Xie Tao, Chen Min, Zhang Qing-Hong, Ma Zheng, Weinstein Lee S
Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19601-6. doi: 10.1073/pnas.0704796104. Epub 2007 Nov 20.
The G protein alpha-subunit G(s)alpha is required for hormone-stimulated cAMP generation. In pancreatic beta cells, G(s)alpha mediates the signaling of glucagon-like peptide 1 and other incretin hormones, which are implicated as important regulators of beta cell survival and insulin release. Studies have suggested that G(s)alpha/cAMP mediates these actions by stimulating insulin receptor substrate 2 (IRS2) expression. Mice with beta cell-specific G(s)alpha deficiency (betaGsKO) were generated by mating G(s)alpha-floxed mice to rat insulin II promoter-cre recombinase mice. betaGsKO mice had poor survival and postnatal growth with low serum insulin-like growth factor 1 levels. betaGsKO mice also developed severe hyperglycemia and glucose intolerance with severe hypoinsulinemia and reduced islet insulin content and glucose-stimulated insulin release. betaGsKO mice had markedly reduced average islet size and beta cell mass, which was partially explained by reduced beta cell size. In addition, betaGsKO mice had significantly reduced beta cell proliferation and increased beta cell apoptosis and markedly reduced expression of the cell cycle protein cyclin D2. The effects on beta cell mass and proliferation, but not apoptosis, were present from birth. Unexpectedly expression of Irs2 and the downstream gene Pdx1 were unaffected. These results show that G(s)alpha/cAMP pathways are critical regulators of beta cell function and proliferation that can work through IRS2-independent mechanisms.
G蛋白α亚基G(s)α是激素刺激产生环磷酸腺苷（cAMP）所必需的。在胰腺β细胞中，G(s)α介导胰高血糖素样肽1及其他肠促胰岛素激素的信号传导，这些激素被认为是β细胞存活和胰岛素释放的重要调节因子。研究表明，G(s)α/cAMP通过刺激胰岛素受体底物2（IRS2）的表达来介导这些作用。通过将G(s)α基因敲除小鼠与大鼠胰岛素II启动子-cre重组酶小鼠交配，培育出了β细胞特异性G(s)α缺陷小鼠（βGsKO）。βGsKO小鼠存活率低，出生后生长缓慢，血清胰岛素样生长因子1水平低。βGsKO小鼠还出现严重的高血糖和葡萄糖不耐受，伴有严重的低胰岛素血症、胰岛胰岛素含量降低以及葡萄糖刺激的胰岛素释放减少。βGsKO小鼠的平均胰岛大小和β细胞量显著减少，部分原因是β细胞大小减小。此外，βGsKO小鼠的β细胞增殖显著减少，β细胞凋亡增加，细胞周期蛋白细胞周期蛋白D2的表达明显降低。对β细胞量和增殖的影响从出生就存在，但对细胞凋亡的影响不存在。出乎意料的是，Irs2和下游基因Pdx1的表达未受影响。这些结果表明，G(s)α/cAMP途径是β细胞功能和增殖的关键调节因子，可通过不依赖IRS2的机制发挥作用。
