title: Inhibition or deletion of soluble epoxide hydrolase prevents hyperglycemia, promotes insulin secretion, and reduces islet apoptosis.
abstract: Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of endogenous inflammatory and antiapoptotic mediators. However, the roles of sEH in diabetes and the pancreas are unknown. Our aims were to determine whether sEH is involved in the regulation of hyperglycemia in diabetic mice and to investigate the reasons for the regulation of insulin secretion by sEH deletion or inhibition in islets. We used two separate approaches, targeted disruption of Ephx2 gene [sEH knockout (KO)] and a selective inhibitor of sEH [trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB)], to assess the role of sEH in glucose and insulin homeostasis in streptozotocin (STZ) mice. We also examined the effects of sEH KO or t-AUCB on glucose-stimulated insulin secretion (GSIS) and intracellular calcium levels in islets. Hyperglycemia in STZ mice was prevented by both sEH KO and t-AUCB. In addition, STZ mice with sEH KO had improved glucose tolerance. More important, when insulin levels were assessed by hyperglycemic clamp study, sEH KO was found to promote insulin secretion. In addition, sEH KO and t-AUCB treatment augmented islet GSIS. Islets with sEH KO had a greater intracellular calcium influx when challenged with high glucose or KCl in the presence of diazoxide. Moreover, sEH KO reduced islet cell apoptosis in STZ mice. These results show not only that sEH KO and its inhibition prevent hyperglycemia in diabetes, but also that sEH KO enhances islet GSIS through the amplifying pathway and decreases islet cell apoptosis in diabetes.
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912, USA.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Luo
authors.forename: Hsin-Hsin
authors.initials: HH
authors.lastname: Chang
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Shali
authors.initials: S
authors.lastname: Zhang
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Cong-Yi
authors.initials: CY
authors.lastname: Wang
authors.forename: Edward W
authors.initials: EW
authors.lastname: Inscho
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Mong-Heng
authors.initials: MH
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D003981:Diazoxide / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D042541:Intracellular Space / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013311:Streptozocin; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D001786:Blood Glucose; D007328:Insulin; D013311:Streptozocin; D014508:Urea; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D003981:Diazoxide