Deletion of CDKAL1 affects first-phase glucose stimulated insulin exocytosis

据报道，CDKAL1基因的变体与2型糖尿病相关。为了确定CDKAL1在β细胞中的作用，我们研究了CDKAL1基因敲除（KO）小鼠的胰岛素释放曲线。CDKAL1 KO β细胞的全内反射荧光成像显示，第一时相胰岛素分泌期间融合事件的数量随着延迟和缓慢的胞质Ca2+增加而减少。KO细胞KATP通道对葡萄糖的反应性减弱。尽管CDKAL 1与CDK5RAP 1同源，但WT和KO胰岛之间的CDK5活性没有差异。因此，CDKAL 1通过促进KATP通道反应性和随后的Ca 2+通道活性（通过CDK 5介导的调节以外的途径）来控制β细胞中的第一时相胰岛素胞吐。由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.