Beneficial effects of inhibition of soluble epoxide hydrolase on glucose homeostasis and islet damage in a streptozotocin-induced diabetic mouse model

Lingdan Chen, Cheng Fan, Yi Zhang, Mahinur Bakri, Hua Dong, Christophe Morisseau, Krishna Rao Maddipati, Pengcheng Luo, Cong Yi Wang, Bruce D. Hammock, Mong Heng Wang

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)42-48
Number of pages7
JournalProstaglandins and Other Lipid Mediators
Volume104-105
DOIs
StatePublished - Jul 2013

Keywords

  • Apoptosis
  • CYP-derived eicosanoids
  • Glucose homeostasis
  • Islets

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Pharmacology
  • Cell Biology

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    Chen, L., Fan, C., Zhang, Y., Bakri, M., Dong, H., Morisseau, C., Maddipati, K. R., Luo, P., Wang, C. Y., Hammock, B. D., & Wang, M. H. (2013). Beneficial effects of inhibition of soluble epoxide hydrolase on glucose homeostasis and islet damage in a streptozotocin-induced diabetic mouse model. Prostaglandins and Other Lipid Mediators, 104-105, 42-48. https://doi.org/10.1016/j.prostaglandins.2012.12.001