Inhibition of prolyl hydroxylases increases hepatic insulin and decreases glucagon sensitivity by an HIF-2α-dependent mechanism.

ABSTRACT:

Objective

Recent evidence indicates that inhibition of prolyl hydroxylase domain (PHD) proteins can exert beneficial effects to improve metabolic abnormalities in mice and humans. However, the underlying mechanisms are not clearly understood. This study was designed to address this question.

Methods

A pan-PHD inhibitor compound was injected into WT and liver-specific hypoxia-inducible factor (HIF)-2α KO mice, after onset of obesity and glucose intolerance, and changes in glucose and glucagon tolerance were measured. Tissue-specific changes in basal glucose flux and insulin sensitivity were also measured by hyperinsulinemic euglycemic clamp studies. Molecular and cellular mechanisms were assessed in normal and type 2 diabetic human hepatocytes, as well as in mouse hepatocytes

SUBMITTER: Riopel M 

PROVIDER: S-EPMC7393408 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature