Foti Daniela, Chiefari Eusebio, Fedele Monica, Iuliano Rodolfo, Brunetti Leonardo, Paonessa Francesco, Manfioletti Guidalberto, Barbetti Fabrizio, Brunetti Arturo, Croce Carlo M, Fusco Alfredo, Brunetti Antonio
Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università di Catanzaro Magna Graecia, via T. Campanella 115, 88100 Catanzaro, Italy.
Nat Med. 2005 Jul;11(7):765-73. doi: 10.1038/nm1254. Epub 2005 May 29.
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.
2型糖尿病是一种广泛传播的疾病，全球数百万人受其影响。尽管遗传因素和环境因素似乎起到一定作用，但这种代谢紊乱疾病的病因在很大程度上仍不明确。在此，我们报告了一个基因缺陷，该缺陷显著降低了高迁移率族蛋白A1（HMGA1）在细胞内的表达，并对来自四名胰岛素抵抗和2型糖尿病患者的细胞及组织中的胰岛素受体表达产生不利影响。恢复患者细胞中HMGA1蛋白的表达可增强胰岛素受体（INSR）基因转录，并恢复细胞表面胰岛素受体蛋白的表达及胰岛素结合能力。通过破坏Hmga1基因在小鼠中诱导Hmga1表达缺失，可显著降低胰岛素作用主要靶点中的胰岛素受体表达，极大损害胰岛素信号传导，并严重减少胰岛素分泌，从而导致具有人类2型糖尿病特征的表型。
