Acute exposure to low glucose rapidly induces endothelial dysfunction and mitochondrial oxidative stress: role for AMP kinase.
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.


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 endothelial nitric oxide synthase 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 endothelial nitric oxide synthase's Ser633 activation site, reversing the adverse effects of low glucose. This protective effect was prevented by L-NG-Nitroarginine methyl ester. 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 inhibit this effect in an NO-dependent manner.
Department of Medicine, Division of Cardiovascular Medicine, Graduate School of Bioscience, Medical College of Wisconsin, 9200 W Wisconsin Ave, FEC Ste E5100, Milwaukee, WI 53226, USA.
Jingli
J
Wang
Anna
A
Alexanian
Rong
R
Ying
Tinoy J
TJ
Kizhakekuttu
Kodlipet
K
Dharmashankar
Jeanette
J
Vasquez-Vivar
David D
DD
Gutterman
Michael E
ME
Widlansky
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000273:Adipose Tissue / Q000098:blood supply*; D000975:Antioxidants / Q000494:pharmacology; D001160:Arterioles / Q000201:enzymology / Q000503:physiopathology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007003:Hypoglycemia / Q000201:enzymology* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D012694:Serine; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D013481:Superoxides; D009569:Nitric Oxide; D012694:Serine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases; D005947:Glucose