Biomedical Laboratory Research Service, John D. Dingell VA Medical Center and Departments of Pharmaceutical Sciences and Internal Medicine, Wayne State University, Detroit, MI 48201, USA.
Biochem Pharmacol. 2020 Oct;180:114138. doi: 10.1016/j.bcp.2020.114138. Epub 2020 Jul 4.
Recent estimates by the International Diabetes Federation suggest that the incidence of diabetes soared to an all-time high of 463 million in 2019, and the federation predicts that by 2045 the number of individuals afflicted with this disease will increase to 700 million. Therefore, efforts to understand the pathophysiology of diabetes are critical for moving toward the development of novel therapeutic strategies for this disease. Several contributors (oxidative stress, endoplasmic reticulum stress and others) have been proposed for the onset of metabolic dysfunction and demise of the islet β-cell leading to the pathogenesis of diabetes. Existing experimental evidence revealed sustained activation of PP2A and Rac1 in pancreatic β-cells exposed to metabolic stress (diabetogenic) conditions. Evidence in a variety of cell types implicates modulatory roles for specific signaling proteins (α4, SET, nm23-H1, Pak1) in the functional regulation of PP2A and Rac1. In this Commentary, I overviewed potential cross-talk between PP2A and Rac1 signaling modules in the onset of metabolic dysregulation of the islet β-cell leading to impaired glucose-stimulated insulin secretion (GSIS), loss of β-cell mass and the onset of diabetes. Potential knowledge gaps and future directions in this fertile area of islet biology are also highlighted. It is hoped that this Commentary will provide a basis for future studies toward a better understanding of roles of PP2A-Rac1 signaling module in pancreatic β-cell dysfunction, and identification of therapeutic targets for the treatment of islet β-cell dysfunction in diabetes.
国际糖尿病联合会最近的估计表明，2019 年糖尿病的发病率飙升至创纪录的 4.63 亿，该联合会预测，到 2045 年，患这种疾病的人数将增加到 7 亿。因此，努力了解糖尿病的病理生理学对于朝着开发这种疾病的新治疗策略前进至关重要。已经提出了几种促成代谢功能障碍和胰岛β细胞死亡从而导致糖尿病发病的因素（氧化应激、内质网应激等）。现有的实验证据表明，在暴露于代谢应激（致糖尿病）条件下的胰腺β细胞中，PP2A 和 Rac1 持续激活。各种细胞类型的证据表明，特定信号蛋白（α4、SET、nm23-H1、Pak1）在 PP2A 和 Rac1 的功能调节中具有调节作用。在这篇评论中，我综述了 PP2A 和 Rac1 信号模块在胰岛β细胞代谢失调发病中的潜在相互作用，导致葡萄糖刺激的胰岛素分泌（GSIS）受损、β细胞数量减少和糖尿病的发生。还强调了这个胰岛生物学肥沃领域中的潜在知识差距和未来方向。希望这篇评论能为未来的研究提供基础，以更好地了解 PP2A-Rac1 信号模块在胰腺β细胞功能障碍中的作用，并确定治疗糖尿病中胰岛β细胞功能障碍的治疗靶点。
