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.

Objective Hundreds of missense mutations in the coding region of PDX1 exist; however, if these mutations predispose to diabetes mellitus is unknown. Methods In this study, we screened a large cohort of subjects with increased risk for diabetes and identified two subjects with impaired glucose tolerance carrying common, heterozygous, missense mutations in the PDX1 coding region leading to single amino acid exchanges (P33T, C18R) in its transactivation domain. We generated iPSCs from patients with heterozygous PDX1 P33T/+ , PDX1 C18R/+ mutations and engineered isogenic cell lines carrying homozygous PDX1 P33T/P33T , PDX1 C18R/C18R mutations and a heterozygous PDX1 loss-of-function mutation ( PDX1 +/− ). Results Using an in vitro β-cell differentiation protocol, we demonstrated that both, heterozygous PDX1 P33T/+ , PDX1 C18R/+ and homozygous PDX1 P33T/P33T , PDX1 C18R/C18R mutations impair β-cell differentiation and function. Furthermore, PDX1 +/− and PDX1 P33T/P33T mutations reduced differentiation efficiency of pancreatic progenitors (PPs), due to downregulation of PDX1-bound genes, including transcription factors MNX1 and PDX1 as well as insulin resistance gene CES1 . Additionally, both PDX1 P33T/+ and PDX1 P33T/P33T mutations in PPs reduced the expression of PDX1-bound genes including the long-noncoding RNA, MEG3 and the imprinted gene NNAT , both involved in insulin synthesis and secretion. Conclusions Our results reveal mechanistic details of how common coding mutations in PDX1 impair human pancreatic endocrine lineage formation and β-cell function and contribute to the predisposition for diabetes.

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