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ARNT/HIF1β缺失介导2型糖尿病患者基因表达改变及胰岛功能障碍。

Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes.

作者信息

Gunton Jenny E, Kulkarni Rohit N, Yim SunHee, Okada Terumasa, Hawthorne Wayne J, Tseng Yu-Hua, Roberson Russell S, Ricordi Camillo, O'Connell Philip J, Gonzalez Frank J, Kahn C Ronald

机构信息

Joslin Diabetes Center and Harvard Medical School, 1 Joslin Place, Boston, Massachusetts 02215, USA.

出版信息

Cell. 2005 Aug 12;122(3):337-49. doi: 10.1016/j.cell.2005.05.027.

Abstract

beta cell dysfunction is a central component of the pathogenesis of type 2 diabetes. Using oligonucleotide microarrays and real-time PCR of pancreatic islets isolated from humans with type 2 diabetes versus normal glucose-tolerant controls, we identified multiple changes in expression of genes known to be important in beta cell function, including major decreases in expression of HNF4alpha, insulin receptor, IRS2, Akt2, and several glucose-metabolic-pathway genes. There was also a 90% decrease in expression of the transcription factor ARNT. Reducing ARNT levels in Min6 cells with small interfering RNA (siRNA) resulted in markedly impaired glucose-stimulated insulin release and changes in gene expression similar to those in human type 2 islets. Likewise, beta cell-specific ARNT knockout mice exhibited abnormal glucose tolerance, impaired insulin secretion, and changes in islet gene expression that mimicked those in human diabetic islets. Together, these data suggest an important role for decreased ARNT and altered gene expression in the impaired islet function of human type 2 diabetes.

摘要

β细胞功能障碍是2型糖尿病发病机制的核心组成部分。通过对从2型糖尿病患者与糖耐量正常对照者分离出的胰岛进行寡核苷酸微阵列和实时PCR分析,我们确定了已知对β细胞功能重要的基因表达的多种变化,包括肝细胞核因子4α(HNF4α)、胰岛素受体、胰岛素受体底物2(IRS2)、蛋白激酶B2(Akt2)以及几个糖代谢途径基因的表达大幅下降。转录因子芳香烃受体核转运蛋白(ARNT)的表达也下降了90%。用小干扰RNA(siRNA)降低Min6细胞中的ARNT水平导致葡萄糖刺激的胰岛素释放明显受损,且基因表达变化类似于人类2型胰岛中的变化。同样,β细胞特异性ARNT基因敲除小鼠表现出异常的葡萄糖耐量、受损的胰岛素分泌以及胰岛基因表达变化,这些变化与人类糖尿病胰岛中的变化相似。总之,这些数据表明ARNT减少和基因表达改变在人类2型糖尿病受损胰岛功能中起重要作用。

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