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Insulin and insulin-like growth factor 1 (Igf1) resistance in pancreatic β-cells causes overt diabetes, thus, therapeutic improvement may protect from β-cell failure 1-3 . Here, we identified a novel inhibitor of insulin (Insr) and Igf1 receptor (Igf1r) signalling in β-cells, which we named insulin inhibitory receptor (Inceptor; Iir). Inceptor contains an extracellular cysteine-rich domain with similarities to the Insr and Igf1r 4 and a mannose-6-phosphate domain found in the Igf2r 5 . Inceptor knock-out (KO) mice die within the first hours after birth with signs of hyperinsulinemia and hypoglycaemia. Molecular and cellular analysis of the Iir -/embryonic and postnatal pancreas showed increased Insr/Igf1r activation, resulting in augmented β-cell proliferation and mass. Similarly, inducible β-cellspecific Iir -/-KO in adult mice and in ex vivo islets led to increased Insr/Igf1r activation and β-cell proliferation, resulting in improved glucose tolerance in vivo. Mechanistically, Inceptor interacts with Insr and Igf1r to facilitate clathrinmediated endocytosis for receptor desensitisation. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of Inceptor retained Inceptor and Insr at the plasma membrane to sustain Insr/Igf1r activation in β-cells. Taken together, Inceptor shields insulin-producing β-cells from constitutive pathway activation and provides a molecular target for Insr/Igf1r sensitisation and potential diabetes therapy.

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