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

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.

• Authors: Ayala Luria, Ahmed Bettaieb, Yannan Xi, Guang-Jong Shieh, Hsin-Chen Liu, Hiromi Inoue, Hsing-Ju Tsai, John D Imig, Fawaz G Haj, Bruce D Hammock
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 22 Pg. 9038-43 (May 31 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21571638 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin
• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• Arachidonic Acid
• Epoxide Hydrolases
• Ephx2 protein, mouse
• Glucose

Topics

• Animals
• Arachidonic Acid (metabolism)
• Diabetes Mellitus, Type 2 (metabolism)
• Epoxide Hydrolases (deficiency, genetics, physiology)
• Glucose (metabolism)
• Homeostasis
• Insulin (metabolism)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance
• Islets of Langerhans (cytology)
• Mice
• Mice, Inbred C57BL
• Obesity, Abdominal
• Pancreas (metabolism)
• Signal Transduction