Role of Mitochondrial Oxidative Stress in Glucose Tolerance,Insulin Resistance,and Cardiac Diastolic Dysfunction

Background: diabetes mellitus (dm) is associated with mitochondrial oxidative stress. we have shown that myocardial oxidative stress leads to diastolic dysfunction in a hypertensive mouse model. therefore,we hypothesized that diabetes mellitus could cause diastolic dysfunction through mitochondrial oxidative stress and that a mitochondria-targeted antioxidant (mitotempo) could prevent diastolic dysfunction in a diabetic mouse model. methods and results: c57bl/6j mice were fed either 60 kcal % fat diet (high-fat diet [hfd]) or normal chow (control) for 8 weeks with or without concurrent mitotempo administration,followed by in vivo assessment of diastolic function and ex vivo studies. hfd mice developed impaired glucose tolerance compared with the control (serum glucose=495±45 mg/dl versus 236±30 mg/dl at 60 minutes after intraperitoneal glucose injection,p<0.05). myocardial tagged cardiac magnetic resonance imaging showed significantly reduced diastolic circumferential strain (ecc) rate in the hfd mice compared with controls (5.0±0.3 1/s versus 7.4±0.5 1/s,p<0.05),indicating diastolic dysfunction in the hfd mice. systolic function was comparable in both groups (left ventricular ejection fraction=66.4±1.4% versus 66.7±1.2%,p>0.05). mitotempo-treated hfd mice showed significant reduction in mitochondria reactive oxygen species,s-glutathionylation of cardiac myosin binding protein c,and diastolic dysfunction,comparable to the control. the fasting insulin levels of mitotempo-treated hfd mice were also comparable to the controls (p>0.05). conclusions: mitotempo treatment prevented insulin resistance and diastolic dysfunction,suggesting that mitochondrial oxidative stress may be involved in the pathophysiology of both conditions. © 2016 the authors. published on behalf of the american heart association,inc.,by wiley blackwell.