Faculty Collaboration Database

Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance. Proc Natl Acad Sci U S A 2011 May 31;108(22):9038-43

Date

05/17/2011

Pubmed ID

21571638

Pubmed Central ID

PMC3107315

DOI

10.1073/pnas.1103482108

Scopus ID

2-s2.0-79959351596 (requires institutional sign-in at Scopus site)   133 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.

Author List

Luria A, Bettaieb A, Xi Y, Shieh GJ, Liu HC, Inoue H, Tsai HJ, Imig JD, Haj FG, Hammock BD

MESH terms used to index this publication - Major topics in bold

Animals
Arachidonic Acid
Diabetes Mellitus, Type 2
Epoxide Hydrolases
Glucose
Homeostasis
Insulin
Insulin Receptor Substrate Proteins
Insulin Resistance
Islets of Langerhans
Mice
Mice, Inbred C57BL
Obesity, Abdominal
Pancreas
Signal Transduction