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

Molecular Metabolism
Matthew RiopelYun Sok Lee

Abstract

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. 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. Administration of a PHD inhibitor compound (PHDi) after the onset of obesity and insulin resistance improved glycemic control by increasing insulin and decreasing glucagon sensitivity in mice, independent of body weight change. Hyperinsulinemic euglycemic clamp studies revealed that these effects of PHDi treatment were mainly due to decreased basal hepatic glucose output and increased liver insulin sensitivity. Hepatocyte-specific deletion of HIF-2α markedly attenuated thes...Continue Reading

Citations

Feb 12, 2021·International Journal of Environmental Research and Public Health·Władysław GrzeszczakMirosław Śnit
Feb 13, 2021·Peptides·Thomas Kietzmann, Ville H Mäkelä
Oct 23, 2021·JCI Insight·Jae-Su MoonYun Sok Lee
Dec 14, 2021·Cellular and Molecular Gastroenterology and Hepatology·Raja Gopal Reddy MooliSadeesh K Ramakrishnan

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Methods Mentioned

BETA
enzyme-linked immunosorbent assay
Assay
PCR

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