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Elevated Blood Interleukin-6 Levels in Hyperketonemic Type 1 Diabetic Patients and Secretion by Acetoacetate-Treated Cultured U937 Monocytes

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

Address correspondence and reprint requests to Dr. Sushil K. Jain, Department of Pediatrics, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130. E-mail: sjain{at}lsuhsc.edu.

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], ß-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 < 0.05) and normal control subjects (P < 0.05). There was a significant correlation between ketosis and IL-6 levels (r = 0.36, P < 0.04, n = 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.

Abbreviations: AA, acetoacetate • AKB, -ketobutyric acid • BHB, ß-hydroxybutyrate • HK, hyperketonemic • IL-6, interleukin-6 • NAC, N-acetylcysteine • NK, normoketonemic • PMA, phorbol 12-myristate 13-acetate • ROS, reactive oxygen species

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