Ren Decheng, Sun Juan, Mao Liqun, Ye Honggang, Polonsky Kenneth S
Department of Medicine, The University of Chicago, Chicago, IL.
Department of Medicine, The University of Chicago, Chicago, IL
Diabetes. 2014 Oct;63(10):3378-87. doi: 10.2337/db13-1814. Epub 2014 Apr 23.
Irs2-deficient mice develop type 2-like diabetes due to a reduction in β-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cells. Insulin receptor substrate 2 (IRS2) suppression induced apoptotic cell death, which was associated with an increase in expression of the BH3-only molecule Bim. Knockdown (KD) of Bim reduced apoptotic β-cell death induced by IRS2 suppression. In Irs2-deficient mice, Bim ablation restored β-cell mass, decreased the number of TUNEL-positive cells, and restored normal glucose tolerance after glucose challenge. FoxO1 mediates Bim upregulation induced by IRS2 suppression, and FoxO1 KD partially inhibits β-cell death induced by IRS2 suppression. These results suggest that Bim plays an important role in mediating the increase in β-cell apoptosis and the reduction in β-cell mass that occurs in IRS2-deficient diabetes.
Irs2基因缺陷型小鼠由于β细胞数量减少以及胰岛无法对胰岛素抵抗作出代偿性增生反应而发展出类似2型糖尿病的症状。为了确定其分子机制，我们在小鼠MIN6胰岛素瘤细胞中敲低了Irs2基因的表达。胰岛素受体底物2（IRS2）的抑制诱导了凋亡性细胞死亡，这与仅含BH3结构域的分子Bim的表达增加有关。敲低Bim可减少由IRS2抑制诱导的凋亡性β细胞死亡。在Irs2基因缺陷型小鼠中，Bim基因缺失可恢复β细胞数量，减少TUNEL阳性细胞的数量，并在葡萄糖刺激后恢复正常的葡萄糖耐量。FoxO1介导由IRS2抑制诱导的Bim上调，并且FoxO1基因敲低可部分抑制由IRS2抑制诱导的β细胞死亡。这些结果表明，Bim在介导Irs2基因缺陷型糖尿病中发生的β细胞凋亡增加和β细胞数量减少方面发挥着重要作用。
