Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes
Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes
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DOI：
10.1016/j.cell.2005.05.027
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发表时间：
2005-08-12
期刊：
影响因子：
64.5
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Gunton, JE;Kulkarni, RN;Kahn, CR
β细胞功能障碍是2型糖尿病发病机制的中心组成部分。使用寡核苷酸微阵列和实时PCR从2型糖尿病患者与正常葡萄糖耐受对照中分离的胰岛，我们确定了已知在β细胞功能中重要的基因表达的多种变化，包括HNF4 α，胰岛素受体，IRS2，Akt2和几种葡萄糖代谢途径基因表达的主要减少。转录因子ARNT的表达也降低了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，基因表达的变化与人类2型胰岛中的相似。同样，β细胞特异性ARNT敲除小鼠表现出异常的葡萄糖耐量、胰岛素分泌受损和胰岛基因表达的变化，这些变化与人类糖尿病胰岛相似。总之，这些数据表明ARNT降低和基因表达改变在人类2型糖尿病胰岛功能受损中的重要作用。
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 HNF4 alpha, 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.