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Moellmann, J.* ; Klinkhammer, B.M.* ; Droste, P.* ; Kappel, B.* ; Haj-Yehia, E.* ; Maxeiner, S.* ; Artati, A. ; Adamski, J. ; Boor, P.* ; Schütt, K.* ; Lopaschuk, G.D.* ; Verma, S.* ; Marx, N.* ; Lehrke, M.*

Empagliflozin improves left ventricular diastolic function of db/db mice.

Biochim. Biophys. Acta-Mol. Basis Dis. 1866:165807 (2020)
Postprint DOI PMC
Open Access Green
Objectives: Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy.Background: SGLT2 inhibition is a new strategy to treat diabetes. In the EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart.Methods: We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress.Results: Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected.Conclusions: In a murine model of severe diabetes empagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Empagliflozin ; Sgtl2 Inhibitors ; Cardiovascular Disease ; Type 2 Diabetes Mellitus ; Branched-chain Amino Acids ; Ketone Bodies; Heart-failure; Ketone-bodies; Inhibition; Hyperglycemia; Dysfunction; Metabolism; Mechanisms; Model
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 0925-4439
e-ISSN 1878-2434
Journal Biochimica et Biophysica Acta - Molecular Basis of Disease
Quellenangaben Volume: 1866, Issue: 8, Pages: , Article Number: 165807 Supplement: ,
Publisher Elsevier
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Reviewing status Peer reviewed
Institute(s) Molekulare Endokrinologie und Metabolismus (MEM)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-505600-003
DOI 10.1016/j.bbadis.2020.165807
WOS ID WOS:000543299900013
Scopus ID 85084442701
PubMed ID 32353614
Erfassungsdatum 2020-06-04
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