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 failure^1,2,3. 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.

胰腺 β 细胞对胰岛素和胰岛素样生长因子 1 (IGF1) 的抵抗导致小鼠出现明显的糖尿病；因此，使 β 细胞对胰岛素敏感的疗法可以保护糖尿病患者免受 β 细胞衰竭^1,2,3。在这里，我们鉴定了小鼠 β 细胞中胰岛素受体 (INSR) 和 IGF1 受体 (IGF1R) 信号传导的抑制剂，我们将其命名为胰岛素抑制受体（受体；由基因Iir编码）。^{Inceptor 包含与 INSR 和 IGF1R 4}相似的胞外富含半胱氨酸结构域，以及在 IGF2 受体 (IGF2R) ⁵中也发现的甘露糖 6-磷酸受体结构域。缺乏感受器的敲除小鼠（Iir ^-/-) 表现出高胰岛素血症和低血糖的迹象，并在出生后数小时内死亡。对来自Iir ^-/-小鼠的胚胎和出生后胰腺的分子和细胞分析显示Iir ^-/-胰腺组织中 INSR-IGF1R 的激活增加，导致 β 细胞的增殖和质量增加。同样，诱导型 β 细胞特异性Iir ^-/-在成年小鼠和离体胰岛中敲除导致 INSR-IGF1R 活化增加和 β 细胞增殖增加，从而改善体内葡萄糖耐量。从机制上讲，inceptor 与 INSR-IGF1R 相互作用以促进网格蛋白介导的内吞作用，从而使受体脱敏。使用针对受体胞外结构域的单克隆抗体阻断这种物理相互作用，导致受体和 INSR 保留在质膜上，以维持 INSR-IGF1R 在 β 细胞中的激活。总之，我们的研究结果表明，受体保护产生胰岛素的 β 细胞免受组成性途径激活，并将受体确定为 INSR-IGF1R 致敏和糖尿病治疗的潜在分子靶标。