Deletion of CDKAL1 affects first-phase glucose stimulated insulin exocytosis

据报道，CDKAL1基因的一种变异与2型糖尿病有关。为了确定CDKAL1在β细胞中的作用，我们研究了CDKAL1基因敲除（KO）小鼠的胰岛素释放谱。CDKAL1 KO β细胞的全内反射荧光成像显示，第一阶段胰岛素分泌过程中融合事件的数量减少，胞浆内Ca2+的增加延迟和缓慢。在KO细胞中，KATP通道对葡萄糖的反应性减弱。虽然CDKAL1与CDK5RAP1是同源的，但在WT和KO的胰岛中，CDK5的活性没有差异。因此，CDKAL1通过促进KATP通道反应和随后的Ca2+通道活性，通过cdk5介导的调节以外的途径，控制β细胞的一期胰岛素胞吐。CDKAL1表达水平降低引起的这一过程中的缺陷可能会增加2型糖尿病的风险。

A variant of the CDKAL1 gene was reported to be associated with type 2 diabetes. To determine the role of CDKAL1 in beta-cells, we studied insulin release profiles in CDKAL1 gene knockout (KO) mice. Total internal reflection fluorescence imaging of CDKAL1 KO beta-cells showed that the number of fusion events during first-phase insulin secretion was reduced with delayed and slow cytosolic Ca2+ increase. The responsiveness of KATP channels to glucose was blunted in KO cells. Although CDKAL1 is homologous to CDK5RAP1, there was no difference in CDK5 activity between WT and KO islets. Thus, CDKAL1 controls first-phase insulin exocytosis in beta-cells by facilitating KATP channel responsiveness and subsequent Ca2+ channels activity through pathways other than CDK5-mediated regulation. Defects in this process caused by decreased CDKAL1 expression levels may confer an increased risk of type 2 diabetes.