Inceptor counteracts insulin signalling in β-cells to control glycaemia

Autor: Michal Grzybek, Matthias H. Tschöp, Oliver Plettenburg, Sara Bilekova, Lena Oppenländer, Johanna Siehler, Michael Sterr, Amir Morshedi, Sarah Homberg, Timo D. Müller, Aurelia Raducanu, Katharina Wißmiller, Felizitas Gräfin von Hahn, Ansarullah, Chirag Jain, Julius Wiener, Ünal Coskun, Johannes Beckers, Heiko Lickert, Gustav Collden, Fataneh Fathi Far, Silvia Schirge, Aimée Bastidas-Ponce, Christin Ahlbrecht, Annette Feuchtinger, Matthias Meier, Martin Irmler, Regina Feederle
Rok vydání: 2021
Předmět:
Blood Glucose
Male
0301 basic medicine
medicine.medical_treatment
Golgi Apparatus
Endoplasmic Reticulum
Insulin Antagonists
Mice
0302 clinical medicine
Insulin-Secreting Cells
Insulin
Insulin-Like Growth Factor I
Receptor
Glucose tolerance test
Multidisciplinary
medicine.diagnostic_test
biology
Chemistry
Endocytosis
Neoplasm Proteins
Knockout mouse
hormones
hormone substitutes
and hormone antagonists
Signal Transduction
endocrine system
medicine.medical_specialty
030209 endocrinology & metabolism
Cell Line
03 medical and health sciences
Commentaries
Internal medicine
medicine
Animals
Humans
Cell Proliferation
Cell Size
Insulin-like growth factor 1 receptor
Growth factor
Insulin-like growth factor 2 receptor
Membrane Proteins
nutritional and metabolic diseases
Glucose Tolerance Test
Clathrin
Receptor
Insulin
Tamoxifen
Insulin receptor
030104 developmental biology
Endocrinology
Commentary
biology.protein
Endocrine Cells
Lysosomes
Zdroj: Nature 590, 326–331 (2021)
Journal of Diabetes Investigation
ISSN: 1476-4687
0028-0836
DOI: 10.1038/s41586-021-03225-8
Popis: 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. The insulin inhibitory receptor (inceptor) is identified as a negative regulator of insulin and IGF1 signalling that could be targeted for β-cell regeneration in treatments for diabetes.
Databáze: OpenAIRE
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