Elevated blood interleukin-6 levels in hyperketonemic type 1 diabetic patients and secretion by acetoacetate-treated cultured U937 monocytes.
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.


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], beta-hydroxybutyrate [BHB]) in the presence or absence of high glucose levels in the medium at 37 degrees 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.
Jain
Sushil K
SK
Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA. sjain@lsuhsc.edu
Kannan
Krishnaswamy
K
Lim
Gideon
G
Matthews-Greer
Janice
J
McVie
Robert
R
Bocchini
Joseph A
JA
D000090:Acetoacetates / Q000494:pharmacology*; D000293:Adolescent; D017668:Age of Onset; D002478:Cells, Cultured; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000276:immunology; D016883:Diabetic Ketoacidosis / Q000097:blood* / Q000276:immunology; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D007657:Ketone Bodies / Q000097:blood; D017382:Reactive Oxygen Species / Q000378:metabolism; D012016:Reference Values; D035781:Siblings; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism
D000090:Acetoacetates; D006442:Glycated Hemoglobin; D015850:Interleukin-6; D007657:Ketone Bodies; D017382:Reactive Oxygen Species; C016635:acetoacetic acid