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Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes.

Abstract

Six skin collagen advanced glycation end products (AGEs) originally measured near to the time of the Diabetes Control and Complications Trial (DCCT) closeout in 1993 may contribute to the "metabolic memory" phenomenon reported in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. We have now investigated whether the addition of four originally unavailable AGEs (i.e., glucosepane [GSPNE], hydroimidazolones of methylglyoxal [MG-H1] and glyoxal, and carboxyethyl-lysine) improves associations with incident retinopathy, nephropathy, and neuropathy events during 13-17 years after DCCT. The complete 10-AGE panel is associated with three-step Early Treatment of Diabetic Retinopathy Study scale worsening of retinopathy (P ≤ 0.002), independent of either mean DCCT or EDIC study A1C level. GSPNE and fructose-lysine (furosine [FUR]) correlate with retinopathy progression, independently of A1C level. The complete panel also correlates with microalbuminuria (P = 0.008) and FUR with nephropathy independently of A1C level (P ≤ 0.02). Neuropathy correlates with the complete panel despite adjustment for A1C level (P ≤ 0.005). MG-H1 and FUR are dominant, independent of A1C level (P < 0.0001), whereas A1C loses significance after adjustment for the AGEs. Overall, the added set of four AGEs enhances the association of the original panel with progression risk of retinopathy and neuropathy (P < 0.04) but not nephropathy, while GSPNE and MG-H1 emerge as the principal new risk factors. Skin AGEs are robust long-term markers of microvascular disease progression, emphasizing the importance of early and sustained implementation of intensive therapy.

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  • Authors+Show Affiliations

    ,

    Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH vmm3@cwru.edu smg15@case.edu.

    ,

    Biostatistics Center, The George Washington University, Rockville, MD.

    ,

    Biostatistics Center, The George Washington University, Rockville, MD.

    ,

    Biostatistics Center, The George Washington University, Rockville, MD.

    ,

    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH.

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    Biostatistics Center, The George Washington University, Rockville, MD.

    ,

    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH vmm3@cwru.edu smg15@case.edu.

    Source

    Diabetes 64:1 2015 Jan pg 266-78

    MeSH

    Adult
    Diabetes Mellitus, Type 1
    Diabetic Angiopathies
    Diabetic Nephropathies
    Diabetic Retinopathy
    Disease Progression
    Female
    Glycation End Products, Advanced
    Humans
    Imidazoles
    Logistic Models
    Male
    Microvessels
    Multivariate Analysis
    Pyruvaldehyde
    Skin
    Young Adult

    Pub Type(s)

    Journal Article
    Multicenter Study
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    25187362

    Citation

    Genuth, Saul, et al. "Skin Advanced Glycation End Products Glucosepane and Methylglyoxal Hydroimidazolone Are Independently Associated With Long-term Microvascular Complication Progression of Type 1 Diabetes." Diabetes, vol. 64, no. 1, 2015, pp. 266-78.
    Genuth S, Sun W, Cleary P, et al. 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(1):266-78.
    Genuth, S., Sun, W., Cleary, P., Gao, X., Sell, D. R., Lachin, J., & Monnier, V. M. (2015). Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes. Diabetes, 64(1), pp. 266-78. doi:10.2337/db14-0215.
    Genuth S, et al. 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(1):266-78. PubMed PMID: 25187362.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes. AU - Genuth,Saul, AU - Sun,Wanjie, AU - Cleary,Patricia, AU - Gao,Xiaoyu, AU - Sell,David R, AU - Lachin,John, AU - ,, AU - Monnier,Vincent M, Y1 - 2014/09/03/ PY - 2014/9/5/entrez PY - 2014/9/5/pubmed PY - 2015/3/12/medline SP - 266 EP - 78 JF - Diabetes JO - Diabetes VL - 64 IS - 1 N2 - Six skin collagen advanced glycation end products (AGEs) originally measured near to the time of the Diabetes Control and Complications Trial (DCCT) closeout in 1993 may contribute to the "metabolic memory" phenomenon reported in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. We have now investigated whether the addition of four originally unavailable AGEs (i.e., glucosepane [GSPNE], hydroimidazolones of methylglyoxal [MG-H1] and glyoxal, and carboxyethyl-lysine) improves associations with incident retinopathy, nephropathy, and neuropathy events during 13-17 years after DCCT. The complete 10-AGE panel is associated with three-step Early Treatment of Diabetic Retinopathy Study scale worsening of retinopathy (P ≤ 0.002), independent of either mean DCCT or EDIC study A1C level. GSPNE and fructose-lysine (furosine [FUR]) correlate with retinopathy progression, independently of A1C level. The complete panel also correlates with microalbuminuria (P = 0.008) and FUR with nephropathy independently of A1C level (P ≤ 0.02). Neuropathy correlates with the complete panel despite adjustment for A1C level (P ≤ 0.005). MG-H1 and FUR are dominant, independent of A1C level (P < 0.0001), whereas A1C loses significance after adjustment for the AGEs. Overall, the added set of four AGEs enhances the association of the original panel with progression risk of retinopathy and neuropathy (P < 0.04) but not nephropathy, while GSPNE and MG-H1 emerge as the principal new risk factors. Skin AGEs are robust long-term markers of microvascular disease progression, emphasizing the importance of early and sustained implementation of intensive therapy. SN - 1939-327X UR - https://www.unboundmedicine.com/medline/citation/25187362/full_citation L2 - http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&amp;pmid=25187362 DB - PRIME DP - Unbound Medicine ER -