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Deletion of CDKAL1 affects first-phase glucose stimulated insulin exocytosis

CDKAL1 缺失影响第一相葡萄糖刺激的胰岛素胞吐作用

基本信息

批准号：
23590369
负责人：
OHARA-IMAIZUMI Mica
金额：
$ 3.41万
依托单位：
Kyorin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2013
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23590369/
关键词：
インスリン分泌開口放出糖尿病 GWAS CDKAL1

项目摘要

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.

据报道，CDKAL1基因的一个变异与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 KOβ细胞的全内反射荧光成像显示，胰岛素分泌第一时相的融合事件数减少，胞内钙离子缓慢和延迟上升。在KO细胞中，KATP通道对葡萄糖的反应减弱。虽然CDKAL1与CDK5RAP1同源，但WT和KO胰岛的CDK5活性没有差异。因此，CDKAL1通过促进KATP通道的反应和随后的钙通道活性来控制β细胞的第一时相胰岛素胞吐，而不是通过CDK5介导的调节途径。CDKAL1表达水平降低导致的这一过程中的缺陷可能会增加患2型糖尿病的风险。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insulin homeostasis through zinc-mediated pancreas-to-liver metabolic communication.

通过锌介导的胰腺-肝脏代谢通讯实现胰岛素稳态。

DOI：
发表时间：
2013
期刊：
J Clin Invest.
影响因子：
0
作者：
Tamaki;M.;Fujitani;Y;Uchida;T.;Tamura;Y.;Takeno;K.;Kawaguchi;M.;Watanabe;T.;Hara;A.;Ogihara;T.;Shimizu;T.;Mita;T.;Hirose;T.;Ohara-Imaizumi;M.;Abe;T.;Kiyonari;H.;Hojyo;S.;Fukada;T.;Nagamatsu;S.;Hirano;T.;Kawamori;R.
通讯作者：
R.

Acute inhibition of PI3K-PDK1-Akt pathway potentiates insulin secretion through upregulation of newcomer granule fusions in pancreatic beta-cells.

PI3K-PDK1-Akt 通路的急性抑制可通过上调胰腺 β 细胞中的新颗粒融合来增强胰岛素分泌。