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

From the Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana

An elevated blood level of tumor necrosis factor (TNF)- 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- 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 ß-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- 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- levels (r = 0.47, P < 0.02; n = 34) in the blood of diabetic patients. Second, ketone body AA treatment increases TNF- secretion, increases oxygen radicals production, and lowers cAMP levels in U937 cells. However, BHB did not have any effect on TNF- 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- secretion caused by AA alone or with high glucose. Similarly, NAC prevented the elevation of TNF- secretion and lowering of cAMP levels in H₂O₂-treated U937 cells. Fourth, the effect of AA on TNF- secretion was inhibited by specific inhibitors of protein kinase A (H89), p38-mitogen-activated protein kinase (SB203580), and nuclear transcription factor (NF)B (NFB-SN50). This study demonstrates that hyperketonemia increases TNF- secretion in cultured U937 monocytic cells and TNF- levels in the blood of type 1 diabetic patients and is apparently mediated by AA-induced cellular oxidative stress and cAMP deficiency.

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