Koike_2021_Free.Radic.Biol.Med__

Reference

Title : Genetic deficiency or pharmacological inhibition of soluble epoxide hydrolase ameliorates high fat diet-induced pancreatic beta-cell dysfunction and loss - Koike_2021_Free.Radic.Biol.Med__
Author(s) : Koike S , Hsu MF , Bettaieb A , Chu B , Matsumoto N , Morisseau C , Havel PJ , Huising MO , Hammock BD , Haj FG
Ref : Free Radic Biol Med , : , 2021
Abstract :

Pancreatic beta-cells are crucial regulators of systemic glucose homeostasis, and their dysfunction and loss are a central feature in type 2 diabetes. Interventions that rectify beta-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 beta-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 beta-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 on 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 beta-cell death in sEH deficient islets. Moreover, pharmacological inhibition of sEH in vivo mitigated, albeit partly, high fat diet-induced beta-cell loss and dedifferentiation. The current observations provide new insights into the role of sEH in beta-cells and information that may be leveraged for the development of a mechanism-based intervention to rectify beta-cell dysfunction and loss.

PubMedSearch : Koike_2021_Free.Radic.Biol.Med__
PubMedID: 34038767

Related information

Citations formats

Koike S, Hsu MF, Bettaieb A, Chu B, Matsumoto N, Morisseau C, Havel PJ, Huising MO, Hammock BD, Haj FG (2021)
Genetic deficiency or pharmacological inhibition of soluble epoxide hydrolase ameliorates high fat diet-induced pancreatic beta-cell dysfunction and loss
Free Radic Biol Med :

Koike S, Hsu MF, Bettaieb A, Chu B, Matsumoto N, Morisseau C, Havel PJ, Huising MO, Hammock BD, Haj FG (2021)
Free Radic Biol Med :