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Skin Advanced Glycation End Products Glucosepane And 266 Diabetes Volume 64, January 2015 Saul Genuth,1 Wanjie Sun,2 Patricia Cleary,2 Xiaoyu Gao,2 David R. Sell,3 John Lachin,2 The DCCT/EDIC Research Group,* and Vincent M. Monnier3,4 Skin Advanced Glycation End Products Glucosepane and Methylglyoxal Hydroimidazolone Are Independently Associated With Long-term Microvascular Complication Progression of Type 1 Diabetes Diabetes 2015;64:266–278 | DOI: 10.2337/db14-0215 Six skin collagen advanced glycation end products panel also correlates with microalbuminuria (P = 0.008) (AGEs) originally measured near to the time of the and FUR with nephropathy independently of A1C level Diabetes Control and Complications Trial (DCCT) close- (P £ 0.02). Neuropathy correlates with the complete COMPLICATIONS out in 1993 may contribute to the “metabolic memory” panel despite adjustment for A1C level (P £ 0.005). phenomenon reported in the follow-up Epidemiology of MG-H1 and FUR are dominant, independent of A1C level Diabetes Interventions and Complications (EDIC) study. (P < 0.0001), whereas A1C loses significance after ad- We have now investigated whether the addition of four justment for the AGEs. Overall, the added set of four originally unavailable AGEs (i.e., glucosepane [GSPNE], AGEs enhances the association of the original panel hydroimidazolones of methylglyoxal [MG-H1] and glyoxal, with progression risk of retinopathy and neuropathy and carboxyethyl-lysine) improves associations with (P < 0.04) but not nephropathy, while GSPNE and incident retinopathy, nephropathy, and neuropathy MG-H1 emerge as the principal new risk factors. Skin events during 13–17 years after DCCT. The complete AGEs are robust long-term markers of microvascular 10-AGE panel is associated with three-step Early Treat- disease progression, emphasizing the importance of ment of Diabetic Retinopathy Study scale worsening early and sustained implementation of intensive therapy. of retinopathy (P £ 0.002), independent of either mean DCCT or EDIC study A1C level. GSPNE and fructose- lysine (furosine [FUR]) correlate with retinopathy pro- A large body of epidemiological evidence and animal gression, independently of A1C level. The complete experimentation underlay the hypothesis that 1Department of Medicine, Case Western Reserve University School of Medicine, This article contains Supplementary Data online at http://diabetes Cleveland, OH .diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0215/-/DC1. 2 Biostatistics Center, The George Washington University, Rockville, MD *A complete list of participants and industry contributors for the DCCT/EDIC 3 Department of Pathology, Case Western Reserve University School of Medicine, Research Group can be found at http://www.nejm.org/doi/full/10.1056/ Cleveland, OH NEJMoa1111732. 4Department of Biochemistry, Case Western Reserve University School of Med- © 2015 by the American Diabetes Association. Readers may use this article as icine, Cleveland, OH long as the work is properly cited, the use is educational and not for profit, and Corresponding authors: Vincent M. Monnier, [email protected], and Saul Genuth, the work is not altered. [email protected]. See accompanying article, p. 9. Received 10 February 2014 and accepted 22 August 2014. Clinical trial reg. nos. NCT00360815 and NCT00360893, clinicaltrials.gov. diabetes.diabetesjournals.org Genuth and Associates 267 hyperglycemia is a causative factor in the develop- previously described (5), 1–2 years prior to DCCT close- ment of microvascular and neuropathic complications in out. One hundred twenty-three participants were from diabetes (1). The demonstration by the Diabetes Control the primary cohort (1–5 years diabetes duration and no and Complications Trial (DCCT) that intensive treatment, retinopathy seen on fundus photography), and 93 were which lowered the mean blood glucose level by ;75 mg/dL from the secondary cohort (1–15 years diabetes dura- and the mean A1C level by ;2.0% (21.9 mmol/mol), tion and at least one retinal microaneurysm seen on compared with conventional treatment, sharply and signif- fundus photography). Retinopathy, nephropathy, and icantly reduced the development and progression of these neuropathy data at 10–13 years of the EDIC follow-up complications (2), confirmed this hypothesis. Nonetheless, were available in 196 of those participants originally the mechanistic connection of hyperglycemia to complica- biopsied. During the early EDIC study period, mean tions appears complex, containing multiple strands, even if A1C levels of the DCCT intensive and conventional glycemic exposure is primary (3). One path from hypergly- treatment groups began to converge and became indis- cemia to complications is the formation of advanced glyca- tinguishable at ;7.9% by 5 years into the EDIC study tion end products (AGEs), which can affect protein structure (11,12). and function both directly and by cross-linking (4). Outcomes We have previously demonstrated cross-sectional asso- Retinopathy ciations between a panel of four AGEs and two solubility abnormalities in collagen from a skin biopsy sample During the EDIC study, retinopathy was assessed by fi obtained prior to DCCT closeout and the presence of standardized seven- eld fundus photography in one- retinopathy, nephropathy, and neuropathy in DCCT subjects quarter of the cohort each year and in the entire cohort (5). These associations included the early glycation product at EDIC study years 4 and 10. All photographs were fructose-lysine (FL) (fructosamine) measured in acid hydro- graded centrally, with graders masked to the therapy fi lysate as furosine (FUR), pentosidine, and carboxymethyl- assignment, using the nal Early Treatment Diabetic lysine (CML). Furthermore, we subsequently demonstrated Retinopathy Study (ETDRS) grading scale (13) and that these AGE abnormalities, especially FUR and CML, were DCCT methods (14). The progression of retinopathy dur- fi highly correlated with the progression of retinopathy and ing the EDIC study was de ned as a three-step or greater nephropathy over the ensuing 10 years in the Epidemiology worsening at any time from the DCCT closeout up to fi of Diabetes Interventions and Complications (EDIC) obser- EDIC study year 16 on the nal ETDRS scale of retinop- vational study of the DCCT cohort of patients (6). athy severity (13) or initial scatter photocoagulation ther- Using a simultaneously obtained skin biopsy sample apy during this interval, among those free of scatter laser near DCCT closeout, which was stored at 280°C awaiting in DCCT. the discovery of AGEs not available in 1993, we have now Nephropathy tested the hypothesis that the previously not available Albumin excretion rate (AER) (15) was measured every 2 AGEs glucosepane (GSPNE) (7), carboxyethyl-lysine (CEL) years in 1,399 participants during the EDIC study. Pro- (8), and hydroimidazolones of glyoxal (G-H1) and meth- gression of nephropathy was defined as the initial devel- ylglyoxal (MG-H1) (9) determined by liquid chromatogra- opment of microalbuminuria (AER $40 mg/24 h, n = 50), phy tandem mass spectrometry, as described by Ahmed dialysis (n = 3), or kidney transplantation (n = 3) at any and Thornalley (10), are correlated with complication risk time between the DCCT closeout and the EDIC study year progression compared with the original set. In that regard, 15 or 16, among those participants free of microalbumin- we recently reported the association between these mark- uria in the DCCT. Since microalbuminuria is known to re- ers and the concurrent progression of diabetes complica- gress (16), sustained microalbuminuria (AER $30 mg/24 h) tions during the DCCT (7), which revealed that GSPNE at two or more consecutive visits was used in a sensitivity was a particularly robust indicator of past cumulative glyce- analysis (Supplementary Tables 1–3) to verify the results mia that was strongly associated with the presence of neph- of a single AER $40 mg/24 h. ropathic, retinopathic, and neuropathic outcomes at the time of the biopsy (7). The current study was consequently Neuropathy undertaken to determine whether GSPNE or any of the Clinical and nerve conduction studies performed during added AGEs were also associated with the long-term pro- the DCCT were repeated in the EDIC study during years spective risk of retinopathy, nephropathy, and neuropathy 13–14 (17). Likewise, cardiovascular autonomic neuropa- progression, individually or in combination with the origi- thy assessment performed in the DCCT was reassessed in nally measured AGEs and solubility markers during the 17 the EDIC study, first during EDIC study years 13–14 (18) years of follow-up of this cohort during the EDIC study. and repeated in years 16–17. Progression of neuropathy was defined as the initial development of confirmed RESEARCH DESIGN AND METHODS clinical neuropathy or cardiac autonomic neuropathy in Subjects the EDIC study, among those free of both complications in Two hundred sixteen participants in the DCCT study the DCCT. Confirmed clinical neuropathy was defined as the from eight clinics volunteered for a skin biopsy, as presence of both definite clinical neuropathy (the presence 268 Collagen AGEs and Microvascular Complications Diabetes Volume 64, January 2015 Table 1—Clinical characteristics of DCCT participants at DCCT baseline and closeout Primary cohort Secondary cohort Intensive Conventional Intensive Conventional (N = 65) (N = 58) P value (N = 57) (N = 36) P value DCCT baseline Age (years) 28 6 6266 7 0.016 30 6 7306 6 Duration (months) 31 6 19 27 6 14 108 6 51 90 6 43 A1C % 8.8 6 1.9 9.1 6 1.9 8.9 6 1.5
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