Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart
Open accessAbstract
Objectives The aim of this study was to determine the impact of diabetes on oxidant balance and mitochondrial metabolism of carbohydrate- and lipid-based substrates in myocardium of type 2 diabetic patients.Background Heart failure represents a major cause of death among diabetic patients. It has been proposed that derangements in cardiac metabolism and oxidative stress may underlie the progression of this comorbidity, but scarce evidence exists in support of this mechanism in humans.Methods Mitochondrial oxygen (O(2)) consumption and hydrogen peroxide (H(2)O(2)) emission were measured in permeabilized myofibers prepared from samples of the right atrial appendage obtained from nondiabetic (n = 13) and diabetic (n = 11) patients undergoing nonemergent coronary artery bypass graft surgery.Results Mitochondria in atrial tissue of type 2 diabetic individuals show a sharply decreased capacity for glutamate and fatty acid-supported respiration, in addition to an increased content of myocardial triglycerides, as compared to nondiabetic patients. Furthermore, diabetic patients show an increased mitochondrial H(2)O(2) emission during oxidation of carbohydrate- and lipid-based substrates, depleted glutathione, and evidence of persistent oxidative stress in their atrial tissue.Conclusions These findings are the first to directly investigate the effects of type 2 diabetes on a panoply of mitochondrial functions in the human myocardium using cellular and molecular approaches, and they show that mitochondria in diabetic human hearts have specific impairments in maximal capacity to oxidize fatty acids and glutamate, yet increased mitochondrial H(2)O(2) emission, providing insight into the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of heart failure in diabetic patients.
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A recent study of subjects with type 2 diabetes offered clear evidence of mitochondrial dysfunction in permeabilized right atrial cardiac fibers.
“A recent study of subjects with type 2 diabetes offered clear evidence of mitochondrial dysfunction in permeabilized right atrial cardiac fibers [271], suggesting improvement to mitochondrial function as a potential therapeutic strategy for obesity and its associated pathologies.”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [271]
A high-fat, high-sucrose diet in the diabetes-prone C57BL6 mouse causes mitochondrial alterations in parallel with enhanced ROS production and impaired insulin sensitivity.
“For example, a high-fat, high-sucrose diet in the diabetes-prone C57BL6 mouse causes mitochondrial alterations in parallel with enhanced ROS production and impaired insulin sensitivity.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [287]
Exposure of muscle cells in vitro to saturated fatty acids or high-fat feeding in mice results in alterations in mitochondrial structure and insulin resistance, both of which are reversed by antioxidants.
“Similarly, exposure of muscle cells in vitro to saturated fatty acids or high-fat feeding in mice results in alterations in mitochondrial structure and insulin resistance, both of which are reversed by antioxidants (286 -288).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [287]
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- Authors
- Anderson, E. J., Kypson, A. P., Rodriguez, E., Anderson, C. A., Lehr, E. J., & Neufer, P. D.
- Affiliations
- East Carolina University (US)
- Corresponding author
- Anderson, Ethan J.
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 54
- Issue
- 20
- Pages
- 1891-1898
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC2800130
- OpenAlex
- W2077261489
- Cited by
- 440
- References
- 26
- Citations by year
- 2026: 16 · 2025: 33 · 2024: 29 · 2023: 29 · 2022: 29 · 2021: 36 · 2020: 33 · 2019: 32 · 2018: 36 · 2017: 22 · 2016: 31 · 2015: 23 · 2014: 29 · 2013: 18 · 2012: 19
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK074825, R01DK073488, DK-073488, R01DK074825)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- type 2 diabetes, diabetic cardiomyopathy, mitochondrial dysfunction, oxidative stress, myocardial metabolism, atrial appendage, mitochondrial oxygen consumption, hydrogen peroxide emission, fatty acid oxidation, glutamate oxidation, myocardial triglycerides, glutathione depletion, heart failure
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adenosine Diphosphate, Adult, Citric Acid Cycle, Diabetes Mellitus, Type 2, Fatty Acids, Female, Glutathione, Heart Atria, Heat-Shock Proteins, Humans, Hydrogen Peroxide, Kinetics, Male, Middle Aged, Mitochondria, Heart, Transcription Factors, Triglycerides, Oxidative Stress, Glutamic Acid, Cell Respiration, PPAR alpha
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