Project

Back to overview

Ischemic stress and metabolism in the diabetic myocardium: Implications for cardioprotection

English title Ischemic stress and metabolism in the diabetic myocardium: Implications for cardioprotection
Applicant Montessuit Christophe
Number 182955
Funding scheme COST (European Cooperation in Science and Technology)
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Cardiovascular Research
Start/End 01.08.2019 - 31.07.2023
Approved amount 308'661.00
Show all

All Disciplines (3)

Discipline
Cardiovascular Research
Pathophysiology
Physiology : other topics

Keywords (5)

glucose transport; metabolic stress; metabolic syndrome; ischemic injury; cardiac myocytes

Lay Summary (French)

Lead
Le diabète, en particulier de type II, augmente la gravité des infarctus du myocarde, en sus de leur fréquence. La stimulation du transport de glucose dans le myocarde en réponse au stress métabolique qu’est l’ischémie (réduction ou interruption de l’apport de sang au myocarde) est cruciale pour permettre au myocarde de supporter cette ischémie, déterminant ainsi la gravité de l’infarctus résultant.Une caractéristique du diabète est la dyslipidémie, soit la présence dans la circulation de lipides en trop grandes quantités. L’impact de la dyslipidémie sur la stimulation du transport de glucose par le stress métabolique est encore très mal compris.
Lay summary
Contenu et objectifs du travail de recherche
L’objectif du travail est de déterminer l’implication de nouveaux mécanismes intracellulaires induit par la dyslipidémie dans l’inhibition du transport de glucose en réponse au stress ischémique, et partant dans la gravité de l’infarctus du myocarde.
Nous déterminerons in vitro, sur des cardiomyocytes exposés à une dyslipidémie, comment ces mécanismes cellulaires influencent le métabolisme du glucose en réponse au stress ischémique. Le cas échéant, les résultats positifs seront transposés sur un modèle animal de cardiomyopathie diabétique. Nous déterminerons la gravité de l’infarctus du myocarde en relation avec le métabolisme du glucose après traitements visant à modifier in vivo les mécanismes cellulaires identifiés in vitro.
Contexte scientifique et social du projet de recherche
L’impact du diabète sur le métabolisme du glucose dans les muscles squelettiques est largement étudié. Par contre, à notre connaissance nous sommes parmi les seuls à nous intéresser à l’impact du diabète sur la stimulation du transport de glucose par le stress métabolique dans le myocarde. 
Le diabète, en particulier de type II, devient un problème de santé publique majeur. Une meilleure compréhension de l’impact du diabète sur le métabolisme myocardique du glucose pourrait mener à une meilleure protection du myocarde diabétique contre l’infarctus.
 
Direct link to Lay Summary Last update: 06.02.2019

Responsible applicant and co-applicants

Employees

Name Institute

Collaboration

Group / person Country
Types of collaboration
AC Gavin's group; PHYME Department; University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
LS2 Cardiovacular Research Meeting 2022 Talk given at a conference Lipid droplets protect cardiomyocytes from lipotoxic impairment of glucose transport 04.07.2022 Bern, Switzerland Vanni Ettore;
9th EU-CARDIOPROTECTION COST Action Final MC/WG meeting Talk given at a conference Lipid droplets protect cardiomyocytes against fatty acid-induced dysregulation of glucose uptake. 02.04.2022 Coimbra, Portugal Montessuit Christophe;
SHVM 2021 Metabolism at the crossroads of health and disease Poster Can a droplet of lipids save your heart? 23.09.2021 Jena, Germany Vanni Ettore;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Journée Portes Ouvertes Diabète et Obésité Performances, exhibitions (e.g. for education institutions) 11.11.2021 Geneva, Switzerland Montessuit Christophe;


Abstract

1.1BackgroundStimulation of glucose transport and metabolism is one of the first line of defense for the myocardium undergoing ischemic stress. Studies in animal models and clinical studies have indicated that the diabetic myocardium is less capable to withstand ischemic stress and demonstrates increased myocardial injury and poorer post-ischemic recovery of function. A reduced capacity to stimulate glucose metabolism during ischemic stress could underlie the worst post-ischemic outcome of the diabetic myocardium.A hallmark of diabetes, mostly of type II diabetes, is dyslipidemia. We have previously shown that chronic exposure of cardiac myocytes to circulating lipids impairs the stimulation of glucose transport by physiologic - insulin - or pathologic - metabolic stress - stimulators.Intracellular metabolism is profoundly altered in conditions of dyslipidemia. The relationship of such alterations with the stimulation of glucose transport by insulin in cardiac myocytes has been investigated, albeit incompletely. In contrast, there is a little information available regarding the impact of altered intracellular metabolism on metabolic stress-stimulated glucose transport, on which the present proposal will focus.1.2General aimThe general aim of the proposed research is to investigate several cellular mechanisms that in response to an excess of fatty acids may dysregulate metabolic stress-stimulated glucose transport. The PhD candidate supported by the grant will focus on two such cellular mechanisms: biogenesis of lipid droplets and disturbances in the protein acetylation/deacetylation balance driven by alterations of NAD+ and acetyl-CoA availability.1.3Experimental approachesComplementary in vitro and in vivo experimental approaches will be followed. Isolated adult rat cardiac myocytes will be chronically exposed in vitro to lipids as a model of the diabetic dyslipidemia. Metabolic, pharmaceutical or genetic manipulations favoring or preventing the biogenesis of lipid droplets (1st specific aim) or the activity of SIRT deacetylases (2nd specific aim) will be applied. The participation of these cellular mechanisms in the impairment or restoration of metabolic stress-stimulated glucose metabolism will be assessed by mean of cellular biology experiments investigating cellular metabolism of glucose and fatty acids, cell signaling and cell morphology. In vivo experiments in an animal model of type II diabetes will attempt to complement and confirm positive in vitro findings. Obese diabetic hyperlipidemic fa/fa rats will be treated with pharmaceutical agents stimulating the biosynthesis of myocardial lipid droplets (1st specific aim) or aiming at replenishing the myocardial NAD+ pool, thereby activating SIRT deacetylases (2nd specific aim). Thereafter ischemia-stimulated myocardial glucose metabolism and ischemia-reperfusion injury will be investigated together with post-ischemic myocardial recovery of contractile function and assessment in myocardial tissue of the cellular mechanisms described above.1.4Expected value of the proposed researchMyocardial metabolic-stress stimulated glucose transport is an important determinant of infarct severity. In the context of the COST action “Cardioprotection”, it is expected that a better comprehension of the cellular mechanisms leading to its impairment in diabetes could eventually, through “reverse engineering”, lead to new concepts in the management of acute coronary syndromes.
-