The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats
| العنوان: | The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats |
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| المؤلفون: | Karl J. Lackner, Siyer Roohani, Maximilian Kopp, Philipp Welschof, Serge P. Bottari, 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 |
| المصدر: | Redox Biology Redox Biology, Vol 13, Iss C, Pp 370-385 (2017) |
| بيانات النشر: | Elsevier BV, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 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, 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 |
| الوصف: | 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). Graphical abstract fx1 Highlights • Hyperglycemia induces vascular complications and cardiovascular disease. • Empagliflozin reduces hyperglycemia and cardiovascular mortality (EMPA-REG trial). • Here, empagliflozin normalized vascular function and oxidative stress in ZDF rats. • Here, empagliflozin reduced AGE/RAGE signaling, inflammation and oxidative stress. • Here, empagliflozin conferred glycemic control, epigenetic and pleiotropic effects. |
| تدمد: | 2213-2317 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fac2319499ec3825e6d4ca81494cb48bTest https://doi.org/10.1016/j.redox.2017.06.009Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....fac2319499ec3825e6d4ca81494cb48b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22132317 |
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