Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice
Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice
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DOI：
10.1038/nm1254
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发表时间：
2005-07-01
期刊：
影响因子：
82.9
通讯作者：
Brunetti, A
中科院分区：
文献类型：
--
作者：
Foti, D;Chiefari, E;Brunetti, A
2型糖尿病是一种广泛传播的疾病，影响着全球数百万人。尽管遗传和环境因素似乎起到了作用，但这种代谢紊乱的原因在很大程度上是未知的。在这里，我们报告了一种基因缺陷，该缺陷显著降低了高迁移率族A1(HMGA1)蛋白在细胞内的表达，并对四名胰岛素抵抗和2型糖尿病患者的细胞和组织中胰岛素受体的表达产生了不利影响。HMGA1蛋白在受试者细胞中的恢复表达增强了INSR基因的转录，并恢复了细胞表面胰岛素受体蛋白的表达和胰岛素结合能力。通过破坏HMGA1基因在小鼠体内诱导的HMGA1表达的丢失，显著降低了主要胰岛素作用靶点的胰岛素受体的表达，极大地削弱了胰岛素信号转导，并严重减少了胰岛素的分泌，导致了人类2型糖尿病的表型特征。
Type 2 diabetes mellitus is a widespread disease, affecting millions of people globally. Although genetics and environmental factors seem to have a role, the cause of this metabolic disorder is largely unknown. Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes.