title: Beneficial effects of inhibition of soluble epoxide hydrolase on glucose homeostasis and islet damage in a streptozotocin-induced diabetic mouse model.
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.
authors.affiliation: Department of Physiology, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Lingdan
authors.initials: L
authors.lastname: Chen
authors.forename: Cheng
authors.initials: C
authors.lastname: Fan
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mahinur
authors.initials: M
authors.lastname: Bakri
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Krishna Rao
authors.initials: KR
authors.lastname: Maddipati
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Luo
authors.forename: Cong-Yi
authors.initials: CY
authors.lastname: Wang
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Mong-Heng
authors.initials: MH
authors.lastname: Wang
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004326:Drinking / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013311:Streptozocin; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D004791:Enzyme Inhibitors; D013311:Streptozocin; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D014508:Urea; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D015126:8,11,14-Eicosatrienoic Acid; D005947:Glucose