sCD40L is a proatherogenic cytokine, part of the tumor necrosis factor (TNF) superfamily and consistently associated with obesity, diabetes, and increased cardiovascular risk. Although the role of sCD40L in the onset/progression of cardiovascular complications of dysmetabolic diseases may be modulated by acute and/or chronic fluctuations of plasma insulin and glucose, very little has been done to clarify this interaction. The kinetic profile of sCD40L (and, in an exploratory manner, of several immunomodulatory factors), were measured during hyperglycemia and euglycemic-hyperinsulinemia in a group of 10 healthy young males (26.8 ± 1.4 years). After an overnight fast, intravenous (iv) catheters were placed in antecubital veins of both arms for blood drawing and dextrose/insulin iv infusions. Procedures lasted 240 minutes including baseline (t = 0-60), hyperglycemia (t = 60-150; plasma glucose ∼220 mg/dL via iv dextrose infusion), and euglycemic-hyperinsulinemia (t = 150-240; glucose infusion continued to clamp glycemic levels between 80 and 110 mg/dL; constant insulin infusion at 1.5 mU/kg/minute).
Plasma for cytokine assays was sampled at 12 separate time-points. Plasma levels of sCD40L were significantly reduced (P < 0.01) during hyperglycemia and euglycemic-hyperinsulinemia, paralleling the kinetic profiles of free fatty acids and ketone bodies. This pattern was also observed in other immunomodulatory factors (notably cortisol and epidermal growth factor), while (interleukin [IL]-1α, IL-4, IL-6, IL-9, IL-10, TNF-α, Eotaxin) did not change significantly. Significant reductions of the proatherogenic cytokine sCD40L were observed during endogenous and exogenous hyperinsulinemia, independent of prevailing glucose concentration, in young healthy males. Our data suggest a mechanism by which correct insulin action may exert a beneficial protective role against inflammation, independent of its immediate glucose-lowering effect.
CancelloR, ClementK. Is obesity an inflammatory illness? Role of low-grade inflammation and macrophage infiltration in human white adipose tissue. BJOG2006;113(10):1141–1147.
2.
HotamisligilGS. Inflammation and metabolic disorders. Nature2006;444(7121):860–867.
3.
Van GaalLF, MertensIL, De BlockCE. Mechanisms linking obesity with cardiovascular disease. Nature2006;444(7121):875–880.
4.
YuY, LyonsTJ.A lethal tetrad in diabetes: hyperglycemia, dyslipidemia, oxidative stress, and endothelial dysfunction. Am J Med Sci2005;330(5):227–232.
5.
DandonaP, AljadaA, ChaudhuriA, MohantyP, GargR. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation2005;111(11):1448–1454.
6.
PereiraFO, FrodeTS, MedeirosYS.Evaluation of tumour necrosis factor alpha, interleukin-2 soluble receptor, nitric oxide metabolites, and lipids as inflammatory markers in type 2 diabetes mellitus. Mediators Inflamm2006;2006(1):39062.
7.
VincentHK, TaylorAG.Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Int J Obes (Lond)2006;30(3):400–418.
8.
JanowskaJ, Zahorska-MarkiewiczB, Olszanecka-GlinianowiczM. Relationship between serum resistin concentration and proinflammatory cytokines in obese women with impaired and normal glucose tolerance. Metabolism2006;55(11):1495–1499.
9.
WarnbergJ, NovaE, MorenoLA, . Inflammatory proteins are related to total and abdominal adiposity in a healthy adolescent population: the AVENA Study. Am J Clin Nutr2006;84(3):505–512.
10.
KlebanovaEM.Oxidative stress, the functional activity of beta-cells, and the content of tumor necrosis factor alpha in patients with type II diabetes mellitus. Klin Med (Mosk)2006;84(8):40–43.
11.
HennV, SlupskyJR, GrafeM, . CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature1998;391(6667):591–594.
12.
DechanetJ, GrossetC, TaupinJL, . CD40 ligand stimulates proinflammatory cytokine production by human endothelial cells. J Immunol1997;159(11):5640–5647.
13.
SlupskyJR, KalbasM, WilluweitA, . Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thromb Haemost1998;80(6):1008–1014.
14.
ZhouL, StordeurP, deLA, . CD40 engagement on endothelial cells promotes tissue factor-dependent procoagulant activity. Thromb Haemost1998;79(5):1025–1028.
15.
AnandSX, Viles-GonzalezJF, BadimonJJ, . Membrane-associated CD40L and sCD40L in atherothrombotic disease. Thromb Haemost2003;90(3):377–384.
16.
LobbesMB, LutgensE, HeenemanS, . Is there more than C-reactive protein and fibrinogen? The prognostic value of soluble CD40 ligand, interleukin-6 and oxidized low-density lipoprotein with respect to coronary and cerebral vascular disease. Atherosclerosis2006;187(1):18–25.
17.
HeeschenC, DimmelerS, HammCW, . Soluble CD40 ligand in acute coronary syndromes. N Engl J Med2003;348(12):1104–1111.
18.
TousoulisD, AntoniadesC, NikolopoulouA, . Interaction between cytokines and sCD40L in patients with stable and unstable coronary syndromes. Eur J Clin Invest2007;37(8):623–628.
19.
WangY, LiL, TanHW, . Transcoronary concentration gradient of sCD40L and hsCRP in patients with coronary heart disease. Clin Cardiol2007;30(2):86–91.
20.
SchonbeckU, VaroN, LibbyP, . Soluble CD40L and cardiovascular risk in women. Circulation2001;104(19):2266–2268.
21.
SchernthanerGH, KoppHP, KrzyzanowskaK, . Soluble CD40L in patients with morbid obesity: significant reduction after bariatric surgery. Eur J Clin Invest2006;36(6):395–401.
22.
GuldikenS, DemirM, ArikanE, . The levels of circulating markers of atherosclerosis and inflammation in subjects with different degrees of body mass index: soluble CD40 ligand and high-sensitivity C-reactive protein. Thromb Res2007;119(1):79–84.
23.
GokulakrishnanK, DeepaR, MohanV, . Soluble P-selectin and CD40L levels in subjects with prediabetes, diabetes mellitus, and metabolic syndrome-the Chennai Urban Rural Epidemiology Study. Metabolism2006;55(2):237–242.
24.
LeeWL, LeeWJ, ChenYT, . The presence of metabolic syndrome is independently associated with elevated serum CD40 ligand and disease severity in patients with symptomatic coronary artery disease. Metabolism2006;55(8):1029–1034.
25.
HardingSA, SommerfieldAJ, SarmaJ, . Increased CD40 ligand and platelet-monocyte aggregates in patients with type 1 diabetes mellitus. Atherosclerosis2004;176(2):321–325.
26.
DevarajS, GlaserN, GriffenS, . Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes. Diabetes2006;55(3):774–779.
27.
KatakamiN, KanetoH, MatsuhisaM, . Association of soluble CD40 ligand with carotid atherosclerosis in Japanese type 1 diabetic patients. Diabetologia200649(7):1670–1676.
28.
YngenM, OstensonCG, HuH, . Enhanced P-selectin expression and increased soluble CD40 ligand in patients with type 1 diabetes mellitus and microangiopathy: evidence for platelet hyperactivity and chronic inflammation. Diabetologia2004;47(3):537–540.
29.
JinchuanY, ZongguiW, JinmingC, . Upregulation of CD40-CD40 ligand system in patients with diabetes mellitus. Clin Chim Acta2004;339(1-2):85–90.
30.
SantilliF, DaviG, ConsoliA, . Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus. J Am Coll Cardiol2006;47(2):391–397.
31.
VaroN, LibbyP, NuzzoR, . Elevated release of sCD40L from platelets of diabetic patients by thrombin, glucose and advanced glycation end products. Diab Vasc Dis Res2005;2(2):81–87.
32.
LimHS, BlannAD, LipGY. Soluble CD40 ligand, soluble P-selectin, interleukin-6, and tissue factor in diabetes mellitus: relationships to cardiovascular disease and risk factor intervention. Circulation2004;109(21):2524–2528.
33.
VishnevetskyD, KiyanistaVA, GandhiPJ.CD40 ligand: a novel target in the fight against cardiovascular disease. Ann Pharmacother2004;38(9):1500–1508.
34.
GalassettiPR, IwanagaK, PontelloAM, . Effect of prior hyperglycemia on IL-6 responses to exercise in children with type 1 diabetes. Am J Physiol Endocrinol Metab2006;290(5):E833–E839.
35.
DevarajS, VenugopalSK, SinghU, . Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase c-{alpha} and -{beta}. Diabetes2005;54(1):85–91.
36.
EspositoK, NappoF,MarfellaR, . Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation2002;106(16):2067–2072.
37.
SampsonMJ, GopaulN, DaviesIR, . Plasma F2-isoprostanes-direct evidence of increased free radical damage during acute hyperglycemia in type 2 diabetes. Diabetes Care2002;25:537–541.
38.
EvansJL, GoldfineID, MadduxBA, . Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev2002;23(5):599–622.
39.
HansenAP, JohansenK.Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normals and juvenile diabetics. Diabetologia1970;6(1):27–33.
40.
BraviMC, ArmientoA, LaurentiO, . Insulin decreases intracellular oxidative stress in patients with type 2 diabetes mellitus. Metabolism2006;55(5):691–695.
41.
VaidyulaVR, RaoAK, MozzoliM, . Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand. Diabetes2006;55(1):202–208.
42.
VaidyulaVR, BodenG, RaoAK.Platelet and monocyte activation by hyperglycemia and hyperinsulinemia in healthy subjects. Platelets2006;17(8):577–585.
43.
LopesHF, MorrowJD, StojiljkovicMP, . Acute hyperlipidemia increases oxidative stress more in African Americans than in white Americans. Am J Hypertens2003;16:331–336.
44.
StojiljkovicMP, LopesHF, ZhangD, . Increasing plasma fatty acids elevates F2-isoprostanes in humans: implications for the cardiovascular risk factor cluster. J Hypertens2002;20:1215–1221.
45.
OguoghoA, FerlitschA, SinzingerH.LDL-apheresis decreases plasma levels and urinary excretion of 8-epi-PGF2alpha. Prostaglandins Leukot Essent Fatty Acids2000;62(4):209–216.
46.
ViardotA, GreyST, MackayF, . Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. Endocrinology2007;148(1):346–353.
47.
AljadaA, GhanimH, SaadehR, . Insulin inhibits NFkappaB and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab2001;86(1):450–453.
48.
HansenTK, ThielS, WoutersPJ, . Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab2003;88(3):1082–1088.
49.
RosaJS, OliverSR, FloresRL, GrafSC, PontelloAM, IbardolazaM, ZaldivarFP, GalassettiPR.Kinetic profiles of 18 systemic pro- and anti-inflammatory mediators during and following exercise in children. J Pediatr Endocrinol Metab.In press2008.
50.
RosaJS, OliverSR, MitsuhashiM, FloresRL, PontelloAM, ZaldivarFP, GalassettiPR.Altered kinetics of IL-6 and other inflammatory mediators during exercise in children with type 1 diabetes. J Investig Med.In press2008.
51.
AstaneieF, AfshariM, MojtahediA, . Total antioxidant capacity and levels of epidermal growth factor and nitric oxide in blood and saliva of insulin-dependent diabetic patients. Arch Med Res2005;36(4):376–381.
52.
HongJP, JungHD, KimYW.Recombinant human epidermal growth factor (EGF) to enhance healing for diabetic foot ulcers. Ann Plast Surg2006;56(4):394–398.
53.
MiettinenPJ, UstinovJ, OrmioP, . Downregulation of EGF receptor signaling in pancreatic islets causes diabetes due to impaired postnatal beta-cell growth. Diabetes2006;55(12):3299–3308.
54.
Suarez-PinzonWL, YanY, PowerR, . Combination therapy with epidermal growth factor and gastrin increases beta-cell mass and reverses hyperglycemia in diabetic NOD mice. Diabetes2005;54(9):2596–2601.
55.
IvandicBT, SpanuthE, HaaseD, . Increased plasma concentrations of soluble CD40 ligand in acute coronary syndrome depend on in vitro platelet activation. Clin Chem2007;53(7):1231–1234.
