glucosepane and Diabetes-Mellitus--Type-1

To study intima media thickness (cIMT) and arterial stiffness in type 1 diabetes of long duration, and their associations with the collagen cross-linker glucosepane and inflammatory and oxidative markers.. Twenty-seven individuals with type 1 diabetes mellitus of 40 years duration from the Oslo Study cohort and 24 age-matched controls were included. cIMT measurements of the carotid artery were performed longitudinally. Pulse wave velocity (PWV), augmentation index (AIx) and augmentation pressure (AP) were assessed cross-sectionally. Glucosepane and the oxidative product methionine sulfoxide (MetSO) were determined in skin collagen by liquid chromatography-mass spectrometry. Circulating inflammatory markers were determined by ELISAs.. The diabetes patients had significantly increased cIMT and arterial stiffness compared to controls. Significant correlations were noted for skin glucosepane with cIMT (r=0.41) and PWV (r=0.44). Skin MetSO and monocyte chemoattractant protein-1 (MCP-1) correlated significantly with AIx and AP. After correcting for age and mean arterial pressure in multiple linear regression analysis, MetSO and MCP-1 were both independently associated with AIx and AP.. These results suggest more premature atherosclerosis and arterial pathology in individuals with diabetes compared to age-matched controls. They also suggest an association between the arterial pathology and markers of collagen crosslinking, oxidative damage and inflammation in type 1 diabetes patients of forty years disease duration.

Topics: Adolescent; Adult; Biomarkers; Carotid Intima-Media Thickness; Case-Control Studies; Collagen; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Female; Follow-Up Studies; Glycation End Products, Advanced; Humans; Male; Middle Aged; Oxidative Stress; Skin; Vascular Stiffness; Young Adult

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).. 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.. 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,. 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.. Registered at Clinical trial reg. nos. NCT00360815 and NCT00360893, http://www.clinicaltrials.gov.

Topics: Adult; Arginine; Asymptomatic Diseases; Biomarkers; Biopsy; Cardiovascular Diseases; Carotid Artery Diseases; Carotid Intima-Media Thickness; Chi-Square Distribution; Collagen; Coronary Artery Disease; Diabetes Mellitus, Type 1; Disease Progression; Female; Glycation End Products, Advanced; Glycosylation; Heart Diseases; Humans; Logistic Models; Lysine; Magnetic Resonance Imaging; Male; Multivariate Analysis; Odds Ratio; Pepsin A; Pyruvaldehyde; Risk Factors; Skin; Time Factors; Vascular Calcification; Young Adult

Six skin collagen advanced glycation end products (AGEs) originally measured near to the time of the Diabetes Control and Complications Trial (DCCT) closeout in 1993 may contribute to the "metabolic memory" phenomenon reported in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. We have now investigated whether the addition of four originally unavailable AGEs (i.e., glucosepane [GSPNE], hydroimidazolones of methylglyoxal [MG-H1] and glyoxal, and carboxyethyl-lysine) improves associations with incident retinopathy, nephropathy, and neuropathy events during 13-17 years after DCCT. The complete 10-AGE panel is associated with three-step Early Treatment of Diabetic Retinopathy Study scale worsening of retinopathy (P ≤ 0.002), independent of either mean DCCT or EDIC study A1C level. GSPNE and fructose-lysine (furosine [FUR]) correlate with retinopathy progression, independently of A1C level. The complete panel also correlates with microalbuminuria (P = 0.008) and FUR with nephropathy independently of A1C level (P ≤ 0.02). Neuropathy correlates with the complete panel despite adjustment for A1C level (P ≤ 0.005). MG-H1 and FUR are dominant, independent of A1C level (P < 0.0001), whereas A1C loses significance after adjustment for the AGEs. Overall, the added set of four AGEs enhances the association of the original panel with progression risk of retinopathy and neuropathy (P < 0.04) but not nephropathy, while GSPNE and MG-H1 emerge as the principal new risk factors. Skin AGEs are robust long-term markers of microvascular disease progression, emphasizing the importance of early and sustained implementation of intensive therapy.

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Female; Glycation End Products, Advanced; Humans; Imidazoles; Logistic Models; Male; Microvessels; Multivariate Analysis; Pyruvaldehyde; Skin; Young Adult