Repeated glucose spikes and insulin resistance synergistically deteriorate endothelial function and bardoxolone methyl ameliorates endothelial dysfunction

Abstract

Background Both insulin resistance and postprandial glucose spikes are known for their potential to induce vascular endothelial dysfunction in individuals with metabolic syndrome. However, these factors are inextricable, and therefore, their relative contributions to inducing endothelial dysfunction remain elusive. In this study, we aimed to disentangle the effects of these factors and clarify whether bardoxolone methyl (CDDO-Me), a novel nuclear factor erythroid 2-related factor 2 (Nrf2) activator, protects against glucose spike-induced endothelial dysfunction. Methods We induced glucose spikes twice daily for a duration of 1 week to rats fed a standard/control diet (CD) and Western-type diet (WTD). Endothelium-dependent relaxation (EDR) was evaluated using isolated thoracic aortas. Gene expression and dihydroethidium (DHE)-fluorescence studies were carried out; the effect of CDDO-Me on aortic endothelial dysfunction in vivo was also evaluated. Results Neither WTD-induced insulin resistance nor pure glucose spikes significantly deteriorated EDR. However, under high-glucose (20 mM) conditions, the EDR of thoracic aortas of WTD-fed rats subjected to glucose spikes was significantly impaired. In this group of rats, we observed significantly enhanced DHE fluorescence as a marker of reactive oxygen species, upregulation of an oxidative stress-related gene (NOX2), and downregulation of an antioxidant gene (SOD2) in the thoracic aortas. As expected, treatment of the thoracic aorta of this group of rats with antioxidant agents significantly improved EDR. We also noted that pretreatment of aortas from the same group with CDDO-Me attenuated endothelial dysfunction, accompanied by a correction of the redox imbalance, as observed in gene expression and DHE fluorescence studies. Conclusions For the first time, we showed that insulin resistance and glucose spikes exert a synergistic effect on aortic endothelial dysfunction. Furthermore, our study reveals that CDDO-Me ameliorates endothelial dysfunction caused by glucose spikes in a rat model of metabolic syndrome.

Luseogliflozin and caloric intake restriction increase superoxide dismutase 2 expression, promote antioxidative effects, and attenuate aortic endothelial dysfunction in diet‐induced obese mice

“…In this study, the high‐fat diet group exhibited a significant increase in ROS production, attenuated endothelial‐dependent vasodilation under increasing concentrations of FFA and SOD ameliorated the FFA induced endothelial dysfunction. On the other hand, a previous study that examined endothelial function with a similar experimental system showed increasing oxidative stress and aortic endothelial dysfunction under hyperglycemic conditions in diet‐induced obesity and insulin resistance model rats 19 . In the study, an antioxidant protected the aortic endothelial function as in our study.…”

“…NF‐E2‐related factor 2 (Nrf2), a major transcription regulator that activates antioxidants, including SOD2, and anti‐inflammatory and cell protective gene expression, may be another factor that increases the expression of SOD2 in the thoracic aorta with luseogliflozin administration. It has been reported that activating Nrf2 by bardoxolone methyl increased SOD2 gene expression 19 . Furthermore, SGLT2 inhibitors could increase Nrf2 expression in both diabetic and non‐diabetic animal models 33 , 34 .…”

“…The analysis of vascular reactivity was performed as described previously 19 . After the mice had been fasted overnight, fasting blood glucose and blood 3‐hydroxybutyric acid (3‐OHBA) were measured using Stat Strip XP3.…”

“…The oxidative fluorescent dye dihydroethidium (DHE) was used to evaluate the production of ROS in the aorta 19 , 23 . After exposure to Lipos + LPL for 40 min, unfixed segments of the thoracic aorta were frozen in OCT compound, and transverse sections (8 μm) were generated with a cryostat and placed on glass slides.…”

Participation of lncRNAs in the development of diabetic complications: Systematic review and meta‐analysis. I. Rat

“…9,10 Microvascular diseases cause damage to smaller blood vessels and can lead to complications such as nephropathy, retinopathy, neuropathy and vascular abnormalities in lower extremities. 11,12 Because the endothelial cells of the microvasculature are insulin independent, 13,14 these tissues constantly receive unregulated glucose input. This increases the prevalence of these complications.…”