小柯机器人

科学家发现β细胞中的新型胰岛素信号抑制因子
2021-01-29 17:03

德国亥姆霍兹慕尼黑中心Heiko Lickert团队在β细胞中发现一种新型胰岛素信号通路的抑制因子,可控制血糖。相关论文于2021年1月27日在线发表在《自然》杂志上。

研究人员鉴定出了小鼠β细胞中胰岛素受体(INSR)和胰岛素样生长因子1(IGF1)受体(IGF1R)信号的抑制因子,并将其命名为胰岛素抑制型受体(由基因Iir编码)。该受体含有一个与INSR和IGF1R4相似的胞内半胱氨酸富集结构域,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。缺乏受体(Iir-/-)的基因敲除小鼠表现出高胰岛素血症和低血糖症的迹象,并在出生后数小时内死亡。

对Iir-/-小鼠的胚胎和产后胰腺进行分子和细胞分析表明,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,成年小鼠和离体胰岛中可诱导的β细胞特异性Iir-/-敲除导致INSR–IGF1R的激活增加和β细胞增殖的增加,从而提高了体内的葡萄糖耐受量。从机理上讲,受体与INSR–IGF1R相互作用以促进网格蛋白介导的内吞作用,使受体脱敏。

使用针对受体胞外域的单克隆抗体阻断这种物理相互作用会导致受体和INSR保留在质膜上,从而维持β细胞中INSR–IGF1R的活化。总之,这些研究结果表明,受体可以保护胰岛素生产性β细胞免受组成途径的激活,并将受体鉴定为INSR–IGF1R敏感化和糖尿病治疗的潜在分子靶标。 

据了解,胰腺β细胞对胰岛素和IGF1的抵抗会在小鼠中引起明显的糖尿病。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细胞衰竭的影响。

附:英文原文

Title: Inceptor counteracts insulin signalling in β-cells to control glycaemia

Author: Ansarullah, Chirag Jain, Fataneh Fathi Far, Sarah Homberg, Katharina Wimiller, Felizitas Grfin von Hahn, Aurelia Raducanu, Silvia Schirge, Michael Sterr, Sara Bilekova, Johanna Siehler, Julius Wiener, Lena Oppenlnder, Amir Morshedi, Aime Bastidas-Ponce, Gustav Collden, Martin Irmler, Johannes Beckers, Annette Feuchtinger, Michal Grzybek, Christin Ahlbrecht, Regina Feederle, Oliver Plettenburg, Timo D. Mller, Matthias Meier, Matthias H. Tschp, nal Coskun, Heiko Lickert

Issue&Volume: 2021-01-27

Abstract: 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 failure1,2,3. 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.

DOI: 10.1038/s41586-021-03225-8

Source: https://www.nature.com/articles/s41586-021-03225-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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