Empagliflozin improves left ventricular diastolic function of db/db mice.
Amino Acids, Branched-Chain
/ blood
Animals
Benzhydryl Compounds
/ pharmacology
Calcium-Calmodulin-Dependent Protein Kinase Type 2
/ antagonists & inhibitors
Clinical Trials as Topic
Diabetes Mellitus, Experimental
/ drug therapy
Diabetes Mellitus, Type 2
/ drug therapy
Diabetic Cardiomyopathies
/ drug therapy
Diet, High-Fat
/ adverse effects
Glucose
/ metabolism
Glucosides
/ pharmacology
Humans
Hypoglycemic Agents
/ pharmacology
Ketone Bodies
/ blood
Male
Mice
Mice, Transgenic
Ryanodine Receptor Calcium Release Channel
/ genetics
Sarcoplasmic Reticulum
/ drug effects
Sodium-Glucose Transporter 2
/ genetics
Sodium-Glucose Transporter 2 Inhibitors
/ pharmacology
Survival Analysis
Ventricular Function, Left
/ drug effects
Branched-chain amino acids
Cardiovascular disease
Empagliflozin
Ketone bodies
SGTL2 inhibitors
Type 2 diabetes mellitus
Journal
Biochimica et biophysica acta. Molecular basis of disease
ISSN: 1879-260X
Titre abrégé: Biochim Biophys Acta Mol Basis Dis
Pays: Netherlands
ID NLM: 101731730
Informations de publication
Date de publication:
01 08 2020
01 08 2020
Historique:
received:
19
12
2019
revised:
09
04
2020
accepted:
15
04
2020
pubmed:
1
5
2020
medline:
5
1
2021
entrez:
1
5
2020
Statut:
ppublish
Résumé
Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy. 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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32353614
pii: S0925-4439(20)30152-6
doi: 10.1016/j.bbadis.2020.165807
pii:
doi:
Substances chimiques
Amino Acids, Branched-Chain
0
Benzhydryl Compounds
0
Glucosides
0
Hypoglycemic Agents
0
Ketone Bodies
0
Ryanodine Receptor Calcium Release Channel
0
Slc5a2 protein, mouse
0
Sodium-Glucose Transporter 2
0
Sodium-Glucose Transporter 2 Inhibitors
0
ryanodine receptor 1, mouse
0
Calcium-Calmodulin-Dependent Protein Kinase Type 2
EC 2.7.11.17
empagliflozin
HDC1R2M35U
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
165807Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest N.M. has received support for clinical trial leadership from Boehringer Ingelheim, N.M. has served as a consultant to Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, NovoNordisk and has received grant support from Boehringer Ingelheim and MSD. In addition, N.M. has served as speaker for Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, NovoNordisk. N.M. declines all personal compensation from pharma or device companies. M.L. has received grant support for experimental and clinical studies from Boehringer Ingelheim and MSD; has served as a consultant to Boehringer Ingelheim, Sanofi-Aventis, MSD, AstraZeneca, Lilly, NovoNordisk, Amgen and Bayer. Has served as a speaker for Boehringer Ingelheim Sanofi-Aventis, MSD, AstraZeneca, Lilly, NovoNordisk and Bayer. S.V. has received speaker honoraria from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, and Sanofi; and received research grant support from Amgen, AstraZeneca, Boehringer Ingelheim, and Eli Lilly. G.D.L.: shareholder in Metabolic Modulators Research Ltd., received grant support from Servier, Boehringer Ingelheim, Sanofi, REMED Biopharmaceuticals. K.S. has received grant support for experimental studies from Boehringer Ingelheim and has served as speaker for Boehringer Ingelheim, Amgen, MSD, Omniamed and NovoNordisk. All other authors report no relevant disclosures.