Glucagon-Like Peptide 1 Stimulates Insulin Secretion via Inhibiting RhoA/ROCK Signaling and Disassembling Glucotoxicity-Induced Stress Fibers
Glucagon-Like Peptide 1 Stimulates Insulin Secretion via Inhibiting RhoA/ROCK Signaling and Disassembling Glucotoxicity-Induced Stress Fibers
复制标题
胰高血糖素样肽 1 通过抑制 RhoA/ROCK 信号传导和分解糖毒性诱导的应力纤维来刺激胰岛素分泌
DOI：
10.1210/en.2014-1314
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发表时间：
2014-12-01
期刊：
影响因子：
4.8
通讯作者：
Ma, Xiaosong
中科院分区：
文献类型：
--
作者：
Kong, Xiangchen;Yan, Dan;Ma, Xiaosong
慢性高血糖导致以葡萄糖刺激的胰岛素分泌(GSIS)减少为特征的胰岛β细胞功能障碍，但涉及的确切细胞过程在很大程度上尚不清楚。在这里，我们表明，与低糖培养的胰岛β细胞相比，长期暴露在高糖水平下的胰岛β细胞显示出大量的应激纤维。高糖状态下的β细胞对葡萄糖诱导的肌动蛋白细胞骨架重塑和胰岛素分泌是不敏感的。重要的是，细胞松弛素B或黑曲霉毒素B的F-肌动蛋白解聚恢复了糖毒性减弱的GSIS。糖毒性对增加应力纤维和降低血糖抑制指数的影响可被Rho相关蛋白(ROCK)特异性抑制剂Y-27632逆转，Y-100可导致肌动蛋白解聚和血糖指数升高。值得注意的是，胰升糖素样肽-1-(7-36)酰胺(GLP-1)，一种在正常和高血糖条件下都能刺激GSIS的多肽激素，也逆转了糖毒性引起的应激纤维增加和GSIS减少。此外，GLP-1还可抑制糖毒诱导的RhoA/ROCK的激活，从而导致肌动蛋白解聚和GSIS的增强。此外，GLP-1的这种作用可被cAMP增效剂Forsklin和3-异丁基-1-甲基黄嘌呤以及蛋白激酶A激动剂6-BNZ-cAMP-AM所模拟，而这种作用可被蛋白激酶A抑制剂RP-腺苷3‘，5’-环单硫代硫代三乙基铵盐所阻断。为了确定我们的研究结果的临床相关性，我们检查了RhoA/ROCK基因变异与稳态模型胰岛素抵抗评估指数中代谢特征的相关性。RHOA内和周围的几个单核苷酸多态与空腹胰岛素升高和胰岛素抵抗的稳态模型评估指数相关，提示可能在代谢失调中起作用。总之，这些发现揭示了一种新的机制，即GLP-1通过解聚F-肌动蛋白细胞骨架，通过蛋白激酶A介导的抑制RhoA-ROCK信号通路来增强糖毒性减弱的GSIS。
Chronic hyperglycemia leads to pancreatic beta-cell dysfunction characterized by diminished glucose-stimulated insulin secretion (GSIS), but the precise cellular processes involved are largely unknown. Here we show that pancreatic beta-cells chronically exposed to a high glucose level displayed substantially increased amounts of stress fibers compared with beta-cells cultured at a low glucose level. beta-Cells at high glucose were refractory to glucose-induced actin cytoskeleton remodeling and insulin secretion. Importantly, F-actin depolymerization by either cytochalasin B or latrunculin B restored glucotoxicity-diminished GSIS. The effects of glucotoxicity on increasing stress fibers and reducing GSIS were reversed by Y-27632, a Rho-associated kinase (ROCK)-specific inhibitor, which caused actin depolymerization and enhanced GSIS. Notably, glucagon-like peptide-1-(7-36) amide (GLP-1), a peptide hormone that stimulates GSIS at both normal and hyperglycemic conditions, also reversed glucotoxicity-induced increase of stress fibers and reduction of GSIS. In addition, GLP-1 inhibited glucotoxicity-induced activation of RhoA/ROCK and thereby resulted in actin depolymerization and potentiation of GSIS. Furthermore, this effect of GLP-1 was mimicked by cAMP-increasing agents forskolin and 3-isobutyl-1-methylxanthine as well as the protein kinase A agonist 6-Bnz-cAMP-AM whereas it was abolished by the protein kinase A inhibitor Rp-Adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt. To establish a clinical relevance of our findings, we examined the association of genetic variants of RhoA/ROCK with metabolic traits in homeostasis model assessment index of insulin resistance. Several single-nucleotide polymorphisms in and around RHOA were associated with elevated fasting insulin and homeostasis model assessment index of insulin resistance, suggesting a possible role in metabolic dysregulation. Collectively these findings unravel a novel mechanism whereby GLP-1 potentiates glucotoxicity-diminished GSIS by depolymerizing F-actin cytoskeleton via protein kinase A-mediated inhibition of the RhoA-ROCK signaling pathway.