Several mechanistic pathways linking hyperglycemia to diabetes complications, including glycation of proteins and formation of advanced glycation end products (AGEs), have been proposed. We investigated the hypothesis that skin collagen glycation and AGEs predict the risk of progression of microvascular disease. We measured glycation products in the skin collagen of 211 Diabetes Control and Complications Trial (DCCT) volunteers in 1992 who continued to be followed in the Epidemiology of Diabetes Interventions and Complications study for 10 years. We determined whether the earlier measurements of glycated collagen and AGE levels correlated with the risk of progression of retinopathy and nephropathy from the end of the DCCT to 10 years later. In multivariate analyses, the combination of furosine (glycated collagen) and carboxymethyllysine (CML) predicted the progression of retinopathy ( 2 ‫؍‬ 59.4, P < 0.0001) and nephropathy ( 2 ‫؍‬ 18.2, P ‫؍‬ 0.0001), even after adjustment for mean HbA 1c (A1C) ( 2 ‫؍‬ 32.7, P < 0.0001 for retinopathy) and ( 2 ‫؍‬ 12.8, P ‫؍‬ 0.0016 for nephropathy). The predictive effect of A1C vanished after adjustment for furosine and CML ( 2 ‫؍‬ 0.0002, P ‫؍‬ 0.987 for retinopathy and 2 ‫؍‬ 0.0002, P ‫؍‬ 0.964 for nephropathy). Furosine explained more of the variation in the 10-year progression of retinopathy and nephropathy than did CML. These results strengthen the role of glycation of proteins and AGE formation in the pathogenesis of retinopathy and nephropathy. Glycation and subsequent AGE formation may explain the risk of these complications associated with prior A1C and provide a rational basis for the phenomenon of "metabolic memory" in the pathogenesis of these diabetes complications. Diabetes 54:3103-3111, 2005 N onenzymatic glycation of proteins and subsequent formation of advanced glycation end products (AGEs) is one of the pathogenetic mechanisms thought to link hyperglycemia to diabetic retinopathy and nephropathy (1,2). Inhibitors of AGE formation (3-8) and breakers of AGE-protein crosslinks (9,10) reduce both microvascular complications in experimental diabetic models. The relationship of longterm intensive control of glycemia and its effect on these complications with indicators of skin collagen glycation (furosine), glycoxidation and AGE formation (pentosidine and carboxymethyllysine [CML]), and cross-linking (acid and pepsin solubility) were previously examined in 215 patients with type 1 diabetes from the Diabetes Control and Complications Trial (DCCT) (11) who underwent a skin biopsy ϳ1 year before the close of the trial. Compared with conventional treatment, intensive treatment was associated with significantly lower levels of furosine, pentosidine, CML, and relative fluorescence and with higher levels of acid-and pepsin-soluble collagen (11). Age-and duration-adjusted collagen variables were significantly associated with the A1C value closest in time to the biopsy and with mean DCCT A1C. Retinopathy, nephropathy, and neuropathy outcomes as dependent variables were sign...

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OBJECTIVEThis multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m2 in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC).RESEARCH DESIGN AND METHODSUrinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation.RESULTSA total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m2 (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%). Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30–300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease. Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs. 1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m2 (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR.CONCLUSIONSMacroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m2. However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.

Background Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes. Long-term outcomes after the development of microalbuminuria are variable. Methods We quantified the incidence of and risk factors for long-term renal outcomes after the development of microalbuminuria in the DCCT/EDIC Study. The DCCT randomly assigned 1441 persons with type 1 diabetes to intensive or conventional diabetes therapy, and participants were subsequently followed during the observational EDIC Study. During DCCT/EDIC, 325 participants developed incident persistent microalbuminuria (albumin excretion rate [AER] ≥ 30 mg/24hr on two consecutive study visits). We assessed their subsequent renal outcomes, including progression to macroalbuminuria (AER ≥ 300 mg/24hr x2), impaired glomerular filtration rate (estimated GFR < 60 mL/min/1.73m2 x2), and end stage renal disease (ESRD), and regression to normoalbuminuria (AER < 30 mg/24hr x2). Results Median follow-up after persistent microalbuminuria diagnosis was 13 years (maximum 23 years). 10-year cumulative incidences of progression to macroalbuminuria, impaired GFR, and ESRD and regression to normoalbuminuria were 28%, 15%, 3%, and 40%, respectively. Albuminuria outcomes were more favorable with intensive diabetes therapy, lower hemoglobin A1c, lack of retinopathy, female gender, lower blood pressure, and lower concentrations of LDL cholesterol and triglyceride. Lower hemoglobin A1c, lack of retinopathy, and lower blood pressure were also associated with decreased risk of impaired GFR. Conclusions After the development of persistent microalbuminuria, progression and regression of kidney disease each occur commonly. Intensive glycemic control, lower blood pressure, and a more favorable lipid profile are associated with improved outcomes.

The Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up of the Diabetes Control and Complications Trial (DCCT) type 1 diabetes cohort, measured coronary artery calcification (CAC), an index of atherosclerosis, with computed tomography (CT) in 1,205 EDIC patients at ϳ7-9 years after the end of the DCCT. We examined the influence of the 6.5 years of prior conventional versus intensive diabetes treatment during the DCCT, as well as the effects of cardiovascular disease risk factors, on CAC. The prevalences of CAC >0 and >200 Agatston units were 31.0 and 8.5%, respectively. Compared with the conventional treatment group, the intensive group had significantly lower geometric mean CAC scores and a lower prevalence of CAC >0 in the primary retinopathy prevention cohort, but not in the secondary intervention cohort, and a lower prevalence of CAC >200 in the combined cohorts. Waistto-hip ratio, smoking, hypertension, and hypercholesterolemia, before or at the time of CT, were significantly associated with CAC in univariate and multivariate analyses. CAC was associated with mean HbA 1c (A1C) levels before enrollment, during the DCCT, and during the EDIC study. Prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced levels of A1C during the DCCT. Diabetes 55: 3556 -3565, 2006 P atients with type 1 diabetes have a high risk of developing cardiovascular disease (CVD), which in young adulthood can be 10-fold higher than in the general population (1,2). The reasons for this increased risk have not been fully elucidated and can only be partly explained by standard cardiovascular risk factors. Surprisingly, cumulative hyperglycemia has not been shown consistently to be a risk factor for cardiovascular events in type 1 diabetes (3-8).The Diabetes Control and Complications Trial (DCCT)/ Epidemiology of Diabetes Interventions and Complications (EDIC) study provides an opportunity to explore the complex relationships among traditional CVD risk factors, glycemia, and CVD outcomes (9). The DCCT demonstrated the importance of glycemic control in preventing or delaying microvascular complications (10), but it did not reach a clear conclusion with respect to macrovascular complications, owing to the low prevalence of macrovascular disease in the relatively young cohort (11). The long-term EDIC follow-up included assessments of subclinical CVD with measurement of carotid intima-media thickness (IMT) (12,13) and with computerized tomography (CT) of the heart to detect and quantitate calcification in the coronary arteries, a marker of atherosclerosis (14). The EDIC study demonstrated a significant protective effect of prior intensive diabetes therapy, compared with conventional therapy, on the progression of IMT over a 6-year period that was associated with the level of HbA 1c (A1C) (13). Progression of IMT was associated with the level of glycemia (A1C) over time, consistent with some (15), but not all (16,17), reports in type 1 di...