Lupse Blaz, Heise Nick, Maedler Kathrin, Ardestani Amin
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Cell Death Discov. 2022 Feb 8;8(1):57. doi: 10.1038/s41420-022-00853-5.
The Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs) are novel therapeutic targets for the restoration of β-cell survival and function in diabetes. Their upregulation and activation in β-cells under conditions of both type 1 and type 2 diabetes directly correlates with β-cell failure; β-cell death and loss of insulin secretory function through disturbance of cell survival control mechanisms. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1 constituting a regulatory triangle loop to control β-cell apoptosis. PHLPP1 deletion in severely diabetic leptin receptor-deficient db/db mice restored normoglycemia and β-cell area through increased β-cell proliferation and reduced β-cell apoptosis. The beneficial effects of PHLPP1 deficiency in a severe mouse model of obesity and diabetes make PHLPP a new target for β-cell-directed diabetes therapy.
普列克底物蛋白同源结构域富含亮氨酸重复序列蛋白磷酸酶（PHLPPs）是恢复糖尿病患者β细胞存活和功能的新型治疗靶点。在1型和2型糖尿病条件下，它们在β细胞中的上调和激活与β细胞功能衰竭直接相关；β细胞死亡以及通过细胞存活控制机制紊乱导致胰岛素分泌功能丧失。PHLPPs直接使β细胞存活依赖激酶AKT和MST1去磷酸化并调节其活性，构成一个调控三角环来控制β细胞凋亡。在严重糖尿病的瘦素受体缺陷db/db小鼠中，PHLPP1缺失通过增加β细胞增殖和减少β细胞凋亡恢复了正常血糖和β细胞面积。PHLPP1缺陷在肥胖和糖尿病严重小鼠模型中的有益作用使PHLPP成为β细胞定向糖尿病治疗的新靶点。
