Glycation and Carboxymethyllysine Levels in Skin Collagen Predict the Risk of Future 10-Year Progression of Diabetic Retinopathy and Nephropathy in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications Participants With Type 1 Diabetes

The Diabetes Control and Complications Trial (DCCT) demonstrated the benefits of intensive treatment of diabetes in reducing glycemic levels and slowing the progression of diabetic nephropathy. The DCCT cohort has been examined annually for another 8 years as part of the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. During the EDIC study, glycemic levels no longer differed substantially between the 2 original treatment groups. To determine the long-term effects of intensive vs conventional diabetes treatment during the DCCT on kidney function during the EDIC study. Observational study begun in 1993 (following DCCT closeout) in 28 medical centers in the United States and Canada. Participants were 1349 (of 1375) EDIC volunteers who had kidney evaluation at years 7 or 8. Development of microalbuminuria, clinical-grade albuminuria, hypertension, or increase in serum creatinine level. Results were analyzed by intention-to-treat analyses, comparing the 2 original DCCT treatment groups. New cases of microalbuminuria occurred during the EDIC study in 39 (6.8%) of the participants originally assigned to the intensive-treatment group vs 87 (15.8%) of those assigned to the conventional-treatment group, for a 59% (95% confidence interval [CI], 39%-73%) reduction in odds, adjusted for baseline values, compared with a 59% (95% CI, 36%-74%) reduction at the end of the DCCT (P<.001 for both comparisons). New cases of clinical albuminuria occurred in 9 (1.4%) of the participants in the original intensive-treatment group vs 59 (9.4%) of those in the original conventional-treatment group, representing an 84% reduction in odds (95% CI, 67%-92%), compared with a reduction of 57% (95% CI, -1% to +81%) at the end of the DCCT. Fewer cases of hypertension (prevalence at year 8, 29.9% vs 40.3%; P<.001) developed in the original intensive-treatment group. Significantly fewer participants reached a serum creatinine level of 2 mg/dL or greater in the intensive-treatment vs the conventional-treatment group (5 vs 19, P =.004), but there were no differences in mean log clearance values. Although small numbers of patients required dialysis and/or transplantation, fewer patients experienced either of these outcomes in the intensive group (4 vs 7, P =.36). The persistent beneficial effects on albumin excretion and the reduced incidence of hypertension 7 to 8 years after the end of the DCCT suggest that previous intensive treatment of diabetes with near-normal glycemia during the DCCT has an extended benefit in delaying progression of diabetic nephropathy.

Collagen molecules in articular cartilage have an exceptionally long lifetime, which makes them susceptible to the accumulation of advanced glycation end products (AGEs). In fact, in comparison to other collagen-rich tissues, articular cartilage contains relatively high amounts of the AGE pentosidine. To test the hypothesis that this higher AGE accumulation is primarily the result of the slow turnover of cartilage collagen, AGE levels in cartilage and skin collagen were compared with the degree of racemization of aspartic acid (% d-Asp, a measure of the residence time of a protein). AGE (N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, and pentosidine) and % d-Asp concentrations increased linearly with age in both cartilage and skin collagen (p < 0.0001). The rate of increase in AGEs was greater in cartilage collagen than in skin collagen (p < 0.0001). % d-Asp was also higher in cartilage collagen than in skin collagen (p < 0.0001), indicating that cartilage collagen has a longer residence time in the tissue, and thus a slower turnover, than skin collagen. In both types of collagen, AGE concentrations increased linearly with % d-Asp (p < 0.0005). Interestingly, the slopes of the curves of AGEs versus % d-Asp, i.e. the rates of accumulation of AGEs corrected for turnover, were identical for cartilage and skin collagen. The present study thus provides the first experimental evidence that protein turnover is a major determinant in AGE accumulation in different collagen types. From the age-related increases in % d-Asp the half-life of cartilage collagen was calculated to be 117 years and that of skin collagen 15 years, thereby providing the first reasonable estimates of the half-lives of these collagens.

Diabetic complications are the major cause of morbidity and mortality in persons with diabetes. Chronic hyperglycemia is a major initiator of diabetic microvascular complications (eg, retinopathy, neuropathy, nephropathy). Glucose processing uses a variety of diverse metabolic pathways; hence, chronic hyperglycemia can induce multiple cellular changes leading to complications. Several predominant well-researched theories have been proposed to explain how hyperglycemia can produce the neural and vascular derangements that are hallmarks of diabetes. These theories can be separated into those that emphasize the toxic effects of hyperglycemia and its pathophysiological derivatives (such as oxidants, hyperosmolarity, or glycation products) on tissues directly and those that ascribe pathophysiological importance to a sustained alteration in cell signaling pathways (such as changes in phospholipids or kinases) induced by the products of glucose metabolism. This article summarizes these theories and the potential therapeutic interventions that may prevent diabetic complications in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.