GGPPS-mediated Rab27A geranylgeranylation regulates β cell dysfunction during type 2 diabetes development by affecting insulin granule docked pool formation
GGPPS-mediated Rab27A geranylgeranylation regulates β cell dysfunction during type 2 diabetes development by affecting insulin granule docked pool formation
复制标题
GGPPS介导的Rab27A香叶基香叶基化通过影响胰岛素颗粒对接池的形成来调节2型糖尿病发展过程中的β细胞功能障碍
DOI：
10.1002/path.4652
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发表时间：
2016-01-01
影响因子：
7.3
通讯作者：
Li, Chao-Jun
中科院分区：
文献类型：
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作者：
Jiang, Shan;Shen, Di;Li, Chao-Jun
与β细胞功能障碍相关的第一时相胰岛素分泌丧失是2型糖尿病（T2 DM）发病的独立预测因子。在这里，我们发现，一个关键的酶参与蛋白质异戊烯化，香叶基香叶基焦磷酸合酶（GGPPS），是需要维持第一时相胰岛素分泌。在T2 DM进展期间，GGPPS在db/db小鼠的胰岛中显示出双相表达模式：GGPPS在胰岛素代偿期增加，随后在β细胞功能障碍期间减少。β细胞中的Ggpps缺失导致典型的T2 DM β细胞功能障碍，伴随葡萄糖刺激的胰岛素分泌减弱和随后的胰岛素分泌不足。然而，胰岛的数量和大小以及胰岛素的生物合成没有改变。透射电子显微镜显示细胞膜附近的胰岛素颗粒数量减少，表明停靠颗粒池形成缺陷，而储备池不受影响。Ggpps消融耗尽GGPP并损害Rab 27 A香叶基香叶基化，这是Ggpps缺失小鼠中对接池缺陷的原因。此外，GGPPS再表达或GGPP施用恢复GGPPS无效胰岛中葡萄糖刺激的胰岛素分泌。这些结果表明，GGPPS控制的蛋白质香叶基香叶基化，调节胰岛素颗粒对接池的形成，是β细胞功能和胰岛素释放在2型糖尿病的发展过程中至关重要。版权所有（c）2015大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Loss of first-phase insulin secretion associated with beta cell dysfunction is an independent predictor of type 2 diabetes mellitus (T2DM) onset. Here we found that a critical enzyme involved in protein prenylation, geranylgeranyl pyrophosphate synthase (GGPPS), is required to maintain first-phase insulin secretion. GGPPS shows a biphasic expression pattern in islets of db/db mice during the progression of T2DM: GGPPS is increased during the insulin compensatory period, followed by a decrease during beta cell dysfunction. Ggpps deletion in beta cells results in typical T2DM beta cell dysfunction, with blunted glucose-stimulated insulin secretion and consequent insulin secretion insufficiency. However, the number and size of islets and insulin biosynthesis are unaltered. Transmission electron microscopy shows a reduced number of insulin granules adjacent to the cellular membrane, suggesting a defect in docked granule pool formation, while the reserve pool is unaffected. Ggpps ablation depletes GGPP and impairs Rab27A geranylgeranylation, which is responsible for the docked pool deficiency in Ggpps-null mice. Moreover, GGPPS re-expression or GGPP administration restore glucose-stimulated insulin secretion in Ggpps-null islets. These results suggest that GGPPS-controlled protein geranylgeranylation, which regulates formation of the insulin granule docked pool, is critical for beta cell function and insulin release during the development of T2DM. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.