Inceptor counteracts insulin signalling in β-cells to control glycaemia
Inceptor counteracts insulin signalling in β-cells to control glycaemia
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DOI：
10.1038/s41586-021-03225-8
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发表时间：
2021-01-27
期刊：
影响因子：
64.8
通讯作者：
Lickert, Heiko
中科院分区：
文献类型：
--
作者：
Ansarullah;Jain, Chirag;Lickert, Heiko
胰腺细胞对胰岛素和胰岛素样生长因子1 （IGF1）的抵抗导致小鼠显性糖尿病；因此，使β细胞对胰岛素敏感的治疗可以保护糖尿病患者免受β细胞衰竭（1-3）。在这里，我们在小鼠β细胞中发现了胰岛素受体（INSR）和IGF1受体（IGF1R）信号的抑制剂，我们将其命名为胰岛素抑制受体（受体，由基因Iir编码）。受体包含一个与INSR和IGF1R相似的细胞外富含半胱氨酸的结构域(4)，以及一个在IGF2受体（IGF2R）中也发现的甘露糖6-磷酸受体结构域(5)。缺乏受体（Iir -/-）的敲除小鼠表现出高胰岛素血症和低血糖的症状，并在出生后几小时内死亡。对Iir（-/-）小鼠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，在成年小鼠和离体胰岛中诱导β细胞特异性Iir（-/-）敲除可导致INSR-IGF1R激活增加和β细胞增殖增加，从而改善体内葡萄糖耐量。从机制上讲，受体与INSR-IGF1R相互作用，促进网格蛋白介导的内吞作用，实现受体脱敏。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在质膜上的保留，以维持β细胞中INSR- igf1r的激活。总之，我们的研究结果表明，受体可以保护产生胰岛素的β细胞免受构成途径激活，并确定受体是INSR-IGF1R致敏和糖尿病治疗的潜在分子靶点。
Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic beta-cells causes overt diabetes in mice; thus, therapies that sensitize beta-cells to insulin may protect patients with diabetes against beta-cell failure(1-3). Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse beta-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 IGF1R(4), 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 beta-cells. Similarly, inducible beta-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 beta-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 beta-cells. Together, our findings show that inceptor shields insulin-producing beta-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR-IGF1R sensitization and diabetes therapy.