Diabetic ketosis activates lymphomonocyte-inducible nitric oxide synthase.
OBJECTIVE
Inappropriate production of nitric oxide (NO) may be responsible for the haemodynamic disturbances of diabetic ketoacidosis. We investigated whether this metabolic condition is associated with increased plasma nitrate (the stable oxidation product of NO) levels and NO synthase gene expression in lymphomonocytes.


METHODS
Plasma nitrate concentrations, lymphomonocyte-inducible nitric oxide synthase (iNOS) gene expression, tumour necrosis factor-alpha (TNF-alpha) and soluble thrombomodulin were measured in 11 Type 1 diabetic patients at baseline, during mild ketosis and after euglycaemia was re-established.


RESULTS
During diabetic ketosis plasma nitrate concentrations were higher (18 (16-21) vs. 9 (7-11) micro mol/l; (95% lower-upper confidence interval) P < 0.05) than at baseline. At baseline lymphomonocyte iNOS mRNA expression and iNOS protein levels were undetectable, but in ketosis both were increased (both at P < 0.0001). After recovery from ketosis, NO3 concentration, iNOS mRNA, and iNOS expression (270 +/- 36%, mean +/- sd) decreased but not significantly. No significant changes were observed in either TNF-alpha or soluble thrombomodulin levels between the three conditions.


CONCLUSIONS
Diabetic ketosis is associated with increased nitrate levels and the activation of iNOS expression in circulating lymphomonocytes, but it does not affect either the proinflammatory cytokine TNF-alpha or a marker of endothelial dysfunction such as thrombomodulin. Our data support the hypothesis that, during diabetic ketosis, alterations in NO homeostasis are present in circulating lymphomonocytes.
Iori
E
E
Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy.
Calò
L
L
Valbusa
D
D
Ceolotto
G
G
Milani
M
M
Pengo
V
V
de Kreutzenberg
S V
SV
Tiengo
A
A
Avogaro
A
A
D000328:Adult; D015153:Blotting, Western; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000201:enzymology*; D016883:Diabetic Ketoacidosis / Q000097:blood / Q000201:enzymology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D009000:Monocytes / Q000201:enzymology*; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018180:Thrombomodulin / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D009566:Nitrates; D012333:RNA, Messenger; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II