The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes

J Diabetes Complications. Mar-Apr 2013;27(2):141-9. doi: 10.1016/j.jdiacomp.2012.10.004. Epub 2012 Nov 12.

Abstract

Purpose: 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.

Publication types

  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / metabolism
  • Cohort Studies
  • Collagen / metabolism*
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / therapy
  • Diabetic Angiopathies / physiopathology*
  • Diabetic Neuropathies / physiopathology*
  • Diabetic Retinopathy / physiopathology
  • Disease Progression
  • Follow-Up Studies
  • Glycated Hemoglobin A / analysis
  • Glycation End Products, Advanced / metabolism*
  • Humans
  • Hyperglycemia / prevention & control
  • Lysine / analogs & derivatives
  • Lysine / metabolism
  • Microvessels / pathology*
  • Severity of Illness Index
  • Skin / metabolism*
  • Skin / pathology
  • Young Adult

Substances

  • Biomarkers
  • Glycated Hemoglobin A
  • Glycation End Products, Advanced
  • hemoglobin A1c protein, human
  • fructosyl-lysine
  • glucosepane
  • Collagen
  • Lysine