Fatrai Szabolcs, Elghazi Lynda, Balcazar Norman, Cras-Méneur Corentin, Krits Irina, Kiyokawa Hiroaki, Bernal-Mizrachi Ernesto
Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Diabetes. 2006 Feb;55(2):318-25. doi: 10.2337/diabetes.55.02.06.db05-0757.
Proliferation is the major component for maintenance of beta-cell mass in adult animals. Activation of phosphoinositide 3-kinase/Akt-kinase pathway is a critical regulator of beta-cell mass. Pancreatic beta-cell overexpression of constitutively active Akt in mice (caAkt(Tg)) resulted in marked expansion of beta-cell mass by increase in beta-cell proliferation and size. The current studies provide new insights into the molecular mechanisms involved in beta-cell proliferation by Akt. Proliferation of beta-cells in caAkt(Tg) was associated with increased cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 (cdk4) activity. To determine the role of cdk4 in beta-cell proliferation induced by Akt, we generated caAkt(Tg) mice that were homozygous, heterozygous, or nullizygous for cdk4. The results of these studies showed that deletion of one cdk4 allele significantly reduced beta-cell expansion in caAkt(Tg) mice by decreased proliferation. CaAkt(Tg) mice deficient in cdk4 developed beta-cell failure and diabetes. These experiments suggest that Akt induces beta-cell proliferation in a cdk4-dependent manner by regulation of cyclin D1, cyclin D2, and p21 levels. These data also indicate that alteration in levels of these cell cycle components could affect the maintenance of beta-cell mass in basal states and the adaptation of beta-cells to pathological states resulting in diabetes.
增殖是成年动物维持β细胞数量的主要组成部分。磷酸肌醇3激酶/蛋白激酶B（Akt）信号通路的激活是β细胞数量的关键调节因子。在小鼠中胰腺β细胞过表达组成型活性Akt（caAkt转基因小鼠），通过增加β细胞增殖和细胞大小，导致β细胞数量显著增加。目前的研究为Akt参与β细胞增殖的分子机制提供了新的见解。caAkt转基因小鼠中β细胞的增殖与细胞周期蛋白D1、细胞周期蛋白D2和p21水平以及细胞周期蛋白依赖性激酶4（cdk4）活性增加有关。为了确定cdk4在Akt诱导的β细胞增殖中的作用，我们构建了cdk4基因纯合、杂合或缺失的caAkt转基因小鼠。这些研究结果表明，缺失一个cdk4等位基因会通过减少增殖显著降低caAkt转基因小鼠的β细胞扩增。缺乏cdk4的caAkt转基因小鼠会出现β细胞功能衰竭和糖尿病。这些实验表明，Akt通过调节细胞周期蛋白D1、细胞周期蛋白D2和p21水平，以cdk4依赖的方式诱导β细胞增殖。这些数据还表明，这些细胞周期成分水平的改变可能会影响基础状态下β细胞数量的维持以及β细胞对导致糖尿病的病理状态的适应性。
