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.
OBJECTIVE
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Matthias
M
Oelze
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Swenja
S
Kröller-Schön
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Philipp
P
Welschof
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Thomas
T
Jansen
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Michael
M
Hausding
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Yuliya
Y
Mikhed
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Paul
P
Stamm
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Michael
M
Mader
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Elena
E
Zinßius
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Saule
S
Agdauletova
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Anna
A
Gottschlich
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Sebastian
S
Steven
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Eberhard
E
Schulz
Laboratory of Fundamental and Applied, Bioenergetics, INSERM U1055, Grenoble-Alpes Université et Pôle de Biologie, CHU, Grenoble, France.
Serge P
SP
Bottari
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
Eric
E
Mayoux
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Thomas
T
Münzel
2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Andreas
A
Daiber
D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D048909:Diabetes Complications / Q000188:drug therapy / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000008:administration & dosage / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013311:Streptozocin / Q000009:adverse effects
D001559:Benzhydryl Compounds; D001786:Blood Glucose; D016207:Cytokines; D005960:Glucosides; D018836:Inflammation Mediators; D007328:Insulin; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013311:Streptozocin; C570240:empagliflozin; D005947:Glucose