title: Perturbation of hyaluronan metabolism predisposes patients with type 1 diabetes mellitus to atherosclerosis.
abstract: OBJECTIVE
  Cardiovascular disease contributes to mortality in type 1 diabetes mellitus, but the specific pathophysiological mechanisms remain to be established. We recently showed that the endothelial glycocalyx, a protective layer of proteoglycans covering the endothelium, is severely perturbed in type 1 diabetes, with concomitantly increased plasma levels of hyaluronan and hyaluronidase. In the present study, we evaluated the relationship between hyaluronan and hyaluronidase with carotid intima-media thickness (cIMT), an established surrogate marker for cardiovascular disease.
  
  
  METHODS
  Non-smoking type 1 diabetes patients without micro- or macrovascular complications and matched controls were recruited and cIMT of both carotid arteries was measured. To evaluate the relationship between cIMT and hyaluronan and hyaluronidase as well as other parameters, uni- or multivariate regression analyses were performed.
  
  
  RESULTS
  We included 99 type 1 diabetes patients (age 10-72 years) and 99 age- and sex-matched controls. Mean cIMT, HbA(1c), high sensitivity C-reactive protein, hyaluronan and hyaluronidase were significantly increased in type 1 diabetes vs controls. Plasma hyaluronan and hyaluronidase were correlated in type 1 diabetes. In univariate regression analyses, mean IMT was associated with plasma hyaluronan, age and male sex, whereas after multivariate analysis only age and sex remained statistically significant.
  
  
  CONCLUSIONS
  We conclude that type 1 diabetes patients show structural changes of the arterial wall associated with increased hyaluronan metabolism. These data may lend further support to altered glycosaminoglycan metabolism in type 1 diabetes as a potential mechanism involved in accelerated atherogenesis.
authors.affiliation: Department of Internal Medicine, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. m.nieuwdorp@amc.uva.nl
authors.forename: M
authors.initials: M
authors.lastname: Nieuwdorp
authors.forename: F
authors.initials: F
authors.lastname: Holleman
authors.forename: E
authors.initials: E
authors.lastname: de Groot
authors.forename: H
authors.initials: H
authors.lastname: Vink
authors.forename: J
authors.initials: J
authors.lastname: Gort
authors.forename: A
authors.initials: A
authors.lastname: Kontush
authors.forename: M J
authors.initials: MJ
authors.lastname: Chapman
authors.forename: B A
authors.initials: BA
authors.lastname: Hutten
authors.forename: C B
authors.initials: CB
authors.lastname: Brouwer
authors.forename: J B L
authors.initials: JB
authors.lastname: Hoekstra
authors.forename: J J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: E S G
authors.initials: ES
authors.lastname: Stroes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000097:blood / Q000453:epidemiology*; D002339:Carotid Arteries / Q000473:pathology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications*; D003925:Diabetic Angiopathies / Q000097:blood / Q000453:epidemiology*; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood*; D006821:Hyaluronoglucosaminidase / Q000097:blood*; D008875:Middle Aged; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
chemical_list: D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase