Department of Physiology, Georgia Health Sciences University, Augusta, GA 30912, USA.
Prostaglandins Other Lipid Mediat. 2013 Jul-Aug;104-105:42-8. doi: 10.1016/j.prostaglandins.2012.12.001. Epub 2012 Dec 13.
Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of endogenous inflammatory and anti-apoptotic mediators. In the present study, we determined the effects of the inhibition of sEH on glucose homeostasis and islet damage in mice treated with streptozotocin (STZ), a model of chemical-induced diabetes. STZ increased daily water intake and decreased visceral (spleen and pancreas) weight in mice; sEH inhibition in STZ mice decreased water intake, but did not affect visceral weight. Hyperglycemia induced by STZ treatment in mice was attenuated by inhibiting sEH. The beneficial effects of sEH inhibition were accompanied, after 2 and 4 weeks of initial administration, by improving glucose tolerance. In contrast, sEH inhibition did not affect insulin tolerance. Using LC/MS analysis, neither STZ nor STZ plus sEH inhibition affected pancreatic and plasma ratios of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), an index of EETs levels. Western blot analysis showed that mouse cytochrome P450 (CYP) 2C enzymes are the major epoxygenases in islets. On day 5 after initial STZ treatment, STZ induced islet cell apoptosis, while sEH inhibition in STZ mice significantly reduced islet cell apoptosis. These studies provide pharmacological evidence that inhibiting sEH activity provides significant protection against islet β-cell damage and improves glucose homeostasis in STZ-induced diabetes.
可溶性环氧化物水解酶（sEH）是一种参与内源性炎症和抗细胞凋亡介质代谢的酶。在本研究中，我们确定了抑制 sEH 对链脲佐菌素（STZ）处理的小鼠葡萄糖稳态和胰岛损伤的影响，STZ 是一种化学诱导型糖尿病模型。STZ 增加了小鼠的日饮水量并降低了内脏（脾脏和胰腺）重量；sEH 抑制可减少 STZ 小鼠的饮水量，但不影响内脏重量。sEH 抑制可减轻 STZ 处理诱导的小鼠高血糖。在初始给药 2 周和 4 周后，sEH 抑制的有益作用伴随着葡萄糖耐量的改善。相比之下，sEH 抑制并不影响胰岛素耐量。通过 LC/MS 分析，无论是 STZ 还是 STZ 加 sEH 抑制均未影响胰腺和血浆中环氧化物水解酶（EETs）与二羟环氧化物水解酶（DHETs）的比值，这是 EETs 水平的一个指标。Western blot 分析表明，小鼠细胞色素 P450（CYP）2C 酶是胰岛中的主要环氧化物酶。在初次 STZ 处理后的第 5 天，STZ 诱导胰岛细胞凋亡，而 sEH 抑制可显著减少 STZ 小鼠的胰岛细胞凋亡。这些研究提供了药理学证据，表明抑制 sEH 活性可显著保护胰岛 β 细胞免受损伤，并改善 STZ 诱导的糖尿病中的葡萄糖稳态。
