Pancreatic β-cells produce insulin, and these cells are also responsive to insulin. Mice with β-cells that lack the insulin receptor (INSR) or are resistant to insulin develop a diabetes-like condition, and similar observations have been made in patients. Ansarullah and colleagues have now found a negative regulator of INSR, endosome/lysosome-associated apoptosis and autophagy regulator 1 (ELAPOR1), which they renamed inceptor, that is found on β-cells and reduces INSR signalling. Mice lacking inceptor on β-cells had improved glucose tolerance. In cultured cells, preventing the interaction between inceptor and INSR kept INSR on the surface and sustained insulin signalling.

Insulin causes β-cells to proliferate, which enables more insulin production. Ansarullah and colleagues hypothesized that mechanisms must therefore have evolved to prevent a positive feedback loop that would lead to uncontrolled β-cell growth. To identify potential regulators, they looked for mRNAs that were expressed at high levels in mice at embryonic day 14.5, when the peak number of β-cells is produced. They identified an mRNA, similar to EIG121 in humans, that was highly upregulated and encoded a protein with domains similar to INSR, insulin-like growth factor receptor 1 (IGF1R) and IGF2R.

The authors then generated mice deficient for Iir (also known as Elapor1), the mouse homologue of EIG121, which encodes inceptor. These mice had increased β-cell mass and died within 5 hours of birth, with low levels of glucose and high levels of insulin in the blood. Glucose injections could prevent death in 50% of pups, suggesting that overproduction of insulin could be responsible for the deaths.

Inducible deletion of Iir specifically in β-cells in adult mice improved glucose tolerance, and these mice had increased insulin secretion after glucose injection. The proliferation of β-cells was also higher in these mice. In Iir^−/− β-cells cultured ex vivo, INSR–IGF1R signalling was increased in response to insulin.

INSR, IGF1R and IGF2R homodimers and heterodimers rapidly internalize following ligand engagement. Inceptor contains a transmembrane domain, extracellular domains that are similar to those found in INSR, and a binding motif for the AP2 complex, which controls clathrin-mediated endocytosis, suggesting that this protein could heterodimerize with INSR and IGFR to control their internalization and resulting signalling events. Confocal microscopy studies demonstrated that inceptor is found at the plasma membrane in small quantities and at higher levels in endosomes and components of the trans-Golgi network, which is used for receptor recycling.

The authors hypothesized that inceptor binds to INSR and IGF1R and promotes their clathrin-mediated endocytosis, thereby reducing insulin signalling. Indeed, Iir^−/− β-cells internalized less labelled insulin than wild-type β-cells. Inceptor co-immunoprecipitated with INSR and IGF1R in β-cells from wild-type mice or cell lines, and also with components of the AP2 complex.

To disrupt the interaction between inceptor and INSR or IGF1R, the investigators raised a monoclonal antibody against the extracellular portion of the molecule. This antibody delayed internalization of INSR and increased signalling from INSR or IGF1R, as measured by receptor phosphorylation, in mouse and human β-cells.

This anti-inceptor antibody is suitable for in vivo studies, and the authors are now using mouse models of diabetes to investigate whether this antibody could be therapeutically useful.

This work highlights the importance of β-cell homeostasis in diabetes, and the importance of clathrin-mediated endocytosis in insulin signalling. In addition, it has identified inceptor as a potential novel therapeutic target for the treatment of diabetes.