Genetic deficiency or pharmacological inhibition of soluble epoxide hydrolase ameliorates high fat diet-induced pancreatic β-cell dysfunction and loss

Shinichiro Koike, Ming Fo Hsu, Ahmed Bettaieb, Bryan Chu, Naoki Matsumoto, Christophe Morisseau, Peter J. Havel, Mark O. Huising, Bruce D. Hammock, Fawaz G. Haj

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic β-cells are crucial regulators of systemic glucose homeostasis, and their dysfunction and loss are central features in type 2 diabetes. Interventions that rectify β-cell dysfunction and loss are essential to combat this deadly malady. In the current study, we sought to delineate the role of soluble epoxide hydrolase (sEH) in β-cells under diet-induced metabolic stress. The expression of sEH was upregulated in murine and macaque diabetes models and islets of diabetic human patients. We postulated that hyperglycemia-induced elevation in sEH leads to a reduction in its substrates, epoxyeicosatrienoic acids (EETs), and attenuates the function of β-cells. Genetic deficiency of sEH potentiated glucose-stimulated insulin secretion in mice, likely in a cell-autonomous manner, contributing to better systemic glucose control. Consistent with this observation, genetic and pharmacological inactivation of sEH and the treatment with EETs exhibited insulinotropic effects in isolated murine islets ex vivo. Additionally, sEH deficiency enhanced glucose sensing and metabolism with elevated ATP and cAMP concentrations. This phenotype was associated with attenuated oxidative stress and diminished β-cell death in sEH deficient islets. Moreover, pharmacological inhibition of sEH in vivo mitigated, albeit partly, high fat diet-induced β-cell loss and dedifferentiation. The current observations provide new insights into the role of sEH in β-cells and information that may be leveraged for the development of a mechanism-based intervention to rectify β-cell dysfunction and loss.

Original languageEnglish (US)
Pages (from-to)48-57
Number of pages10
JournalFree Radical Biology and Medicine
Volume172
DOIs
StatePublished - Aug 20 2021

Keywords

  • Dedifferentiation
  • Epoxyeicosatrienoic acids
  • Oxidative stress
  • Pharmacological inhibition
  • Soluble epoxide hydrolase
  • Type 2 diabetes
  • β-Cell dysfunction

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Fingerprint

Dive into the research topics of 'Genetic deficiency or pharmacological inhibition of soluble epoxide hydrolase ameliorates high fat diet-induced pancreatic β-cell dysfunction and loss'. Together they form a unique fingerprint.

Cite this