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 HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial.

Abstract

The relationships between long-term intensive control of glycemia and indicators 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 primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 years of intensive treatment was associated with 30-32% lower furosine, 9% lower 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 the exception of CML and acid-soluble collagen. Age- and duration-adjusted collagen variables were significantly associated with the HbA1c value nearest the biopsy and with cumulative prior HbA1c values. Multiple logistic regression analyses with six nonredundant collagen parameters as independent variables and various expressions of retinopathy, nephropathy, and neuropathy outcomes as dependent variables showed that the complications were significantly associated with the full set of collagen variables. Surprisingly, the percentage of total variance (R2) in complications explained by the collagen variables ranged from 19 to 36% with the intensive treatment and from 14 to 51% with conventional treatment. These associations generally remained significant even after adjustment for HbA1c, and, most unexpectedly, in conventionally treated subjects, glycated collagen was the parameter most consistently associated with diabetic complications. Continued monitoring 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 be even better predictors than glycated hemoglobin (HbA1c).

Modulation of Soluble Receptor for Advanced Glycation End Products by Angiotensin-Converting Enzyme-1 Inhibition in Diabetic Nephropathy

“…With evidence from the Diabetes Control and Complications Trial of patients with type 1 diabetes showing that skin CML levels are a major predictor of progression to diabetic complications (39), it is important to delineate the exact regulation not only of plasma but also of tissue components of the AGE pathway. Indeed, assessment of tissue collagen-associated AGE provides us with a more accurate record of historical levels of circulating AGE and glucose.…”

A Post-Amadori Inhibitor Pyridoxamine Also Inhibits Chemical Modification of Proteins by Scavenging Carbonyl Intermediates of Carbohydrate and Lipid Degradation

“…The Schiff base product of this reaction rearranges to an Amadori intermediate that, in turn, is converted to AGEs (see Fig. 7, step 1), most prominently to CML (13), which is detected at an increased concentration in animal and human tissues in diabetes, neurodegenerative diseases, and aging (45)(46)(47)(48). AGE modifications have been implicated as a source of structural and functional damage of proteins in diseases such as diabetes (49 - 7).…”

Alterations in peripheral blood levels of TIMP-1, MMP-2, and MMP-9 in patients with type-2 diabetes

“…Alterations in vascular structure, characterized by extracellular matrix deposits in the capillary and arteriolar basement membranes, contribute to the pathogenesis of vascular complications of diabetes [3][4][5][6][7]. As shown by the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS), hyperglycemia is an important factor in the development of diabetic complications [8][9][10][11]. Among several biochemical pathways mediated by hyperglycemia, the accumulation of advanced glycation end products (AGEs) has been shown to correlate with the degree of diabetic complications [10].…”

“…As shown by the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS), hyperglycemia is an important factor in the development of diabetic complications [8][9][10][11]. Among several biochemical pathways mediated by hyperglycemia, the accumulation of advanced glycation end products (AGEs) has been shown to correlate with the degree of diabetic complications [10]. In particular, increases in extracellular matrix are associated with the accumulation of AGEs, which reduces matrix turnover.…”