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.