Effect of Vildagliptin, Compared to Sitagliptin, on the Onset of Hyperglycemia-Induced Metabolic Memory in Human Umbilical Vein Endothelial Cells

Abstract

Background: Metabolic memory, the long-term effect of poor glycemic control in the initial stages of diabetes, leads to vascular complications that negatively affect patients' outcome. As oxidative stress plays a major role in metabolic memory onset, the use of drugs with antioxidant properties may be clinically beneficial. Objectives:To test the effects of two dipeptidyl peptidase-4 inhibitors, vildagliptin and sitagliptin, on hyperglycemia-induced oxidative stress and apoptosis in Human Umbilical Vein Endothelial Cells (HUVECs).Methods: HUVECs were treated with 5 nM vildagliptin or sitagliptin for 1 h, after 21 days of culture under conditions of continuous normal or high glucose (NG and HG, respectively), Oscillating Glucose (OG) or HG/OG memory (HM and OM, respectively). The effects of the two drugs on the following markers of oxidative stress were tested by different techniques: Reactive Oxygen Species (ROS), 8-hydroxy-deoxy-guanosine, 3-nitrotyrosine, thioredoxin-interacting protein (TXNIP) mRNA and PKC-β protein. Moreover, the levels of BCL-2 (anti-apoptotic) and BAX (pro-apoptotic) transcripts and of caspase-3 protein were assayed.Results: In HUVECs, vildagliptin was able to significantly counteract the oxidative stress triggered by OG, HG and memory conditions, as measured by the levels of ROS, DNA and protein damage markers, TXNIP and PKC-β. Also, a significant increase of BCL-2 and decrease of BAX mRNA levels was observed upon OG and HG. Sitagliptin exerted a less evident effect. No significant effect on caspase-3 levels was detected by either drug. Conclusions:Our findings point toward antioxidant and antiapoptotic properties of vildagliptin in HUVECs exposed to HG, OG and metabolic memory conditions, whereas the effects of sitagliptin were less prominent. If these results on the vascular protective effects of vildagliptin will be confirmed, its use may be implemented in the setting of diabetes to prevent the onset of metabolic memory.

The Legacy Effect in the Prevention of Cardiovascular Disease

“…These oxidative stress markers can persist in endothelial cells despite glucose normalisation after prolonged hyperglycaemia, suggesting a metabolic memory phenomenon (Figure 1) [4,5]. Furthermore, postprandial glucose oscillations in diabetic patients have been associated with increased ROS marker levels and vascular stress; the cells' inability to adapt to this dynamic environment leads to cell damage and elevated collagen and fibronectin levels that remain abnormal for several days after glucose levels have normalised [11][12][13]. In hypertension models, the overproduction of ROS by NADPH oxidase upregulation due to renin-angiotensin system activation appeared to persist after cessation of the hypertensive period and was related to deleterious effects.…”

“…Some medications could alter these pathways and, consequently, prevent the development of CVD. Metformin, pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to prevent AGE formation or decrease inflammation by blocking AGE and NF-κB pathways, reversing the metabolic memory phenomenon [12,[16][17][18]. Also, angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor type 1 (AT-1) blockers can reduce AGE formation and, subsequently, the inhibition of superoxide generation [17].…”