TITLE

Hyperketonemia Increases Tumor Necrosis Factor-α Secretion in Cultured U937 Monocytes and Type 1 Diabetic Patients and Is Apparently Mediated by Oxidative Stress and cAMP Deficiency

AUTHOR(S)
Jain, Sushil K.; Kannan, Krishnaswamy; Lim, Gideon; McVie, Robert; Bocchini, Jr., Joseph A.
PUB. DATE
July 2002
SOURCE
Diabetes;Jul2002, Vol. 51 Issue 7, p2287
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
An elevated blood level of tumor necrosis factor (TNF)-α is a validated marker of vascular inflammation, which can result in the development of vascular disease and atherosclerosis. This study examined the hypothesis that ketosis increases the TNF-α secretion, both in a cell culture model using U937 monocytes and in type 1 diabetic patients in vivo. U937 cells were cultured with ketone bodies (acetoacetate [AA] and β-hydroxybutyrate [BHB]) in the presence or absence of high levels of glucose in medium at 37°C for 24 h. This study demonstrates the following points. First, hyperketonemic diabetic patients have significantly higher levels of TNF-α than normoketonemic diabetic patients (P < 0.01) and normal control subjects (P < 0.01). There was a significant correlation (r = 0.36, P < 0.05; n = 34) between ketosis and oxidative stress as well as between oxidative stress and TNF-α levels (r = 0.47, P < 0.02; n = 34) in the blood of diabetic patients. Second, ketone body AA treatment increases TNF-α secretion, increases oxygen radicals production, and lowers cAMP levels in U937 cells. However, BHB did not have any effect on TNF-α secretion or oxygen radicals production in U937 cells. Third, exogenous addition of dibutyryl cAMP, endogenous stimulation of cAMP production by forskolin, and antioxidant N-acetylcysteine (NAC) prevented stimulation of TNF-α secretion caused by AA alone or with high glucose. Similarly, NAC prevented the elevation of TNF-α secretion and lowering of cAMP levels in H[sub 2]O[sub 2]-treated U937 cells. Fourth, the effect of AA on TNF-α secretion was inhibited by specific inhibitors of protein kinase A (H89), p38-mitogen-activated protein kinase (SB203580), and nuclear transcription factor (NF)κB (NFκB-SN50). This study demonstrates that hyperketonemia increases TNF-α secretion in cultured U937 monocytic cells and TNF-α levels in the blood of type 1 diabetic patients and is apparently mediated by AA-induced cellular oxidative stress and cAMP deficiency.
ACCESSION #
7075834

 

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