Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance
Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance
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DOI：
10.1073/pnas.1103482108
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发表时间：
2011-05-31
影响因子：
11.1
通讯作者：
Hammock, Bruce D.
中科院分区：
文献类型：
--
作者：
Luria, Ayala;Bettaieb, Ahmed;Hammock, Bruce D.
内脏肥胖被定义为代谢综合征的一个重要因素，并导致胰岛素抵抗和心血管疾病的发生。增加内源性环氧二十碳三烯酸 (EET) 水平因其镇痛、抗高血压和抗炎作用而闻名。 EET 的可用性主要受到可溶性环氧化物水解酶（sEH、EPHX2）的限制，该酶将 EET 代谢为其活性较低的二醇。在这项研究中，我们检验了 EET 参与血糖调节和延缓胰岛素抵抗发展的假设。为了阐明 EET 在调节葡萄糖稳态和胰岛素信号传导中的作用，我们使用了 sEH 靶向基因缺失的小鼠（Ephx2 缺失小鼠），并随后使用选择性 sEH 抑制剂进行了研究。当野生型小鼠被喂食高脂肪饮食时，就会出现胰岛素抵抗。然而，敲除或抑制 sEH 活性会导致血浆葡萄糖显着降低。这些发现的特点是胰岛素受体、胰岛素受体底物 1 及其下游级联的酪氨酰磷酸化增强。此外，当 sEH 被破坏时，胰岛会变得更大。这种效应与脉管系统的增加有关。这些观察结果得到了 sEH 药理抑制的支持。这些数据表明，sEH 基因敲除导致 EET 增加，导致胰岛大小增加，并改善胰岛素信号传导和敏感性。
Visceral obesity has been defined as an important element of the metabolic syndrome and contributes to the development of insulin resistance and cardiovascular disease. Increasing endogenous levels of epoxyeicosatrienoic acids (EETs) are known for their analgesic, antihypertensive, and antiinflammatory effects. The availability of EETs is limited primarily by the soluble epoxide hydrolase (sEH, EPHX2), which metabolizes EETs to their less active diols. In this study, we tested the hypothesis that EETs are involved in glucose regulation and in retarding the development of insulin resistance. To address the role of EETs in regulating glucose homeostasis and insulin signaling, we used mice with targeted gene deletion of sEH (Ephx2-null mice) and a subsequent study with a selective sEH inhibitor. When wild-type mice are fed a high fat diet, insulin resistance develops. However, knockout or inhibition of sEH activity resulted in a significant decrease in plasma glucose. These findings are characterized by enhancement of tyrosyl phosphorylation of the insulin receptor, insulin receptor substrate 1, and their downstream cascade. In addition, pancreatic islets were larger when sEH was disrupted. This effect was associated with an increase in vasculature. These observations were supported by pharmacological inhibition of sEH. These data suggest that an increase in EETs due to sEH-gene knockout leads to an increase in the size of islets and improved insulin signaling and sensitivity.