The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats
Sebastian Steven,
Matthias Oelze,
Alina Hanf,
Swenja Kröller-Schön,
Fatemeh Kashani,
Siyer Roohani,
Philipp Welschof,
Maximilian Kopp,
Ute Gödtel-Armbrust,
Ning Xia,
Huige Li,
Eberhard Schulz,
Karl J. Lackner,
Leszek Wojnowski,
Serge P. Bottari,
Philip Wenzel,
Eric Mayoux,
Thomas Münzel,
Andreas Daiber
Affiliations
Sebastian Steven
Center for Cardiology, Cardiology I – Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Matthias Oelze
Center for Cardiology, Cardiology I – Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Alina Hanf
Center for Cardiology, Cardiology I – Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Swenja Kröller-Schön
Center for Cardiology, Cardiology I – Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Fatemeh Kashani
Center for Cardiology, Cardiology I – Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Siyer Roohani
Center for Cardiology, Cardiology I – Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Philipp Welschof
Center for Cardiology, Cardiology I – Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Maximilian Kopp
Center for Cardiology, Cardiology I – Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Ute Gödtel-Armbrust
Department of Pharmacology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Ning Xia
Institute of Clinical Chemistry and Laboratory Medicine, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Huige Li
Institute of Clinical Chemistry and Laboratory Medicine, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Eberhard Schulz
Center for Cardiology, Cardiology I – Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Karl J. Lackner
Institute for Advanced Biosciences, INSERM U1209 – CNRS UMR 5309, Grenoble-Alps University and Institute for Biology and Pathology, CHU, Grenoble, France
Leszek Wojnowski
Department of Pharmacology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Serge P. Bottari
German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
Philip Wenzel
Center for Cardiology, Cardiology I – Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
Hyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance®), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male ZDF rats were used as a model of T2DM (35 diabetic ZDF‐Leprfa/fa and 16 ZDF-Lepr+/+ controls). Empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 6 weeks. Treatment with empagliflozin restored glycemic control. Empagliflozin improved endothelial function (thoracic aorta) and reduced oxidative stress in the aorta and in blood of diabetic rats. Inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by SGLT2i treatment (ChIP). Linear regression analysis revealed a significant inverse correlation of endothelial function with HbA1c, whereas leukocyte-dependent oxidative burst and C-reactive protein (CRP) were positively correlated with HbA1c. Viability of hyperglycemic endothelial cells was pleiotropically improved by SGLT2i. Empagliflozin reduces glucotoxicity and thereby prevents the development of endothelial dysfunction, reduces oxidative stress and exhibits anti-inflammatory effects in ZDF rats, despite persisting hyperlipidemia and hyperinsulinemia. Our preclinical observations provide insights into the mechanisms by which empagliflozin reduces cardiovascular mortality in humans (EMPA-REG trial).
