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

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 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>40 mg/24 hr (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.

DAF in diabetic patients is subject to glycation/inactivation at its active site residues

“…These modifications are produced by reaction of aldehydes and ketones with amino groups of lysine and arginine. Long-lived extracellular proteins such as skin collagen (Vishwanath et al, 1986; Genuth et al, 2015; Monnier et al, 2013) and eye lens protein (Perry et al, 1987) and retina have been shown to be targets of these carbohydrate-mediated reactions but nonenzymatic glycation occurs also on short-lived proteins (Bidasee etal., 2003). The pentosidine modification identified in DAF of diabetic patients is known to induce crosslinking involving the nearby R residues.…”

Biomarkers in Diabetic Retinopathy

“…Noninvasively assessed skin AGEs were also associated with retinopathy in the DCCT/EDIC cohort [173]. Skin collagen AGEs measured biochemically on skin biopsies were independent predictors of diabetic retinopathy (and other microvascular complications) in the DCCT/EDIC cohort [174][175]. Recently, a panel of 10 AGEs measured chemically in skin biopsy collagen taken near DCCT close-out has been shown to be predictive of the subsequent retinopathy status [50].…”

Optical and structural properties of biological tissues under diabetes mellitus

“…The aging of organism is accompanied by structural and functional modifications of macromolecules [70]. The changes that occur in the tissues of the organism under the development of diabetes mellitus are investigated both in laboratory animals using experimental models [9][10][11]17, 39, 40, 42, 45-47, [71][72][73][74][75][76][77] and directly in patients in the course of clinical examination [12,35,[78][79][80][81][82][83][84][85][86][87].…”

“…All of them show a sufficiently effective glycation of proteins during 10-11 days of incubation, a change in the mechanical properties of tissues due to the formation of collagen cross-links. In work [82], an increase in the glucosapane content in the skin with age and with the development of hyperglycemia in patients with type 1 diabetes mellitus was recorded. After eight months of glycation of the rabbit Achilles tendon in ribose solution [139] the increased maximum load, deformation stress, Young modulus of elasticity, and viscosity, indicating the fact that the glycation increases the stiffness of the tendon matrix, were observed.…”

“…The development of diabetes mellitus is related to increased risk of micro-and macrovascular complications (angiopathy) [8,9,13,19,[62][63][64]82], such as retinopathy that leads to blindness [8,9,10,13,31,60], neuropathy [8,9,13,60], and nephropathy [8,9,13,60]. Diabetes mellitus considerably enhances the risk of vascular diseases that finally result in the cerebral stroke [13,19,60,63].…”