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首页> 外文期刊>Endocrinology >Glucagon-Like Peptide 1 Stimulates Insulin Secretion via Inhibiting RhoA/ROCK Signaling and Disassembling Glucotoxicity-Induced Stress Fibers
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Glucagon-Like Peptide 1 Stimulates Insulin Secretion via Inhibiting RhoA/ROCK Signaling and Disassembling Glucotoxicity-Induced Stress Fibers

机译：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激纤维刺激胰岛素分泌。

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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.
机译：慢性高血糖症会导致胰腺β细胞功能异常，其特征是葡萄糖刺激的胰岛素分泌（GSIS）减少，但所涉及的确切细胞过程尚不清楚。在这里，我们显示了长期暴露于高葡萄糖水平的胰腺β细胞与低葡萄糖水平培养的β细胞相比，其应力纤维的数量显着增加。高葡萄糖时的β细胞难以抵抗葡萄糖诱导的肌动蛋白细胞骨架重塑和胰岛素分泌。重要的是，通过细胞松弛素B或latrunculin B进行的F-肌动蛋白解聚反应可恢复葡萄糖毒性降低的GSIS。葡萄糖毒性对增加应力纤维和降低GSIS的作用被Rho相关激酶（ROCK）特异性抑制剂Y-27632逆转，后者引起肌动蛋白解聚并增强GSIS。值得注意的是，胰高血糖素样肽-1-（7-36）酰胺（GLP-1）是一种在正常和高血糖条件下均能刺激GSIS的肽激素，也逆转了由葡萄糖毒性引起的应激纤维增加和GSIS降低的现象。此外，GLP-1抑制了糖毒性诱导的RhoA / ROCK活化，从而导致肌动蛋白解聚和GSIS增强。此外，GLP-1的这种作用可通过cAMP增强剂毛喉素和3-异丁基-1-甲基黄嘌呤以及蛋白激酶A激动剂6-Bnz-cAMP-AM来模仿，而被蛋白激酶A抑制剂Rp消除。 -腺苷3′，5′-环一硫代磷酸三乙铵盐。为了建立我们发现的临床意义，我们在胰岛素抵抗稳态模型评估指标中检查了RhoA / ROCK遗传变异与代谢性状的关联。 RHOA及其周围的几个单核苷酸多态性与空腹胰岛素升高和胰岛素抵抗稳态模型评估指数有关，提示其可能在代谢异常中发挥作用。这些发现共同揭示了一种新的机制，其中GLP-1通过蛋白激酶A介导的RhoA-ROCK信号通路抑制作用使F-肌动蛋白细胞骨架解聚，从而增强了葡萄糖毒性，从而降低了GSIS。

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