Regulator of G protein signaling 2 is a key regulator of pancreatic β-cell mass and function.
Regulator of G protein signaling 2 is a key regulator of pancreatic β-cell mass and function.
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DOI：
10.1038/cddis.2016.216
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发表时间：
2017-05-25
影响因子：
9
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Dong H;Zhang Y;Wang J;Kim DS;Wu H;Sjögren B;Gao W;Luttrell L;Wang H
胰腺β细胞死亡和功能障碍有助于1型和2型糖尿病的发病机制。我们的目的是研究G蛋白信号传导蛋白2（RGS 2）的调节剂，G蛋白偶联受体（GPCR）信号传导的多功能抑制剂，是否影响β细胞死亡和功能。在RGS 2敲除（RGS 2 −/−）小鼠及其野生型（RGS 2 +/+）同窝对照小鼠中测量代谢表型、β细胞分泌功能以及葡萄糖和胰岛素耐受性。通过流式细胞术、蛋白质印迹、ELISA、TUNEL染色和凋亡RT 2 profiler PCR阵列分析，在RGS 2敲低和过表达β细胞和RGS 2 −/−胰岛中评价β细胞死亡。在1日龄、4周龄和25周龄的RGS 2 −/−和RGS 2 +/+小鼠的胰腺中评价β细胞质量。我们的数据表明，当用葡萄糖或exendin-4激发时，RGS 2 −/−胰岛比RGS 2 +/+胰岛分泌更多的胰岛素。RGS 2敲减细胞对缺氧诱导的细胞死亡敏感，而RGS 2过表达细胞受到保护免于细胞死亡。胰岛中RGS 2的消耗改变了胰岛细胞凋亡相关基因的表达，与RGS 2 +/+胰岛相比，RGS 2 −/−胰岛更容易发生凋亡。最终，与25周龄的RGS 2 +/+小鼠相比，胰岛素分泌过多和β细胞凋亡增加导致RGS 2 −/−小鼠的胰腺β细胞质量减少70%。RGS 2通过调节β细胞功能和细胞凋亡在维持胰腺β细胞质量方面发挥关键作用。它可以作为一个药物靶点，帮助预防糖尿病治疗中的胰腺β细胞损失。
Pancreatic β-cell death and dysfunction contributes to the pathogenesis of both type 1 and type 2 diabetes. We aimed to examine whether the regulator of G protein signaling protein 2 (RGS2), a multifunctional inhibitor of G protein-coupled receptor (GPCR) signaling, impacts β-cell death and function. Metabolic phenotypes, β-cell secretory function, and glucose and insulin tolerance were measured in RGS2 knockout (RGS2−/−) mice and their wild-type (RGS2+/+) littermate controls. β-Cell death was evaluated in RGS2-knockdown and -overexpressing β cells and RGS2−/− islets by flow cytometry, western blot, ELISA, TUNEL staining, and apoptosis RT2 profiler PCR array analysis. β-Cell mass was evaluated in pancreases from RGS2−/− and RGS2+/+ mice at 1 day, 4 weeks, and 25 weeks of age. Our data show that RGS2−/− islets secreted more insulin than RGS2+/+ islets when challenged with glucose or exendin-4. RGS2-knockdown cells are susceptible to hypoxia induced cell death while RGS2-overexpressing cells are protected from cell death. Depletion of RGS2 in islets alters expression of apoptosis-related genes and RGS2−/− islets are prone to apoptosis compared with RGS2+/+ islets. Ultimately, excessive insulin secretion and increased β-cell apoptosis contributed to a 70% reduction in pancreatic β-cell mass in RGS2−/− mice compared with RGS2+/+ mice at 25 weeks of age. RGS2 has critical roles in maintaining pancreatic β-cell mass via modulating β-cell function and apoptosis. It may serve as a druggable target to help prevent pancreatic β-cell loss in the treatment of diabetes.
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