Monocyte and endothelial dysfunction induced by hyperglycemia is reversed by Empagliflozin mainly through glucose-transport independent mechanisms

Abstract Type II Diabetes mellitus (T2DM) leads via hyperglycemia (HG)-associated inflammation and oxidative stress to vascular cell dysfunction. The EMPA-REG trial revealed a reduction of cardiovascular mortality in T2DM patients by Empagliflozin, sodium-glucose co-transporter-2 (SGLT-2) inhibitor. SGLT-2 is expressed on monocytes endothelial cells (EC), therefore the aim this study was investigate potential role Empagliflozin for glucose transport regulation improvement HG-induced dysfunction EC. HUVEC HCAEC were used as EC model cells. Primary human isolated from healthy controls. exposed HG conditions vitro presence 40 or 100 ng/ml Empagliflozin. Using RT-qPCR FACS, expression levels analysed. Glucose uptake assays performed with fluorescent derivative glucose, 2-NBDG. To measure reactive oxygen species (ROS) accumulation, we H2DFFDA method FACS fluorescence microscopy. Monocyte chemotaxis analysed using modified Boyden chamber assays. We could prove an primary transcripts did not show difference. SGLT2-levels altered HG. In GLUT inhibitor ability inhibition mildly supress uptake, whereas remained comparable. Nevertheless, ROS accumulation (1.3-fold, p=0.021) ECs (1.5-fold, p=0.003) reduced. readily exhibited impaired behaviour. Treating reversed PlGF-1 resistance phenotype (1.4-fold, p=0.002). Comparably, able rescued blunted VEGF-A responses (1.35-fold, p=0.028), which be ascribed restoration VEGFR-2 receptor surface. Most aberrant phenotypes entirely recapitulated induction stress. mimic these effects general antioxidant N-acetyl-L-cysteine (NAC). Our reveals beneficial reversing does serve transporter. So it highly speculate that HG-mediated enhanced glucotoxicity those prevented through itself. Reduction central mechanism improved function vitro. Finally, conclude properties reverse independently transport. This likely support effect disease. Funding Acknowledgement funding sources: Public Institution(s). Main source(s): Medical Faculty, University Münster, Germany