The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats

6533b823fe1ef96bd127f85b

RESEARCH PRODUCT

The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats

Karl J. Lackner Siyer Roohani Maximilian Kopp Philipp Welschof Serge P. Bottari Andreas Daiber Andreas Daiber Matthias Oelze Philip Wenzel Ning Xia Ute Gödtel-armbrust Eric Mayoux Huige Li Leszek Wojnowski Thomas Münzel Swenja Kröller-schön Sebastian Steven Alina Hanf Eberhard Schulz Fatemeh Kashani

subject

Male 0301 basic medicine endocrine system diseases Diabetic Cardiomyopathies FPS-ZM1 RAGE inhibitor Clinical Biochemistry Aorta Thoracic RAGE receptor for AGE ICAM-1 intercellular adhesion molecule-1 ECL enhanced chemiluminescence 030204 cardiovascular system & hematology DPP-4 dipeptidyl peptidase-4 medicine.disease_cause TNF-α tumor necrosis factor-α Biochemistry eNOS endothelial •NO synthase (type 3)0302 clinical medicine Glucosides ecSOD extracellular superoxide dismutase Insulin-Secreting Cells CCL-2 see MCP-1 Hyperlipidemia Hyperinsulinemia GTN glyceryl trinitrate (nitroglycerin)IFN-γ interferon-γ DHE dihydroethidine Endothelial dysfunction Endothelial dysfunction IL-6 interleukin-6 lcsh:QH301-705.5 HO-1 heme oxygenase-1 lcsh:R5-920 ICAM-1 NG normoglycemia Diabetes Nox catalytic subunit of NADPH oxidase SGLT2 inhibitor β-cell content L-012 8-amino-5-chloro-7-phenylpyrido[3 4-d]pyridazine-1 4-(2H 3H)dione sodium salt ChIP chromatin immunoprecipitation C-Reactive Protein CRP C-reactive protein AGE advanced glycation end products HbA1c glycohemoglobin lcsh:Medicine (General)Research Paper Zucker diabetic fatty rats medicine.medical_specialty DMSO dimethylsulfoxide MCP-1 monocyte-chemoattractant-protein-1 qRT-PCR quantitative reverse transcription polymerase chain reaction ZDF Zucker diabetic fatty (rat)Low-grade inflammation 03 medical and health sciences ROS reactive oxygen species Sodium-Glucose Transporter 2 Physiology (medical)Internal medicine Diabetes mellitus PKC protein kinase C Empagliflozin medicine Animals Hypoglycemic Agents Benzhydryl Compounds COX2 cyclooxygenase-2 SGLT2i SGLT2 inhibitor Sodium-Glucose Transporter 2 Inhibitors Glycated Hemoglobin ACh acetylcholine business.industry Organic Chemistry nutritional and metabolic diseases Type 2 Diabetes Mellitus medicine.disease H2K9me2 histone3 lysine9 dimethylation Rats Rats Zucker DHFR dihydrofolate reductase SGLT2 sodium-glucose co-transporter-2 Oxidative Stress sGC soluable guanylyl cyclase Glucose 030104 developmental biology Endocrinology lcsh:Biology (General)ALDH-2 mitochondrial aldehyde dehydrogenase Endothelium Vascular AGE/RAGE signaling HG hyperglycemia business Oxidative stress

description

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).

year	journal	country	edition	language
2017-05-29	Redox Biology

https://doi.org/10.1016/j.redox.2017.06.009