Adverse Alterations in Mitochondrial Function Contribute to Type 2 Diabetes Mellitus–Induced Endothelial Dysfunction in Humans
Objective—Mitochondrial dysfunction plays a key pathophysiological role in type 2 diabetes mellitus (T2DM)–related endothelial dysfunction. Data delineating relationships between mitochondrial and endothelial dysfunction in humans with T2DM are lacking.
Methods and Results—In 122 human subjects (60 with T2DM, 62 without T2DM), we measured endothelial function by brachial artery ultrasound (flow mediated dilation %) and digital pulse amplitude tonometery. Endothelial function in arterioles isolated from gluteal subcutaneous adipose was measured by videomicroscopy. In arterioles and mononuclear cells, we measured inner mitochondrial membrane potential (Δψm), mitochondrial mass, and mitochondrial superoxide production using fluorophores. Endothelial function was impaired in T2DM versus nondiabetes mellitus. Δψm magnitude was larger, and mitochondrial mass was lower in arterioles and mononuclear cells in T2DM. Mononuclear mitochondrial mass correlated with flow-mediated dilation % and pulse amplitude tonometery (r=0.38 and 0.33, P=0.001 and 0.02, respectively), and mononuclear mitochondrial superoxide production inversely correlated with flow-mediated dilation % (ρ=−0.58, P=0.03). Endothelial function was impaired in T2DM. Low doses of 2 different mitochondrial uncoupling agents (carbonyl cyanide m-chlorophenyl hydrazone and 2,4-dinitrophenol) that reduce Δψm magnitude and a mitochondrial-targeted antioxidant (MitoTEMPOL) improved endothelial function and reduced mitochondrial superoxide levels.
Conclusion—Mitochondrial dysfunction may play a central role in the origin and maintenance of endothelial dysfunction in T2DM.
- Received July 13, 2011.
- Accepted July 25, 2012.
- © 2012 American Heart Association, Inc.