No abstract

No abstract

OBJECTIVE -Diabetic patients have elevated blood levels of interleukin-6 (IL-6), which is known to increase inflammation and the development of vascular disease and atherosclerosis. This study examined the hypothesis that ketosis increases the circulating levels of IL-6 in type 1 diabetic patients as well as the secretion of IL-6 in vitro in a cell culture model using U937 monocytes.RESEARCH DESIGN AND METHODS -Fasting blood was obtained from type 1 diabetic patients and healthy siblings. To examine the effect of ketosis, U937 monocytes were cultured with ketone bodies (acetoacetate [AA], ␤-hydroxybutyrate [BHB]) in the presence or absence of high glucose levels in the medium at 37°C for 24 h. IL-6 was determined by the sandwich enzyme-linked immunosorbent assay method, and intracellular reactive oxygen species (ROS) generation was detected using dihydroethidium dye. RESULTS-The blood level of IL-6 was higher in hyperketonemic (HK) diabetic patients than in normoketonemic (NK) diabetic patients (P Ͻ 0.05) and normal control subjects (P Ͻ 0.05). There was a significant correlation between ketosis and IL-6 levels (r ϭ 0.36, P Ͻ 0.04, n ϭ 34) in the blood of diabetic patients. Cell culture studies found that exogenous addition of the ketone body AA, but not BHB, increases IL-6 secretion and ROS generation in U937 cells. N-acetylcysteine (NAC) prevented the IL-6 secretion in acetoacetate-treated U937 monocytes.CONCLUSIONS -This study demonstrates that hyperketonemia increases IL-6 levels in the blood of type 1 diabetic patients and that NAC can inhibit IL-6 secretion by U937 monocytic cells cultured in a ketotic medium. Diabetes Care 26:2139 -2143, 2003I nterleukin-6 (IL-6), which is secreted by macrophages, lymphocytes, and other cells (1), is an important cytokine that can initiate events leading to atherogenesis by induction of adhesion molecules, monocyte-endothelial interactions, and inflammation injury (1-5). Anti-IL-6 therapy significantly prevents the inflammatory process in mice (6). The role of IL-6 in vascular inflammation has also been shown using IL-6 knockout mice that exhibit resistance to splanchnic artery occlusion shock (6), and in studies (7) that show increased levels of lipid peroxidation and inflammation in mice that overexpress IL-6. This suggests that elevated blood levels of IL-6 are associated with the development of vascular inflammation and atherosclerosis (1,2).IL-6 levels in blood are higher or similar in diabetic patients compared with normal subjects (4,8 -10). Cell culture studies have shown that high glucose concentrations can increase the IL-6 secretion in cultured monocytes (4,11,12). In addition to hyperglycemia, type 1 diabetic patients frequently experience ketosis (hyperketonemia) from excessive fat breakdown because body fuel is derived mainly from fat when the body is in a state of insulin deficiency (13). The blood concentration of ketone bodies (acetoacetate [AA], ␤-hydroxybutyrate [BHB]) may reach 10 mmol/l in patients with severe ketosis, as compared with levels of Ͻ0.5 ...