Tags

Type your tag names separated by a space and hit enter

Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice.
J Physiol 2018JP

Abstract

KEY POINTS

Hearts from type 2 diabetic animals display perturbations in excitation-contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns. Under high glucose and β-adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice, improving contractility and relaxation while restoring coronary perfusion pressure. Fluxome calculations of central catabolism in diabetic hearts show that, in the presence of palmitate, there is a metabolic remodelling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments. Under high glucose and increased energy demand, the metabolic/fluxomic redirection leading to restored redox balance imparted by palmitate helps explain maintained LV function and may contribute to designing novel therapeutic approaches to prevent cardiac dysfunction in diabetic patients.

ABSTRACT

Type-2 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose is central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy/redox balance under excess glucose, rescuing β-adrenergic-stimulated cardiac excitation-contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodelling associated with cardiac function in diabetic db/db mice subjected to stress given by β-adrenergic stimulation with isoproterenol and high glucose compared to their non-diabetic controls (+/+, WT) under euglycaemic conditions. When perfused with Palm, T2DM hearts exhibited improved contractility/relaxation compared to WT, accompanied by extensive metabolic remodelling as demonstrated by metabolomics-fluxomics combined with bioinformatics and computational modelling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids and redox metabolism. Using a validated computational model of heart's central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are ∼2-fold lower in heart from T2DM vs. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced β-oxidation and decreased glucose uptake, leading to flux-redirection away from redox-consuming pathways (e.g. polyol) while maintaining the flux through redox-generating pathways together with glucose-FA 'shared fuelling' of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycaemia and increased workload.

Authors+Show Affiliations

Laboratory of Cardiovascular Science, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, MD, 21205, USA. Posgraduate Program in Rehabilitation Sciences, Dept. Health Sciences, Federal University of Santa Catarina, Ararangua, SC, Brazil.Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, MD, 21205, USA. Dipartimento di Scienze Mediche Traslazionali, Universita' degli Studi di Napoli Federico II Via Pansini 5, Edificio 2, 80131, Napoli, Italy.Translational Gerontology Branch, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.Translational Gerontology Branch, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, MD, 21205, USA. Department of Biomedical Sciences, University of Padova, via Marzolo 3, 35131, Padova, Italy.Laboratory of Cardiovascular Science, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.Laboratory of Cardiovascular Science, National Institute on Aging/NIH, Baltimore, MD, 21224, USA. Translational Gerontology Branch, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30462352

Citation

Cortassa, Sonia, et al. "Metabolic Remodelling of Glucose, Fatty Acid and Redox Pathways in the Heart of Type 2 Diabetic Mice." The Journal of Physiology, 2018.
Cortassa S, Caceres V, Tocchetti CG, et al. Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice. J Physiol (Lond). 2018.
Cortassa, S., Caceres, V., Tocchetti, C. G., Bernier, M., de Cabo, R., Paolocci, N., ... Aon, M. A. (2018). Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice. The Journal of Physiology, doi:10.1113/JP276824.
Cortassa S, et al. Metabolic Remodelling of Glucose, Fatty Acid and Redox Pathways in the Heart of Type 2 Diabetic Mice. J Physiol (Lond). 2018 Nov 21; PubMed PMID: 30462352.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice. AU - Cortassa,Sonia, AU - Caceres,Viviane, AU - Tocchetti,Carlo G, AU - Bernier,Michel, AU - de Cabo,Rafael, AU - Paolocci,Nazareno, AU - Sollott,Steven J, AU - Aon,Miguel A, Y1 - 2018/11/21/ PY - 2018/07/13/received PY - 2018/11/15/accepted PY - 2018/11/22/pubmed PY - 2018/11/22/medline PY - 2018/11/22/entrez KW - diabetic cardiomyopathy KW - fluxomics KW - metabolomics JF - The Journal of physiology JO - J. Physiol. (Lond.) N2 - KEY POINTS: Hearts from type 2 diabetic animals display perturbations in excitation-contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns. Under high glucose and β-adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice, improving contractility and relaxation while restoring coronary perfusion pressure. Fluxome calculations of central catabolism in diabetic hearts show that, in the presence of palmitate, there is a metabolic remodelling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments. Under high glucose and increased energy demand, the metabolic/fluxomic redirection leading to restored redox balance imparted by palmitate helps explain maintained LV function and may contribute to designing novel therapeutic approaches to prevent cardiac dysfunction in diabetic patients. ABSTRACT: Type-2 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose is central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy/redox balance under excess glucose, rescuing β-adrenergic-stimulated cardiac excitation-contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodelling associated with cardiac function in diabetic db/db mice subjected to stress given by β-adrenergic stimulation with isoproterenol and high glucose compared to their non-diabetic controls (+/+, WT) under euglycaemic conditions. When perfused with Palm, T2DM hearts exhibited improved contractility/relaxation compared to WT, accompanied by extensive metabolic remodelling as demonstrated by metabolomics-fluxomics combined with bioinformatics and computational modelling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids and redox metabolism. Using a validated computational model of heart's central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are ∼2-fold lower in heart from T2DM vs. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced β-oxidation and decreased glucose uptake, leading to flux-redirection away from redox-consuming pathways (e.g. polyol) while maintaining the flux through redox-generating pathways together with glucose-FA 'shared fuelling' of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycaemia and increased workload. SN - 1469-7793 UR - https://www.unboundmedicine.com/medline/citation/30462352/Metabolic_remodelling_of_glucose_fatty_acid_and_redox_pathways_in_the_heart_of_type_2_diabetic_mice_ L2 - https://doi.org/10.1113/JP276824 DB - PRIME DP - Unbound Medicine ER -