Acute Exposure to Low Glucose Rapidly Induces Endothelial Dysfunction and Mitochondrial Oxidative Stress

Abstract

Objective Hypoglycemia is associated with increased mortality. The reasons for this remain unclear and the effects of low glucose exposure on vascular endothelial function remain largely unknown. We endeavored to determine the effects of low glucose on endothelial cells and intact human arterioles. Methods and Results We exposed human umbilical vein endothelial cells to low glucose conditions in a clinically relevant range (40–70 mg/dL) and found rapid and marked reductions in nitric oxide (NO) bioavailability (P<0.001). This was associated with concomitantly increased mitochondrial superoxide production (P<0.001) and NO-dependent mitochondrial hyperpolarization (P<0.001). Reduced NO bioavailability was rapid and attributable to reduced eNOS activity and destruction of NO. Low glucose rapidly activated AMP Kinase but physiological activation failed to restore NO bioavailability. Pharmacological AMP Kinase activation led to phosphorylation of eNOS’s Ser633 activation site, reversing the adverse effects of low glucose, and this protective effect was prevented by L-NAME. Intact human arterioles exposed to low glucose demonstrated marked endothelial dysfunction which was prevented by either metformin or TEMPOL. Conclusions Our data suggest that moderate low glucose exposure rapidly impairs NO bioavailability and endothelial function in the human endothelium, and that pharmacological AMP Kinase activation can inhibit this effect in an NO-dependent manner.

Endothelial Dysfunction Plays a Key Role in Increasing Cardiovascular Risk in Type 2 Diabetes

“…Second, glucose levels may not accurately reflect the mechanisms by which hyperglycemia leads to endothelial dysfunction and cardiovascular events (ie, advanced glycation end products and oxidative stress). 9 Third, it has been suggested that glucose variability 21 and episodes of hypoglycemia 22 may be more strongly associated with endothelial dysfunction than mean blood glucose levels (ie, hemoglobin A1c). Nevertheless, we cannot exclude the play of chance.…”

Allicin Decreases Lipopolysaccharide-Induced Oxidative Stress and Inflammation in Human Umbilical Vein Endothelial Cells through Suppression of Mitochondrial Dysfunction and Activation of Nrf2

“…Endothelial cell dysfunction is an important characteristic of AS [4, 5]. Both oxidative stress and mitochondrial dysfunction are responsible for the development of endothelial dysfunction [6, 7]. Given that endothelial dysfunction plays an important role in AS, protection of the vascular system is important.…”

Transendothelial glucose transport is not restricted by extracellular hyperglycaemia

“…Thus glucose uptake and metabolism is critical for healthy endothelial physiology, and endothelial glucose transporters are especially important in the brain, where glucose can only cross the blood brain barrier via this mechanism [16]. On the other hand, dysregulated glucose transport and metabolism is linked to pathophysiological states [17][18][19]; increased GLUT expression is associated with carcinogenesis and tumour progression [20][21][22] and both hypo-and hyperglycaemia can lead to increased endothelial stress and inflammation, contributing to cardiovascular disease [23][24][25]. Despite the critical functional role of glucose in the endothelium, our understanding of its uptake and utilization by endothelial cells remains limited.…”