Modulation of regional nitric oxide metabolism: blood glucose control or insulin?
OBJECTIVE
Tight glycaemic control by intensive insulin therapy (IIT) reduces morbidity and mortality in critically ill patients. As potential mechanisms contributing to the clinical benefits we hypothesized that glycaemic control affects regional nitric oxide (NO) bioavailability by changing NO synthases (NOS) activity, NOS transcription, NOS substrate availability or the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) levels.


METHODS
Prospective, randomized experimental study.


METHODS
University medical laboratory.


METHODS
In a rabbit model of prolonged critical illness we assessed the relative impact of maintaining normal insulin/normoglycaemia (n = 8), high insulin/normoglycaemia (n = 8), normal insulin/hyperglycaemia (n = 9) and high insulin/hyperglycaemia (n = 8) plasma levels over 7 days on activity and gene expression of endothelial and inducible NOS isoforms in muscle, liver and aorta biopsies, and on plasma levels of NO, arginine and ADMA.


RESULTS
Compared with normoglycaemic groups, both hyperglycaemic groups revealed 53% higher day-3 NO plasma levels (p < 0.05), 40% lower NOS activity in muscle (p < 0.01) and 35% lower endothelium-mediated relaxation of aortic rings (p < 0.01), 515% higher gene expression of iNOS in muscle (p < 0.01) and 99% higher eNOS gene expression in aorta (p < 0.01). Only the hyperglycaemic/hyperinsulinaemic group showed lower arginine plasma levels (53% lower, p < 0.0001). Compared with healthy controls, normoglycaemic animals revealed 33% lower ADMA levels (p < 0.05).


CONCLUSIONS
In this animal model of prolonged critical illness, maintaining normoglycaemia, and not glycaemia-independent actions of insulin, prevented excessive systemic NO release on day 3 and appeared to preserve local endothelial function. Factors contributing to this finding may comprise direct endothelial cell damage, direct effects on the enzyme activity, decreased substrate availability or less NO-induced inhibition.
Ellger
Björn
B
Department of Intensive Care Medicine, Katholieke Universiteit Leuven, 3000, Leuven, Belgium. ellger@anit.uni-muenster.de
Langouche
Lies
L
Richir
Milan
M
Debaveye
Yves
Y
Vanhorebeek
Ilse
I
Teerlink
Tom
T
Van Leeuwen
Paul A
PA
Van den Berghe
Greet
G
D000818:Animals; D001120:Arginine / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010289:Parenteral Nutrition, Total; D011817:Rabbits
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase