title: Increased Nepsilon-(carboxymethyl)-lysine levels in cerebral blood vessels of diabetic patients and in a (streptozotocin-treated) rat model of diabetes mellitus.
abstract: OBJECTIVE
  Non-enzymatic glycation of proteins and their end products (advanced glycation end products, AGE) have been implicated in the pathogenesis of diabetic complications. Our aim was to evaluate the association between diabetes mellitus (DM) and the accumulation of one of the most abundant AGEs, Nepsilon-(carboxymethyl)-lysine (CML), in cerebral vessels.
  
  
  METHODS
  Brain tissue samples were obtained by autopsy from 20 DM patients and 13 age-matched controls. In addition, we investigated brain tissue samples of seven rats after induction of diabetes with streptozotocin (STZ) and six non-diabetic control rats. We used an immunohistochemical staining method to examine the CML immunoreactivity in the cerebral vessels.
  
  
  RESULTS
  Staining intensity of CML was significantly higher in cerebral vessels of diabetic patients than in non-diabetic subjects (median of the immunohistochemical intensity score/cm(2) in the diabetic group of 0.85 (interquartile range (IQR) 0.66-1.52) vs 0.63 in the control group (IQR 0.44-0.70); P=0.002). Furthermore, there was a similar significant difference in CML staining intensity of cerebral vessels between STZ diabetic rats and non-diabetic control rats (median of the immunohistochemical intensity score/cm(2) in the diabetic group of 1.08 (IQR 0.73-1.43) vs 0.23 in the control group (IQR 0.12-0.43); P=0.003).
  
  
  CONCLUSIONS
  Accumulation of CML-modified proteins is significantly greater in the cerebral vessels of the diabetic patients than their age-matched controls. This association has been confirmed in the insulin-deficient diabetic rat model. It may be possible that the excessive accumulation of AGE-modified proteins in the cerebral vasculature alters the local environment and microcirculation and thereby contributes to the development of cognitive impairments in diabetes. Therefore, additional study on the causal link between AGE accumulation and cognitive dysfunction and the potential benefits of AGE-blocking and/or breaking compounds is indicated.
authors.affiliation: Department of Endocrinology/Diabetes Center, VU University Medical Center, PO Box 7057, 1007 MB, Boelelaan 1117, Amsterdam, The Netherlands.
authors.forename: A W
authors.initials: AW
authors.lastname: van Deutekom
authors.forename: H W M
authors.initials: HW
authors.lastname: Niessen
authors.forename: C G
authors.initials: CG
authors.lastname: Schalkwijk
authors.forename: R J
authors.initials: RJ
authors.lastname: Heine
authors.forename: S
authors.initials: S
authors.lastname: Simsek
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002560:Cerebrovascular Circulation; D002648:Child; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D017127:Glycation End Products, Advanced / Q000097:blood*; D006801:Humans; D007150:Immunohistochemistry; D008239:Lysine / Q000031:analogs & derivatives* / Q000097:blood; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar
chemical_list: D017127:Glycation End Products, Advanced; C048496:N(6)-carboxymethyllysine; D008239:Lysine