title: Fibulin-1 is a marker for arterial extracellular matrix alterations in type 2 diabetes.
abstract: BACKGROUND
  Extracellular matrix alterations are important elements in the arterial changes seen in diabetes, being associated with increased vascular stiffness and the development of cardiovascular diseases. However, no biomarkers for diabetes-related arterial changes have been defined.
  
  
  METHODS
  Mammary artery specimens from 17 men with type 2 diabetes and 18 nondiabetic individuals were used for microarray expression profiling, quantitative real-time PCR, immunoassay, and immunohistochemical analyses. A derived candidate marker, fibulin-1, which is an elastin-associated matrix molecule, was measured immunochemically in plasma from (a) 70 patients scheduled for vascular surgery, (b) 305 patients with type 2 diabetes examined with carotid ultrasonography and echocardiography, and (c) 308 patients with type 2 diabetes, followed for 15 years.
  
  
  RESULTS
  The most upregulated transcript in nonatherosclerotic arterial tissue from patients with type 2 diabetes encoded the extracellular matrix protein, fibulin-1. Higher concentrations of fibulin-1-protein were present in artery extracts from patients with diabetes than extracts from individuals without diabetes, and increased fibulin-1 immunostaining was apparent around the external elastic lamina of diabetic arteries. Patients with diabetes displayed increased plasma concentrations of fibulin-1 (P = 0.006). Plasma fibulin-1 concentrations correlated with hemoglobin A(1c) (P < 0.001), arterial stiffness indices including pulse pressure (P < 0.001), and carotid compliance (P = 0.004), as well as plasma N-terminal pro-B-type natriuretic peptide concentrations (P < 0.001) and were predictive of 15-year mortality (P = 0.013).
  
  
  CONCLUSIONS
  Fibulin-1 accumulates in the arterial wall and in plasma of patients with type 2 diabetes, and appears to be a factor associated with arterial extracellular matrix changes in type 2 diabetes.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Institute of Molecular Medicine and Clinical Institute, Odense University Hospital, University of Southern Denmark.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cangemi
authors.forename: Vibe
authors.initials: V
authors.lastname: Skov
authors.forename: Michael Kjaer
authors.initials: MK
authors.lastname: Poulsen
authors.forename: Jonas
authors.initials: J
authors.lastname: Funder
authors.forename: Waleed O
authors.initials: WO
authors.lastname: Twal
authors.forename: Mari-Anne
authors.initials: MA
authors.lastname: Gall
authors.forename: Vibeke
authors.initials: V
authors.lastname: Hjortdal
authors.forename: Marie Louise
authors.initials: ML
authors.lastname: Jespersen
authors.forename: Torben A
authors.initials: TA
authors.lastname: Kruse
authors.forename: Jan
authors.initials: J
authors.lastname: Aagard
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.forename: Steen
authors.initials: S
authors.lastname: Knudsen
authors.forename: Poul-Flemming
authors.initials: PF
authors.lastname: Høilund-Carlsen
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Henriksen
authors.forename: William Scott
authors.initials: WS
authors.lastname: Argraves
authors.forename: Lars Melholt
authors.initials: LM
authors.lastname: Rasmussen
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000097:blood / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007118:Immunoassay; D007150:Immunohistochemistry; D008297:Male; D008323:Mammary Arteries / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C060820:fibulin