Inceptor counteracts insulin signalling in β-cells to control glycaemia

Ansarullah, Chirag Jain, Fataneh Fathi Far, Sarah Homberg, Katharina Wißmiller, Felizitas Gräfin Hahn, Aurelia Raducanu, Silvia Schirge, Michael Sterr, Sara Bilekova, Johanna Siehler, Julius Wiener, Lena Oppenländer, Amir Morshedi, Aimée Bastidas-Ponce, Gustav Collden, Martin Irmler, Johannes Beckers, Annette Feuchtinger, Michal Grzybek, Christin Ahlbrecht, Regina Feederle, Oliver Plettenburg, Timo D. Müller, Matthias Meier, Matthias H. Tschöp, Ünal Coskun and Heiko Lickert ()
Additional contact information
Ansarullah: Helmholtz Center Munich
Chirag Jain: Helmholtz Center Munich
Fataneh Fathi Far: Helmholtz Center Munich
Sarah Homberg: Helmholtz Center Munich
Katharina Wißmiller: Helmholtz Center Munich
Felizitas Gräfin Hahn: Helmholtz Center Munich
Aurelia Raducanu: Helmholtz Center Munich
Silvia Schirge: Helmholtz Center Munich
Michael Sterr: Helmholtz Center Munich
Sara Bilekova: Helmholtz Center Munich
Johanna Siehler: Helmholtz Center Munich
Julius Wiener: Helmholtz Pioneer Campus, Helmholtz Center Munich
Lena Oppenländer: Helmholtz Center Munich
Amir Morshedi: Helmholtz Center Munich
Aimée Bastidas-Ponce: Helmholtz Center Munich
Gustav Collden: Institute of Diabetes and Obesity, Helmholtz Center Munich
Martin Irmler: German Center for Diabetes Research (DZD)
Johannes Beckers: German Center for Diabetes Research (DZD)
Annette Feuchtinger: Helmholtz Center Munich
Michal Grzybek: German Center for Diabetes Research (DZD)
Christin Ahlbrecht: German Center for Diabetes Research (DZD)
Regina Feederle: Helmholtz Center Munich
Oliver Plettenburg: German Center for Diabetes Research (DZD)
Timo D. Müller: German Center for Diabetes Research (DZD)
Matthias Meier: Helmholtz Pioneer Campus, Helmholtz Center Munich
Matthias H. Tschöp: German Center for Diabetes Research (DZD)
Ünal Coskun: German Center for Diabetes Research (DZD)
Heiko Lickert: Helmholtz Center Munich

Nature, 2021, vol. 590, issue 7845, 326-331

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03225-8

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