Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance

Ayala Luria, Ahmed Bettaieb, Yannan Xi, Guang Jong Shieh, Hsin Chen Liu, Hiromi Inoue, Hsing Ju Tsai, John D. Imig, Fawaz Haj, Bruce D. Hammock

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

Visceral obesity has been defined as an important element of the metabolic syndrome and contributes to the development of insulin resistance and cardiovascular disease. Increasing endogenous levels of epoxyeicosatrienoic acids (EETs) are known for their analgesic, antihypertensive, and antiinflammatory effects. The availability of EETs is limited primarily by the soluble epoxide hydrolase (sEH, EPHX2), which metabolizes EETs to their less active diols. In this study, we tested the hypothesis that EETs are involved in glucose regulation and in retarding the development of insulin resistance. To address the role of EETs in regulating glucose homeostasis and insulin signaling, we used mice with targeted gene deletion of sEH (Ephx2-null mice) and a subsequent study with a selective sEH inhibitor. When wild-type mice are fed a high fat diet, insulin resistance develops. However, knockout or inhibition of sEH activity resulted in a significant decrease in plasma glucose. These findings are characterized by enhancement of tyrosyl phosphorylation of the insulin receptor, insulin receptor substrate 1, and their downstream cascade. In addition, pancreatic islets were larger when sEH was disrupted. This effect was associated with an increase in vasculature. These observations were supported by pharmacological inhibition of sEH. These data suggest that an increase in EETs due to sEH-gene knockout leads to an increase in the size of islets and improved insulin signaling and sensitivity.

Original languageEnglish (US)
Pages (from-to)9038-9043
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number22
DOIs
StatePublished - May 31 2011

Keywords

  • Arachidonic acid pathway
  • Pancreas
  • Type 2 diabetes

ASJC Scopus subject areas

  • General

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