Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes - Relevance of glycated collagen products versus HbA(1c) as markers of diabetic complications

The relationships between long-term intensive control of glycemia and indic ators of skin collagen glycation (furosine), glycoxidation (pentosidine and N-epsilon-[carboxymethyl]-lysine [CML]), and crosslinking (acid and pepsin solubility) were examined in 216 patients with type 1 diabetes from the pr imary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 year s of intensive treatment was associated with 30-32% lower furosine, 9%, low er pentosidine, 9-13% lower CML, 24% higher acid-soluble collagen, and 50% higher pepsin-soluble collagen. All of these differences were statistically significant in the subjects of the primary prevention cohort (P < 0.006-0. 001) and also of the secondary intervention cohort (P < 0.015-0.001) with t he exception of CML and acid-soluble collagen. Age- and duration-adjusted c ollagen variables were significantly associated with the HbA(1c) value near est the biopsy and with cumulative prior HbA(1c) values. Multiple logistic regression analyses with six nonredundant collagen parameters as independen t variables and various expressions of retinopathy, nephropathy, and neurop athy outcomes as dependent variables showed that the complications were sig nificantly associated with the full set of collagen variables. Surprisingly , the percentage of total variance (R-2) in complications explained by the collagen variables ranged from 19 to 36% with the intensive treatment and f rom 14 to 51% with conventional treatment. These associations generally rem ained significant even after adjustment for HbA(1c), and, most unexpectedly , in conventionally treated subjects, glycated collagen was the parameter m ost consistently associated with diabetic complications. Continued monitori ng of these subjects may determine whether glycation products in the skin, and especially the early Amadori product (furosine), have the potential to be predictors of the future risk of developing complications, and perhaps b e even better predictors than glycated hemoglobin (HbA(1c)).