Zooming in on Diabetes Journal Club February 11, 2021
Zooming in on Diabetes Thursday, February 11 at 9:00 am (PST)
Presenter: Dr. Søs Skovsø, Research Associate, former Post Doctoral Research Fellow, Johnson Lab, Life Sciences Institute, University of British Columbia (Vancouver)
Title: Inceptor counteracts insulin signalling in β-cells to control glycaemia
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 failure1,2,3. 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.
Citation: Ansarullah, Jain, C., Far, F.F. et al. Inceptor counteracts insulin signalling in β-cells to control glycaemia. Nature (2021). https://doi.org/10.1038/s41586-021-03225-8
PMID: 33505018
URL link to article:
https://www.nature.com/articles/s41586-021-03225-8
“Zooming in on Diabetes” is a virtual journal club and was launched in March 2020.
It is a joint initiative across the University of British Columbia campuses including the Life Sciences Centre and the BC Children’s Hospital.
This Journal Club is designed for trainees to develop skills in critical evaluation of recent articles in the scientific literature related to diabetes research.
The intended audience are academic research trainees and faculty involved in diabetes research in British Columbia, Canada.
The journal club is held on Tuesdays and Thursdays via ZOOM.