The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity

• Published in: PloS one Vol. 9; no. 11; p. e112394
• Main Authors: Oelze, Matthias, Kröller-Schön, Swenja, Welschof, Philipp, Jansen, Thomas, Hausding, Michael, Mikhed, Yuliya, Stamm, Paul, Mader, Michael, Zinßius, Elena, Agdauletova, Saule, Gottschlich, Anna, Steven, Sebastian, Schulz, Eberhard, Bottari, Serge P, Mayoux, Eric, Münzel, Thomas, Daiber, Andreas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.11.2014; Public Library of Science (PLoS)
• Subjects: Advanced glycosylation end products; Age; Animals; Antidiabetics; Aorta; Benzhydryl Compounds - administration & dosage; Benzhydryl Compounds - pharmacology; Blood; Blood glucose; Blood Glucose - drug effects; Blood vessels; Cardiology; Chemiluminescence; Cytokines - genetics; Cytokines - metabolism; Dehydrogenases; Diabetes; Diabetes Complications - drug therapy; Diabetes Complications - metabolism; Diabetes mellitus; Diabetes Mellitus, Experimental; Diabetes therapy; Diabetic Angiopathies - drug therapy; Diabetic Angiopathies - metabolism; Diabetic neuropathy; Drinking water; Drugs; Enzyme-linked immunosorbent assay; Excretion; Fluorescence; Gene Expression; Glucose; Glucose - metabolism; Glucose transporter; Glucosides - administration & dosage; Glucosides - pharmacology; Glycosylation; Health aspects; Hemodynamics - drug effects; Hyperglycemia; Hypoglycemic agents; Inflammation; Inflammation Mediators - metabolism; Inhibitors; Injection; Insulin; Insulin - blood; Insulin - metabolism; Intravenous administration; Isometric; Laboratory animals; Male; Medicine and Health Sciences; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Pancreas; Polymerase chain reaction; Rats; Receptor for Advanced Glycation End Products; Receptors, Immunologic - metabolism; RNA; RNA, Messenger - genetics; Rodents; Signal Transduction; Signaling; Sodium; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Staining; Streptozocin; Streptozocin - adverse effects; Studies; Type 1 diabetes; Type 2 diabetes; United States > US; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0112394

In diabetes, vascular dysfunction is characterized by impaired endothelial function due to increased oxidative stress. Empagliflozin, as a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), offers a novel approach for the treatment of type 2 diabetes by enhancing urinary glucose excretion. The aim of the present study was to test whether treatment with empagliflozin improves endothelial dysfunction in type I diabetic rats via reduction of glucotoxicity and associated vascular oxidative stress. Type I diabetes in Wistar rats was induced by an intravenous injection of streptozotocin (60 mg/kg). One week after injection empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 7 weeks. Vascular function was assessed by isometric tension recording, oxidative stress parameters by chemiluminescence and fluorescence techniques, protein expression by Western blot, mRNA expression by RT-PCR, and islet function by insulin ELISA in serum and immunohistochemical staining of pancreatic tissue. Advanced glycation end products (AGE) signaling was assessed by dot blot analysis and mRNA expression of the AGE-receptor (RAGE). Treatment with empagliflozin reduced blood glucose levels, normalized endothelial function (aortic rings) and reduced oxidative stress in aortic vessels (dihydroethidium staining) and in blood (phorbol ester/zymosan A-stimulated chemiluminescence) of diabetic rats. Additionally, the pro-inflammatory phenotype and glucotoxicity (AGE/RAGE signaling) in diabetic animals was reversed by SGLT2i therapy. Empagliflozin improves hyperglycemia and prevents the development of endothelial dysfunction, reduces oxidative stress and improves the metabolic situation in type 1 diabetic rats. These preclinical observations illustrate the therapeutic potential of this new class of antidiabetic drugs.