Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells in an Insulin-Dependent and Independent Manner
Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells in an Insulin-Dependent and Independent Manner
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间歇性缺氧以胰岛素依赖和独立的方式破坏肝细胞中的葡萄糖稳态
DOI：
10.1159/000490169
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Li, Qing Yun
中科院分区：
文献类型：
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作者：
Gu, Chen Juan;Yi, Hua Hua;Li, Qing Yun
背景/目的：阻塞性睡眠呼吸暂停与糖尿病和胰岛素抵抗有关，但其潜在机制尚不清楚。本研究的目的是确定间歇性缺氧（IH）对肝脏胰岛素信号传导和葡萄糖稳态的分子效应，以及c-Jun NH 2-terminal-kinase（JNK）是否有助于肝细胞对IH的代谢反应。研究方法：将人HepG 2细胞和大鼠FAO细胞暴露于10、30、120、240或360个循环的IH（1%O2持续60 s，随后21%O2持续60 s，7.5个循环/小时）或作为对照的常氧。在一个亚组中，我们将细胞暴露于含有JNK抑制剂SP 600125的360个周期的IH。IH暴露后，使用比色测定试剂盒测量细胞糖原含量和葡萄糖输出。通过Western blot和定量聚合酶链反应检测典型胰岛素信号转导和促胰岛素分泌基因。结果如下：IH以时间依赖性方式降低胰岛素刺激的蛋白激酶B（AKT）/糖原合成酶激酶-3 β（GSK-3β）磷酸化，同时抑制不依赖于胰岛素信号传导的叉头盒蛋白O 1（FOXO 1）表达和磷酸烯醇式丙酮酸羧激酶（PEPCK）转录。JNK抑制剂SP 600125可部分恢复AKT/ GSK-3β磷酸化和糖原合成，但不影响IH诱导的其他葡萄糖代谢变化。结论：IH可通过激活JNK抑制AKT/GSK-3β磷酸化，从而影响胰岛素在肝细胞内的信号转导。IH以非胰岛素依赖的方式抑制FOXO 1和胰岛素生成。
Background/Aims: Obstructive sleep apnea is associated with diabetes and insulin resistance, but the underlying mechanisms remain unclear. The purpose of the current study was to determine the molecular effects of intermittent hypoxia (IH) on hepatic insulin signaling and glucose homeostasis, and whether c-Jun NH2-terminal-kinase (JNK) contributed to metabolic responses to IH in liver cells. Methods: The human HepG2 cells and rat FAO cells were exposed to 10, 30, 120, 240 or 360 cycles of IH (1% O2 for 60 s followed by 21% O2 for 60s, 7.5 cycles per hour) or normoxia as a control. In a subgroup, we exposed cells to 360 cycles of IH with the JNK inhibitor SP600125. After IH exposure, cell glycogen content and glucose output were measured using colorimetric assay kits. Canonical insulin signaling and gluconeogenic genes were measured by western blot and quantitative polymerase chain reaction. Results: IH decreased insulin-stimulated protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β) phosphorylation in a time-dependent manner, while inhibiting forkhead box protein O1 (FOXO1) expression and phosphoenolpyruvate carboxykinase (PEPCK) transcription independent of insulin signaling. JNK inhibitor SP600125 partially restored AKT/ GSK-3β phosphorylation and glycogen synthesis, but did not affect other IH-induced glucose metabolic changes. Conclusion: IH in vitro impaired insulin signal transduction in liver cells as assessed by inhibited AKT/GSK-3β phosphorylation via JNK activation. IH inhibited FOXO1 and gluconeogenesis in an insulin-independent manner.