TY - JOUR
T1 - Beneficial effects of inhibition of soluble epoxide hydrolase on glucose homeostasis and islet damage in a streptozotocin-induced diabetic mouse model
AU - Chen, Lingdan
AU - Fan, Cheng
AU - Zhang, Yi
AU - Bakri, Mahinur
AU - Dong, Hua
AU - Morisseau, Christophe
AU - Maddipati, Krishna Rao
AU - Luo, Pengcheng
AU - Wang, Cong Yi
AU - Hammock, Bruce D.
AU - Wang, Mong Heng
N1 - Funding Information:
Grant : This study was supported by AHA Grant-in-Aid grant ( AHASE0054 ) and GHSU intramural grant (DODI Synergy Award) to M.H. Wang. Partial support was provided by National Institutes of Health grant ( ES-002710 ) to B.D. Hammock, and National Natural Science Foundation of China ( NSFCN81000341 ) to P. Luo.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
KW - Apoptosis
KW - CYP-derived eicosanoids
KW - Glucose homeostasis
KW - Islets
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U2 - 10.1016/j.prostaglandins.2012.12.001
DO - 10.1016/j.prostaglandins.2012.12.001
M3 - Article
C2 - 23247129
AN - SCOPUS:84879694969
SN - 1098-8823
VL - 104-105
SP - 42
EP - 48
JO - Prostaglandins and Other Lipid Mediators
JF - Prostaglandins and Other Lipid Mediators
ER -