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

Euy Myoung Jeong, Jaehoon Chung, Hong Liu, Yeongju Go, Scott Gladstein, Afshin Farzaneh-Far, E. Douglas Lewandowski, Samuel C. Dudley

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere003046
JournalJournal of the American Heart Association
Volume5
Issue number5
DOIs
StatePublished - May 2016

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants P01 HL058000, R01 HL104025, R01 HL106592, Veterans Administration Merit Award, and R41 HL112355 (SCD); R37 HL49244 (EDL).

Keywords

  • Diastolic dysfunction
  • Insulin resistance
  • Mitochondrial oxidative stress

Fingerprint Dive into the research topics of 'Role of Mitochondrial Oxidative Stress in Glucose Tolerance, Insulin Resistance, and Cardiac Diastolic Dysfunction'. Together they form a unique fingerprint.

Cite this