Acute Low Glucose Induced Loss of Bioavailable Nitric Oxide Leads to the Development of Mitochondrial and Endothelial Dysfunction in Humans

Mitochondrial hyperpolarization is a well‐recognized stimulus for mitochondrial ROS production. We hypothesized physiologically relevant levels of low glucose (LG, 40–70 mg/dL) would induce mitochondrial hyperpolarization, superoxide production, and endothelial dysfunction in intact human arterioles. LG exposure increased mitochondrial membrane potential (ΔΨ m , measured by JC‐1) magnitude relative to NG (90 mg/dL). Exogenous NO donor NONOate significantly blunted ΔΨ m hyperpolarization under LG conditions, while NO inhibition using L‐NAME led to hyperpolarization under LG and NG conditions (JC‐1 red:green ratios of 3.4±0.3, 4.5±0.2, 3.8±0.2, and 4.9±0.3 for NG, LG, LG+NONOate and NG+L‐NAME, respectively, p<0.01). Vasodilation to acetylcholine was significantly impaired by LG, while PEG‐SOD effectively reversed LG‐induced endothelial dysfunction (P<0.001). A greater percentage of human mononuclear cells adhered to HUVECs under LG conditions compared to NG (31 vs. 16%, P<0.004). LG rapidly induces endothelial dysfunction in human vessels due to excessive oxidative stress in part from mitochondrial sources. LG‐induced impairment of NO bioavailability leads to ΔΨ m hyperpolarization and subsequent mitochondrial superoxide production. These data suggest endothelial dysfunction and mitochondrial oxidative stress may be mechanistically related to hypoglycemia‐related morbidity.