title: Circulating dickkopf-1 in diabetes mellitus: association with platelet activation and effects of improved metabolic control and low-dose aspirin.
abstract: BACKGROUND
  Dickkopf-1 (DKK-1) is a major regulator of the Wnt signaling pathway, involved in inflammation, atherogenesis, and the regulation of glucose metabolism. Because platelets are major contributors to circulating levels of DKK-1 in other clinical settings, we aimed at characterizing the platelet contribution to DKK-1 in type 2 diabetes mellitus (T2DM) and evaluating associations of DKK-1 with glucose metabolism, platelet activation, and endothelial dysfunction.
  
  
  RESULTS
  A cross-sectional comparison of DKK-1, soluble CD40L (sCD40L; reflecting platelet-mediated inflammation), asymmetric dimethylarginine (ADMA; marker of endothelial dysfunction), and urinary 11-dehydro-thromboxane B2 (in vivo marker of platelet activation) was performed among 214 diabetic patients (90 receiving aspirin at 100 mg/day) and 30 healthy controls. Plasma DKK-1 levels were markedly higher in patients with T2DM than in healthy patients (P<0.0001). DKK-1 levels were significantly lower in diabetic patients receiving compared with those not on aspirin treatment (P=0.008); in the latter, DKK-1 was significantly correlated with 11-dehydro-thromboxane B2, ADMA, and CD40L (ρ=0.303. P<0.0001, ρ=0.45. P<0.0001, and ρ=0.37, P<0.0001, respectively) but not with glycemic control or DM duration. Among patients not receiving aspirin, improvement of metabolic control in a subgroup of newly diagnosed patients treated with acarbose for 20 weeks and in a group treated with rosiglitazone for 24 weeks was associated with concurrent significant reductions in DKK-1 (P=0.005 and P=0.004) and 11-dehydro-thromboxane B2 (P=0.005 and P=0.004).
  
  
  CONCLUSIONS
  Circulating DKK-1 is increased in T2DM and associated with endothelial dysfunction and platelet activation. Plasma DKK-1 levels are reduced with improvement of glycemic control and low-dose aspirin treatment.
authors.affiliation: Center of Excellence on Aging, "G. d'Annunzio" University of Chieti, Italy (S.L., F.S., R.L., N.V., P.D.F., G.F., A.C., G.D.).
authors.forename: Stefano
authors.initials: S
authors.lastname: Lattanzio
authors.affiliation: Center of Excellence on Aging, "G. d'Annunzio" University of Chieti, Italy (S.L., F.S., R.L., N.V., P.D.F., G.F., A.C., G.D.).
authors.forename: Francesca
authors.initials: F
authors.lastname: Santilli
authors.affiliation: Center of Excellence on Aging, "G. d'Annunzio" University of Chieti, Italy (S.L., F.S., R.L., N.V., P.D.F., G.F., A.C., G.D.).
authors.forename: Rossella
authors.initials: R
authors.lastname: Liani
authors.affiliation: Center of Excellence on Aging, "G. d'Annunzio" University of Chieti, Italy (S.L., F.S., R.L., N.V., P.D.F., G.F., A.C., G.D.).
authors.forename: Natale
authors.initials: N
authors.lastname: Vazzana
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.U., A.).
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.affiliation: Center of Excellence on Aging, "G. d'Annunzio" University of Chieti, Italy (S.L., F.S., R.L., N.V., P.D.F., G.F., A.C., G.D.).
authors.forename: Patrizia
authors.initials: P
authors.lastname: Di Fulvio
authors.affiliation: Center of Excellence on Aging, "G. d'Annunzio" University of Chieti, Italy (S.L., F.S., R.L., N.V., P.D.F., G.F., A.C., G.D.).
authors.forename: Gloria
authors.initials: G
authors.lastname: Formoso
authors.affiliation: Center of Excellence on Aging, "G. d'Annunzio" University of Chieti, Italy (S.L., F.S., R.L., N.V., P.D.F., G.F., A.C., G.D.).
authors.forename: Agostino
authors.initials: A
authors.lastname: Consoli
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway (T.U., A.).
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Center of Excellence on Aging, "G. d'Annunzio" University of Chieti, Italy (S.L., F.S., R.L., N.V., P.D.F., G.F., A.C., G.D.).
authors.forename: Giovanni
authors.initials: G
authors.lastname: Davì
mesh_terms: D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D001241:Aspirin / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D023201:CD40 Ligand / Q000097:blood*; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine; D060449:Wnt Signaling Pathway
chemical_list: D001120:Arginine; D001241:Aspirin; D015415:Biomarkers; D023201:CD40 Ligand; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D036341:Intercellular Signaling Peptides and Proteins; D010975:Platelet Aggregation Inhibitors; D013929:Thromboxane B2; C501126:DKK1 protein, human; C517652:hemoglobin A1c protein, human; C018524:N,N-dimethylarginine; C049235:11-dehydro-thromboxane B2
keywords: DKK‐1; diabetes mellitus; endothelial dysfunction; inflammation; platelet activation; platelet‐derived factor