Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones.
BACKGROUND
Considerable evidence implicates the proinflammatory cytokine CD40 ligand (CD40L) in atherosclerosis and accumulating data link type 1 and 2 diabetes, conditions associated with accelerated atherosclerosis, to inflammation. This study therefore evaluated the hypothesis that diabetic patients have elevated plasma levels of soluble CD40L (sCD40L) and that treatment with the insulin-sensitizing thiazolidinediones lowers this index of inflammation.


RESULTS
Subjects with type 1 (n=49) or type 2 diabetes (n=48) had higher (P<0.001) sCD40L plasma levels (6.56+/-3.27 and 6.67+/-2.90 ng/mL, respectively) compared with age-matched control groups (1.40+/-2.21 and 1.32+/-2.68 ng/mL, respectively). Multiple regression analysis demonstrated a significant (P<0.001) association between plasma sCD40L and type 1 as well as type 2 diabetes, independent of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, body mass index, gender, C-reactive protein, and soluble intracellular adhesion molecule-1. Furthermore, in a pilot study, administration of troglitazone (12 weeks, 600 mg/day), but not placebo, to type 2 diabetics (n=68) significantly (P<0.001) diminished sCD40L plasma levels by 29%. The thiazolidinedione lowered plasma sCD40L in type 2 diabetic patients with long-standing disease (>3 years) with or without macrovascular complications (-34% and -29%, respectively) as well as in type 2 diabetic patients with more recent (<3 years) onset of the disease (-27%; all P<0.05).


CONCLUSIONS
This study provides new evidence that individuals with type 1 or 2 diabetes have a proinflammatory state as indicated by elevated levels of plasma sCD40L. Troglitazone treatment of type 2 diabetic patients diminishes sCD40L levels, suggesting a novel antiinflammatory mechanism for limiting diabetes-associated arterial disease.
Varo
Nerea
N
Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston, Mass 02115, USA.
Vicent
David
D
Libby
Peter
P
Nuzzo
Rebecca
R
Calle-Pascual
Alfonso L
AL
Bernal
María Rosa
MR
Fernández-Cruz
Arturo
A
Veves
Aristidis
A
Jarolim
Petr
P
Varo
Jose Javier
JJ
Goldfine
Allison
A
Horton
Edward
E
Schönbeck
Uwe
U
D000208:Acute Disease; D000328:Adult; D000368:Aged; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology; D015992:Body Mass Index; D023201:CD40 Ligand / Q000097:blood*; D002839:Chromans / Q000627:therapeutic use*; D002908:Chronic Disease; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008137:Longitudinal Studies; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D010865:Pilot Projects; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D012016:Reference Values; D012307:Risk Factors; D012995:Solubility; D013030:Spain; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D023201:CD40 Ligand; D008687:Metformin; D000077288:Troglitazone