Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart.
OBJECTIVE
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.
Anderson
Ethan J
EJ
Department of Cardiovascular Sciences and East Carolina Heart Institute, East Carolina University, Greenville, North Carolina 27835, USA. andersonet@ecu.edu.
Kypson
Alan P
AP
Rodriguez
Evelio
E
Anderson
Curtis A
CA
Lehr
Eric J
EJ
Neufer
P Darrell
PD
D000244:Adenosine Diphosphate / Q000378:metabolism; D000328:Adult; D019069:Cell Respiration; D002952:Citric Acid Cycle; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006325:Heart Atria / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism*; D018384:Oxidative Stress; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D005227:Fatty Acids; D006360:Heat-Shock Proteins; D047493:PPAR alpha; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D014280:Triglycerides; D018698:Glutamic Acid; D000244:Adenosine Diphosphate; D006861:Hydrogen Peroxide; D005978:Glutathione