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. Results 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 these effects of PHDi treatment, showing PHDi effects are HIF-2α dependent. At the molecular level, HIF-2α induced increased Irs2 and cyclic AMP-specific phosphodiesterase gene expression, leading to increased and decreased insulin and glucagon signaling, respectively. These effects of PHDi treatment were conserved in human and mouse hepatocytes. Conclusions Our results elucidate unknown mechanisms for how PHD inhibition improves glycemic control through HIF-2α-dependent regulation of hepatic insulin and glucagon sensitivity.

ANT2 drives proinflammatory macrophage activation in obesity

“…For insulin tolerance tests (ITTs), mice were fasted for 6 hours, and basal blood samples were taken, followed by intraperitoneal injection of insulin (0.35 and 0.6 U/kg for NCD-and HFD-fed mice, respectively). HOMA-IR was calculated as described previously (93,94).…”

Whether Prolyl Hydroxylase Blocker—Roxadustat—In the Treatment of Anemia in Patients with Chronic Kidney Disease Is the Future?

“…Following a thorough review of the results provided by the previously presented randomized trials in phase 2 and 3 [ 33 , 34 , 35 , 36 , 37 , 38 ], a question arises whether the effect of roxadustat (hemoglobin level and the number of red blood cells) is the same in patients with or without diabetes and with or without obesity. The authors of the above-mentioned studies did not take into account the separate effects of roxadustat on the level of hemoglobin and the number of erythrocytes in patients with or without diabetes and with or without obesity.…”

Intestinal HIF-2α Regulates GLP-1 Secretion via Lipid Sensing in L-Cells

“…Our data provide a strong mechanistic insight into the role of HIF-2a in regulating GLP-1 secretion through lipid sensing. Given that DMOG potentiates GLP-1 secretion via intestinal HIF-2a and targeted delivery of PHD inhibitors to the intestine is feasible, 55,56 our study provides a strong rationale for future investigations determining the pharmacologic targeting of intestinal HIF signaling in metabolic diseases. Further investigations using mouse models with L-specific HIF-2a gain-or loss-of-function studies also may unfold novel targets to stimulate endogenous GLP-1 production.…”