)
Publ. Version/Full Text DOI
Open Access Green: Postprint online available 09/2021
Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic β-cells causes overt diabetes in mice; thus, therapies that sensitize β-cells to insulin may protect patients with diabetes against β-cell failure1–3. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse β-cells, which we name the insulin inhibitory receptor (inceptor; encoded by the gene Iir). Inceptor contains an extracellular cysteine-rich domain with similarities to INSR and IGF1R4, and a mannose 6-phosphate receptor domain that is also found in the IGF2 receptor (IGF2R)5. Knockout mice that lack inceptor (Iir−/−) exhibit signs of hyperinsulinaemia and hypoglycaemia, and die within a few hours of birth. Molecular and cellular analyses of embryonic and postnatal pancreases from Iir−/− mice showed an increase in the activation of INSR–IGF1R in Iir−/− pancreatic tissue, resulting in an increase in the proliferation and mass of β-cells. Similarly, inducible β-cell-specific Iir−/− knockout in adult mice and in ex vivo islets led to an increase in the activation of INSR–IGF1R and increased proliferation of β-cells, resulting in improved glucose tolerance in vivo. Mechanistically, inceptor interacts with INSR–IGF1R to facilitate clathrin-mediated endocytosis for receptor desensitization. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of inceptor resulted in the retention of inceptor and INSR at the plasma membrane to sustain the activation of INSR–IGF1R in β-cells. Together, our findings show that inceptor shields insulin-producing β-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR–IGF1R sensitization and diabetes therapy.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Receptor; Hyperinsulinemia; Kiaa1324
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 590, Issue: , Pages: 326–331 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Regeneration Research (IDR)
Helmholtz Pioneer Campus (HPC)
Institute of Diabetes and Obesity (IDO)
Institute of Experimental Genetics (IEG)
Research Unit Analytical Pathology (AAP)
Institute for Pancreatic Beta Cell Research (IPI)
Institute of Medicinal Chemistry (IMC)
Monoclonal Antibody (IDO-MAB)
Grants Hans-Seidl-Stiftung e.V.
German Center for Diabetes Research (DZD e.V.)
German Research Foundation
Helmholtz Portfolio Theme 'Metabolic Dysfunction and Common Disease'
Helmholtz Society
Helmholtz Future Topic 'Aging and Metabolic programming' (AMPro)