Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI 53705, USA.
Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA.
Cell Rep. 2021 Jan 26;34(4):108690. doi: 10.1016/j.celrep.2021.108690.
Hallmarks of mature β cells are restricted proliferation and a highly energetic secretory state. Paradoxically, cyclin-dependent kinase 2 (CDK2) is synthesized throughout adulthood, its cytosolic localization raising the likelihood of cell cycle-independent functions. In the absence of any changes in β cell mass, maturity, or proliferation, genetic deletion of Cdk2 in adult β cells enhanced insulin secretion from isolated islets and improved glucose tolerance in vivo. At the single β cell level, CDK2 restricts insulin secretion by increasing K conductance, raising the set point for membrane depolarization in response to activation of the phosphoenolpyruvate (PEP) cycle with mitochondrial fuels. In parallel with reduced β cell recruitment, CDK2 restricts oxidative glucose metabolism while promoting glucose-dependent amplification of insulin secretion. This study provides evidence of essential, non-canonical functions of CDK2 in the secretory pathways of quiescent β cells.
成熟β细胞的特征是增殖受限和高度活跃的分泌状态。矛盾的是，细胞周期依赖性激酶 2（CDK2）在整个成年期都被合成，其细胞质定位增加了非细胞周期依赖性功能的可能性。在β细胞质量、成熟度或增殖没有任何变化的情况下，成年β细胞中 Cdk2 的基因缺失增强了分离胰岛中的胰岛素分泌，并改善了体内的葡萄糖耐量。在单个β细胞水平上，CDK2 通过增加 K 电导来限制胰岛素分泌，从而提高了对磷酸烯醇丙酮酸（PEP）循环与线粒体燃料激活的膜去极化的设定点。与β细胞募集减少平行的是，CDK2 限制氧化葡萄糖代谢，同时促进葡萄糖依赖性胰岛素分泌的放大。这项研究提供了 CDK2 在静止β细胞分泌途径中具有重要的、非典型功能的证据。
