title: The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes.
abstract: OBJECTIVE
  We determined the association between novel and acid-labile skin collagen-linked advanced glycation endproducts (AGEs) and the progression of microvascular and neuropathic complications from baseline to near study closeout in the Diabetes Control and Complications Trial (DCCT).
  
  
  METHODS
  From a skin biopsy obtained near the close of the DCCT, proteolytic collagen digests were analyzed by liquid chromatography/mass spectrometry (LC/MS/MS) for glucosepane (GSPNE), glyoxal and methylglyoxal hydroimidazolones (G-H1 and MG-H1) and the glycation product fructose-lysine (FL) using isotope dilution method.
  
  
  RESULTS
  GSPNE and MG-H1 correlated with age and diabetes duration (P<0.02), while GSPNE and FL correlated with the history of glycemia expressed as mean A1c (P≤0.003). Age and duration-adjusted GSPNE and FL levels were lower in intensive (INT) vs. conventional (CONV) treatment subjects in the primary prevention DCCT cohort (P<0.0001), and FL was lower in INT in the secondary intervention cohort (P<0.0001). GSPNE was associated with increased incidence of retinopathy progression (odds ratio (OR) / unit increase in GSPNE: 2.5 for 3 step progression on the ETDRS scale, P=0.003) and sustained≥3 microaneurysms (MA) (OR=4.8, P<0.0001) from DCCT baseline up to the time of the biopsy, and prevalence of microalbuminuria or AER>40mg/24h (OR=5.3, P<0.0001), and confirmed clinical neuropathy (OR=3.4, P=0.015) at the time of the biopsy. GSPNE adjusted for mean A1c remained significant for ≥3 MA (P=0.0252) and AER (P=0.0006). The strong association of complications with A1c was reduced or eliminated when adjusted for GSPNE.
  
  
  CONCLUSIONS
  Glucosepane is a novel AGE marker of diabetic complications that is robustly associated with nephropathic, retinopathic and neuropathic outcomes despite adjustment for A1c, suggesting that it could be one mediator of these complications with possible diagnostic implications.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. vmm3@cwru.edu
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Monnier
authors.forename: David R
authors.initials: DR
authors.lastname: Sell
authors.forename: Christopher
authors.initials: C
authors.lastname: Strauch
authors.forename: Wanjie
authors.initials: W
authors.lastname: Sun
authors.forename: John M
authors.initials: JM
authors.lastname: Lachin
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Cleary
authors.forename: Saul
authors.initials: S
authors.lastname: Genuth
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D003094:Collagen / Q000378:metabolism*; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000503:physiopathology; D018450:Disease Progression; D005500:Follow-Up Studies; D006442:Glycated Hemoglobin / Q000032:analysis; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D055806:Microvessels / Q000473:pathology*; D012720:Severity of Illness Index; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003094:Collagen; D006442:Glycated Hemoglobin; D017127:Glycation End Products, Advanced; D008239:Lysine; C517652:hemoglobin A1c protein, human; C033186:fructosyl-lysine; C543060:glucosepane