• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Inceptor counteracts insulin signalling in β-cells to control glycaemia
【24h】

Inceptor counteracts insulin signalling in β-cells to control glycaemia

机译：Inclever抵消β-细胞中的胰岛素信号传导控制糖血症

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

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~(1-3). 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 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 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.
机译：胰腺β细胞中胰岛素和胰岛素样生长因子1（IGF1）导致小鼠的明显糖尿病;因此，使β细胞对胰岛素感染的疗法可以保护患有糖尿病的患者免受β细胞衰竭〜（1-3）。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，我们命名胰岛素抑制剂（INCENTOR;由基因IIR编码）。 Incleter含有细胞外半胱氨酸的域，其与INSR和IGF1R〜（4）的相似，以及在IGF2受体（IGF2R）〜（5）中也发现的甘露糖6-磷酸受体结构域。缺乏从始体（IIR〜（ - / - ））表现出高胰岛素血症和低血糖症的迹象，并且在几小时内死亡。来自IIR〜（/ - / - ）小鼠的胚胎和产后胰腺的分子和细胞分析表明IIR〜（/ - ）胰组织中INSR-IGF1R的激活增加，导致β的增殖和质量增加-细胞。类似地，成年小鼠和在前体内胰岛中的诱导β-细胞特异性IIR〜（ - / - ）敲除导致INSR-IGF1R的激活和β-细胞增殖增加的增加，导致体内改善葡萄糖耐量。机械地，Incleventor与Insr-IGF1R相互作用，以促进Clathrin介导的因子脱敏的内吞作用。使用针对患者的细胞外结构域的单克隆抗体阻断这种物理相互作用导致在质膜上保持活泼和INSR，以维持β细胞中INSR-IGF1R的活化。我们的研究结果表明，从组成型途径激活的人们屏蔽了生成胰岛素的β细胞，并将Inclever识别为Insr-IGF1R致敏和糖尿病治疗的潜在分子靶标。

著录项

  • 来源
    《Nature》 |2021年第7845期|326-331|共6页
  • 作者

    Chirag Jain; Fataneh Fathi Far; Sarah Homberg; Katharina Wißmiller; Felizitas Gräfin von Hahn; Aurelia Raducanu; Silvia Schirge; Michael Sterr; Sara Bilekova; Johanna Siehler; Julius Wiener; Lena Oppenländer; Amir Morshedi; Aimée Bastidas-Ponce; Gustav Collden; Martin Irmler; Johannes Beckers; Annette Feuchtinger; Michal Grzybek; Christin Ahlbrecht; Regina Feederle; Oliver Plettenburg; Timo D Müller; Matthias Meier; Matthias H Tschöp; Ünal Coskun; Heiko Lickert;

  • 作者单位

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|German Center for Diabetes Research (DZD) Neuherberg Germany;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|School of Medicine Technical University of Munich;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|School of Medicine Technical University of Munich;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|School of Medicine Technical University of Munich;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|School of Medicine Technical University of Munich;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|German Center for Diabetes Research (DZD) Neuherberg Germany;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|German Center for Diabetes Research (DZD) Neuherberg Germany;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|German Center for Diabetes Research (DZD) Neuherberg Germany|School of Medicine Technical University of Munich;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|School of Medicine Technical University of Munich;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|School of Medicine Technical University of Munich;

    Helmholtz Pioneer Campus Helmholtz Center Munich Neuherberg Germany|Department of Microsystems Engineering (IMTEK) University of Freiburg;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|School of Medicine Technical University of Munich;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|German Center for Diabetes Research (DZD) Neuherberg Germany|School of Medicine Technical University of Munich;

    Institute of Diabetes and Obesity Helmholtz Center Munich Neuherberg;

    German Center for Diabetes Research (DZD) Neuherberg Germany|Institute of Experimental Genetics Helmholtz Center Munich Neuherberg Germany;

    German Center for Diabetes Research (DZD) Neuherberg Germany|Institute of Experimental Genetics Helmholtz Center Munich Neuherberg Germany| School of Life Sciences Weihenstephan Technical University of Munich;

    Core Facility Pathology and Tissue Analytics Helmholtz Center Munich Neuherberg;

    German Center for Diabetes Research (DZD) Neuherberg Germany|Paul Langerhans Institute Dresden of Helmholtz Center Munich Dresden University of Technology;

    German Center for Diabetes Research (DZD) Neuherberg Germany|Institute for Medicinal Chemistry Helmholtz Center Munich Neuherberg Germany|Institute of Organic Chemistry Center of Biomolecular Research Leibniz University Hannover;

    Monoclonal Antibody Core Facility Helmholtz Center Munich Neuherberg;

    German Center for Diabetes Research (DZD) Neuherberg Germany|Institute for Medicinal Chemistry Helmholtz Center Munich Neuherberg Germany|Institute of Organic Chemistry Center of Biomolecular Research Leibniz University Hannover;

    German Center for Diabetes Research (DZD) Neuherberg Germany|Institute of Diabetes and Obesity Helmholtz Center Munich Neuherberg Germany;

    Helmholtz Pioneer Campus Helmholtz Center Munich Neuherberg Germany|Department of Microsystems Engineering (IMTEK) University of Freiburg;

    German Center for Diabetes Research (DZD) Neuherberg Germany|School of Medicine Technical University of Munich|Institute of Diabetes and Obesity Helmholtz Center Munich Neuherberg Germany;

    German Center for Diabetes Research (DZD) Neuherberg Germany|Department of Microsystems Engineering (IMTEK) University of Freiburg;

    Institute of Diabetes and Regeneration Research Helmholtz Center Munich Neuherberg Germany|German Center for Diabetes Research (DZD) Neuherberg Germany|School of Medicine Technical University of Munich;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号