Escribano Oscar, Gómez-Hernández Almudena, Díaz-Castroverde Sabela, Nevado Carmen, García Gema, Otero Yolanda F, Perdomo Liliana, Beneit Nuria, Benito Manuel
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
Mol Cell Endocrinol. 2015 Jul 5;409:82-91. doi: 10.1016/j.mce.2015.03.008. Epub 2015 Mar 19.
The main compensatory response to insulin resistance is the pancreatic beta cell hyperplasia to account for increased insulin secretion. In fact, in a previous work we proposed a liver-pancreas endocrine axis with IGF-I (insulin-like growth factor type I) secreted by the liver acting on IRA insulin receptor in beta cells from iLIRKO mice (inducible Liver Insulin Receptor KnockOut) that showed a high IRA/IRB ratio. However, the role of insulin receptor isoforms in the IGF-I-induced beta cell proliferation as well as the underlying molecular mechanisms remain poorly understood. For this purpose, we have used four immortalized mouse beta cell lines: bearing IR (IRLoxP), lacking IR (IRKO), expressing exclusively IRA (IRA), or alternatively expressing IRB (IRB). Pancreatic beta cell proliferation studies showed that IRA cells are more sensitive than those expressing IRB to the mitogenic response induced by IGF-I, acting through the pathway IRA/IRS-1/2/αp85/Akt/mTORC1/p70S6K. More importantly, IRA beta cells, but not IRB, showed an increased glucose uptake as compared with IRLoxP cells, this effect being likely owing to an enhanced association between Glut-1 and Glut-2 with IRA. Overall, our results strongly suggest a prevalent role of IRA in glucose availability and IGF-I-induced beta cell proliferation mainly through mTORC1. These results could explain, at least partially, the role played by the liver-secreted IGF-I in the compensatory beta cell hyperplasia observed in response to severe hepatic insulin resistance in iLIRKO mice.
对胰岛素抵抗的主要代偿反应是胰腺β细胞增生，以增加胰岛素分泌。事实上，在之前的一项研究中，我们提出了一种肝-胰腺内分泌轴，即肝脏分泌的IGF-I（胰岛素样生长因子I型）作用于iLIRKO小鼠（诱导性肝脏胰岛素受体敲除小鼠）β细胞中的IRA胰岛素受体，这些小鼠表现出较高的IRA/IRB比率。然而，胰岛素受体亚型在IGF-I诱导的β细胞增殖中的作用以及潜在的分子机制仍知之甚少。为此，我们使用了四种永生化小鼠β细胞系：携带IR（IRLoxP）、缺乏IR（IRKO）、仅表达IRA（IRA）或表达IRB（IRB）。胰腺β细胞增殖研究表明，IRA细胞比表达IRB的细胞对IGF-I诱导的促有丝分裂反应更敏感，通过IRA/IRS-1/2/αp85/Akt/mTORC1/p70S6K途径发挥作用。更重要的是，与IRLoxP细胞相比，IRAβ细胞而非IRB细胞的葡萄糖摄取增加，这种效应可能是由于Glut-1和Glut-2与IRA之间的结合增强。总体而言，我们的结果强烈表明IRA在葡萄糖供应和IGF-I诱导的β细胞增殖中起主要作用，主要通过mTORC1。这些结果至少可以部分解释肝脏分泌的IGF-I在iLIRKO小鼠中对严重肝脏胰岛素抵抗所观察到的代偿性β细胞增生中所起的作用。
