Skin collagen advanced glycation endproducts (AGEs) and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes

Abstract

BackgroundWe 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).MethodsSkin collagen AGE measurements obtained from stored specimens were related to clinical data from the DCCT/EDIC using Spearman correlations and multivariable logistic regression analyses.ResultsSpearman correlations showed furosine (early glycation) was associated with future mean CAC (p < 0.05) and CAC >0 (p = 0.39), 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,ConclusionsIn 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.Trial registration: Registered at Clinical trial reg. nos. NCT00360815 and NCT00360893, http://www.clinicaltrials.gov

The C-terminal tails of 4,4'-diphenylmethane-bis(methyl) carbamate are essential for binding to receptor for advanced glycation end products to attenuate advanced glycation end products-induced inflammation and apoptosis responses in human umbilical vein endothelial cells

“…The accumulation of compounds in the extracellular space and within the cells of vessel wall contributed to the accelerated endothelial dysfunction in diabetes . In type 1 diabetes, multiple AGEs are associated with intima‐media thickness progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated cross‐linking on matrix accumulation in coronary arteries . Takeuchi et al .…”

“…[20] In type 1 diabetes, multiple AGEs are associated with intima-media thickness progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated cross-linking on matrix accumulation in coronary arteries. [21] Takeuchi et al [22] believed that toxic compounds glyceraldehyde-derived AGEs (AGE-2) and glycolaldehyde derived AGEs (AGE-3) were the contributors for the damage of AGEs on endothelial dysfunction, but not all compounds. The endothelial dysfunction activity of AGE-2 and AGE-3 might be associated with the following com-pounds: trihydroxy-triosidine, triosidine-carbaldehyde, arg-hydroxy-triosidine, lys-hydroxy-triosidine, GA-pyridine, tetrahydro-pyrimidine and so on.…”

Glycation and cardiovascular disease in diabetes: A perspective on the concept of metabolic memory

“…36,37 Skin collagen AGEs obtained from skin biopsies at the close of DCCT, such as glucosepane and methylglyoxal hydroimidazolone, were reported to be correlated with the progression of carotid IMT during the DCCT-EDIC even after adjustment for mean HbA1c values. 38 Furthermore, total fluorescence of collagen digests and long-wave fluorophore 1 (LW-1), a collagen-linked fluorescent product that has a lysine residue coupled to a sugar molecule, were also associated with IMT progression and left ventricular mass at Years 12 and 14-16 in the DCCT-EDIC, respectively. 39…”

The AGE receptor, OST48 drives podocyte foot process effacement and basement membrane expansion in experimental diabetic kidney disease via promotion of endoplasmic reticulum stress

“…Increases in AGE formation on skin collagen [10][11][12] and within the circulation [13,14] predict poor prognosis for patients with diabetes including increased risk for kidney and cardiovascular disease. The kidneys are a major site of AGE detoxification through the filtration of circulating AGEs and their subsequent active uptake and excretion [15,16].…”