PPARβ activation restores the high glucose‐induced impairment of insulin signalling in endothelial cells

Abstract

Background and Purpose PPARβ enhances insulin sensitivity in adipocytes and skeletal muscle cells, but its effects on insulin signalling in endothelial cells are not known. We analysed the effects of the PPARβ/δ (PPARβ) agonists, GW0742 and L165041, on impaired insulin signalling induced by high glucose in HUVECs and aortic and mesenteric arteries from diabetic rats. Experimental Approach Insulin‐stimulated NO production, Akt‐Ser473 and eNOS‐Ser1177 phosphorylation, and reactive oxygen species (ROS) production were studied in HUVECs incubated in low‐ or high‐glucose medium. Insulin‐stimulated relaxations and protein phosphorylation in vessels from streptozotocin (STZ)‐induced diabetic rats were also analysed. Key Results HUVECs incubated in high‐glucose medium showed a significant reduction in insulin‐stimulated production of NO. High glucose also reduced insulin‐induced Akt‐Ser473 and eNOS‐Ser1177 phosphorylation, increased IRS‐1‐Ser636 and ERK1/2‐Thr183‐Tyr185 phosphorylation and increased ROS production. The co‐incubation with the PPARβ agonists GW0742 or L165041 prevented all these effects induced by high glucose. In turn, the effects induced by the agonists were suppressed when HUVEC were also incubated with the PPARβ antagonist GSK0660, the pyruvate dehydrogenase kinase (PDK)4 inhibitor dichloroacetate or after knockdown of both PPARβ and PDK4 with siRNA. The ERK1/2 inhibitor PD98059, ROS scavenger catalase, inhibitor of complex II thenoyltrifluoroacetone or uncoupler of oxidative phosphorylation, carbonyl cyanide m‐chlorophenylhydrazone, also prevented glucose‐induced insulin resistance. In STZ diabetic rats, oral GW0742 also improved insulin signalling and the impaired NO‐mediated vascular relaxation. Conclusion and Implications PPARβ activation in vitro and in vivo restores the endothelial function, preserving the insulin‐Akt‐eNOS pathway impaired by high glucose, at least in part, through PDK4 activation.

A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling

“…NO release was determined using, diaminofluorescein-2 (DAF-2) [24]. Briefly, cells were washed with PBS and incubated with L-arginine (100 μmol/L /PBS) for 5 min at 37ºC before incubating with DAF-2 (0.1 μmol/L) for 2 min, followed by the calcium ionophore calimycin (A23187, 1 μmol/L) for 30 minutes.…”

Ellagic Acid Reduces High Glucose-Induced Vascular Oxidative Stress Through ERK1/2/NOX4 Signaling Pathway

“…HG activates MAPKs, mainly ERK1/2 [39,40]. In order to determine whether EA inhibits HG-induced ERK1/2 activation and consequently NOX4, we examined the levels of , a potent and selective inhibitor of ERK1/2 [42], was used as a positive control.…”

Black ginseng extract exerts anti-hyperglycemic effect via modulation of glucose metabolism in liver and muscle

“…4(C) and (D)). Insulin receptor activation results in phosphorylation of multiple tyrosine residues of IRS-1, which then activates the Akt/PI3-K signaling pathway leading to translocation of glucose transporter on the cell surface and the expression of glycolytic enzymes in the cytoplasm (Quintela et al, 2014;DeBerardinis et al, 2008). The 'mechanistic target of rapamycin' (mTOR) activated by Akt subsequently regulates cell proliferation and protein synthesis (Wullschleger et al, 2006).…”