Skin collagen advanced glycation endproducts (AGEs) and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes.
BACKGROUND
We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies obtained at DCCT study closeout and the long-term progression of microvascular disease in EDIC, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs (fluorescence to be reported elsewhere) correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC) at EDIC year 7-9 (n = 187), change of carotid intima-media thickness (IMT) from EDIC year 1 to year 6 and 12 (n = 127), and cardiac MRI outcomes at EDIC year 15-16 (n = 142).


METHODS
Skin collagen AGE measurements obtained from stored specimens were related to clinical data from the DCCT/EDIC using Spearman correlations and multivariable logistic regression analyses.


RESULTS
Spearman correlations showed furosine (early glycation) was associated with future mean CAC (p < 0.05) and CAC >0 (p = 0.039), [corrected] but not with CAC score <100 vs. >100. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change from year 1 to 6(all P < 0.05). Left ventricular (LV) mass (cMRI) correlated with MG-H1, and inversely with pepsin solubility (both p < 0.05), while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1 (both p < 0.05), and highly with CML (p < 0.01). In multivariate analysis only furosine (p = 0.01) was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane,


CONCLUSIONS
In type 1 diabetes, multiple AGEs are associated with IMT progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation.


BACKGROUND
Registered at Clinical trial reg. nos. NCT00360815 and NCT00360893, http://www.clinicaltrials.gov.
Departments of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA. vmm3@cwru.edu.|Departments of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA. vmm3@cwru.edu.
Vincent M
VM
Monnier
The Biostatistics Center, The George Washington University, Rockville, MD, USA. ws8021@hotmail.com.
Wanjie
W
Sun
The Biostatistics Center, The George Washington University, Rockville, MD, USA. xgao@bsc.gwu.edu.
Xiaoyu
X
Gao
Departments of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA. drs7@case.edu.
David R
DR
Sell
The Biostatistics Center, The George Washington University, Rockville, MD, USA. cleary@bsc.gwu.edu.
Patricia A
PA
Cleary
The Biostatistics Center, The George Washington University, Rockville, MD, USA. jlm@bsc.gwu.edu.
John M
JM
Lachin
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA. smg15@case.edu.
Saul
S
Genuth
D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism; D059168:Carotid Intima-Media Thickness; D016009:Chi-Square Distribution; D003094:Collagen / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006031:Glycosylation; D006331:Heart Diseases / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism; D006801:Humans; D016015:Logistic Models; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D015999:Multivariate Analysis; D016017:Odds Ratio; D010434:Pepsin A / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism; D012307:Risk Factors; D012867:Skin / Q000378:metabolism*; D013997:Time Factors; D061205:Vascular Calcification / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism; D055815:Young Adult
D015415:Biomarkers; D017127:Glycation End Products, Advanced; C018948:furosine; C543060:glucosepane; D011765:Pyruvaldehyde; D003094:Collagen; D001120:Arginine; C062187:pentosidine; D010434:Pepsin A; D008239:Lysine