Koster Joseph C, Remedi Maria S, Masia Ricard, Patton Brian, Tong Ailing, Nichols Colin G
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110, USA.
Diabetes. 2006 Nov;55(11):2957-64. doi: 10.2337/db06-0732.
Glucose metabolism in pancreatic beta-cells elevates cytoplasmic [ATP]/[ADP], causing closure of ATP-sensitive K(+) channels (K(ATP) channels), Ca(2+) entry through voltage-dependent Ca(2+) channels, and insulin release. Decreased responsiveness of K(ATP) channels to the [ATP]/[ADP] ratio should lead to decreased insulin secretion and diabetes. We generated mice expressing K(ATP) channels with reduced ATP sensitivity in their beta-cells. Previously, we described a severe diabetes, with nearly complete neonatal lethality, in four lines (A-C and E) of these mice. We have now analyzed an additional three lines (D, F, and G) in which the transgene is expressed at relatively low levels. These animals survive past weaning but are glucose intolerant and can develop severe diabetes. Despite normal islet morphology and insulin content, islets from glucose-intolerant animals exhibit reduced glucose-stimulated insulin secretion. The data demonstrate that a range of phenotypes can be expected for a reduction in ATP sensitivity of beta-cell K(ATP) channels and provide models for the corollary neonatal diabetes in humans.
胰腺β细胞中的葡萄糖代谢会提高细胞质中[ATP]/[ADP]的比值，导致ATP敏感性钾通道（KATP通道）关闭，钙离子通过电压依赖性钙通道内流，进而引发胰岛素释放。KATP通道对[ATP]/[ADP]比值的反应性降低会导致胰岛素分泌减少及糖尿病。我们培育出了在β细胞中表达ATP敏感性降低的KATP通道的小鼠。此前，我们描述过这些小鼠的四个品系（A - C和E）患有严重糖尿病，且几乎完全出现新生期致死情况。我们现在又分析了另外三个品系（D、F和G），其中转基因表达水平相对较低。这些动物能存活至断奶后，但葡萄糖耐量受损，且会发展为严重糖尿病。尽管胰岛形态和胰岛素含量正常，但葡萄糖耐量受损动物的胰岛显示出葡萄糖刺激的胰岛素分泌减少。数据表明，β细胞KATP通道的ATP敏感性降低会出现一系列表型，并为人类相应的新生儿糖尿病提供了模型。
