Skin Advanced Glycation End Products Glucosepane and Methylglyoxal Hydroimidazolone Are Independently Associated With Long-term Microvascular Complication Progression of Type 1 Diabetes
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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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Higher levels of AGE cross-links are commonly detected in experimental animal models and autopsied tissue samples from people who are aging or have cancer, obesity, or diabetic complications.
“In fact, higher levels of AGE cross-links are commonly detected in experimental animal models and autopsied tissue samples from people who are aging or have cancer, obesity, or diabetic complications31–33.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [33]
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Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · see citing works
(1993) · New England Journal of Medicine · doi:10.1056/nejm199309303291401 · Cited by 24,667 · see citing works
The Diabetes Control and Complications Trial Research Group (1995) · Diabetes · doi:10.2337/diab.44.8.968 · Cited by 1,301 · see citing works
Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2003) · JAMA · doi:10.1001/jama.290.16.2159 · Cited by 1,010 · see citing works
Regression of Microalbuminuria in Type 1 Diabetes
Perkins, B. A., Ficociello, L., Silva, K. H., Finkelstein, D. M., Warram, J. H., & Królewski, A. S. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa021835 · Cited by 799 · see citing works
Early Treatment Diabetic Retinopathy Study Design and Baseline Patient Characteristics
* (1991) · Ophthalmology · doi:10.1016/s0161-6420(13)38009-9 · Cited by 683 · see citing works
Ahmed, M. U., Frye, E. B., Degenhardt, T. P., Thorpe, S. R., & Baynes, J. (1997) · Biochemical Journal · doi:10.1042/bj3240565 · Cited by 605 · see citing works
Diabetes Control and Complications Trial
Yue, D. K., Colagiuri, S., McElduff, A., & Silink, M. (1993) · The Medical Journal of Australia · doi:10.5694/j.1326-5377.1993.tb141357.x · Cited by 575 · see citing works
The formation of methylglyoxal from triose phosphates
Phillips, S. A., & Thornalley, P. J. (1993) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1993.tb17638.x · Cited by 565 · see citing works
Monnier, V. M., Bautista, O., Kenny, D., Sell, D. R., Fogarty, J., Dahms, W., Cleary, P. A., Lachin, J., & Genuth, S. (1999) · Diabetes · doi:10.2337/diabetes.48.4.870 · Cited by 469 · see citing works
Self-citationGENUTH, S. M., Sun, W., Cleary, P. A., Sell, D. R., Dahms, W. T., Malone, J. I., Sivitz, W. I., Monnier, V. M., & for the DCCT Skin Collagen Ancillary Study Group (2005) · Diabetes · doi:10.2337/diabetes.54.11.3103 · Cited by 428 · see citing works
Self-citationNeuropathy among the diabetes control and complications trial cohort 8 years after trial completion
Martin, C. L., Albers, J., Herman, W. H., Cleary, P., Waberski, B., Greene, D. A., Stevens, M. J., & Feldman, E. L. (2006) · Diabetes Care · doi:10.2337/diacare.29.02.06.dc05-1549 · Cited by 350 · see citing works
Self-citationAhmed, N., Argirov, O. K., Minhas, H. S., CORDEIRO, C. A., & Thornalley, P. J. (2002) · Biochemical Journal · doi:10.1042/bj3640001 · Cited by 336 · see citing works
(1995) · Archives of Ophthalmology · doi:10.1001/archopht.1995.01100010038019 · Cited by 325 · see citing works
Muscle Capillary Basement Membrane Changes Related to Aging and to Diabetes Mellitus
Kilo, C., Vogler, N. J., & Williamson, J. R. (1972) · Diabetes · doi:10.2337/diab.21.8.881 · Cited by 278 · see citing works
Biostatistical methods : the assessment of relative risks
Lachin, J. M. (2000) · Cited by 272 · see citing works
Self-citationDobler, D., Ahmed, N., Song, L., Eboigbodin, K. E., & Thornalley, P. J. (2006) · Diabetes · doi:10.2337/db05-1634 · Cited by 269 · see citing works
Modification of the glyoxalase system in human red blood cells by glucose in vitro
Thornalley, P. J. (1988) · Biochemical Journal · doi:10.1042/bj2540751 · Cited by 239 · see citing works
White, N. H., Sun, W., Cleary, P. A., Tamborlane, W. V., Danis, R. P., Hainsworth, D. P., & Davis, M. D. (2010) · Diabetes · doi:10.2337/db09-1216 · Cited by 235 · see citing works
Self-citationLachin, J. M. (2000) · Wiley series in probability and statistics · doi:10.1002/9780470317051 · Cited by 201 · see citing works
Self-citationGlycation Products as Markers and Predictors of the Progression of Diabetic Complications
Monnier, V. M., Sell, D. R., & GENUTH, S. M. (2005) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1333.065 · Cited by 182 · see citing works
Self-citationAhmed, N., & Thornalley, P. J. (2003) · Biochemical Society Transactions · doi:10.1042/bst0311417 · Cited by 152 · see citing works
Lederer, M. O., & Klaiber, R. (1999) · Bioorganic & Medicinal Chemistry · doi:10.1016/s0968-0896(99)00212-6 · Cited by 146 · see citing works
Pop‐Busui, R., Lu, J., Lopes, N., & Jones, T. L. Z. (2009) · Journal of the Peripheral Nervous System · doi:10.1111/j.1529-8027.2009.00200.x · Cited by 133 · see citing works
Baseline analysis of renal function in the Diabetes Control and Complications Trial
Molitch, M. E., Steffes, M. W., Cleary, P. A., & Nathan, D. M. (1993) · Kidney International · doi:10.1038/ki.1993.96 · Cited by 74 · see citing works
Self-citationSmall- and Large-Fiber Neuropathy After 40 Years of Type 1 Diabetes
Sveen, K. A., Karimé, B., Jørum, E., Mellgren, S. I., Fagerland, M. W., Monnier, V. M., Dahl‐Jørgensen, K., & Hanssen, K. F. (2013) · Diabetes Care · doi:10.2337/dc13-0788 · Cited by 74 · see citing works
Self-citationBhatwadekar, A. D., Glenn, J. V., Li, G., Curtis, T. M., Gardiner, T. A., & Stitt, A. W. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-1015 · Cited by 62 · see citing works
Monnier, V. M., Sell, D. R., Strauch, C., Sun, W., Lachin, J. M., Cleary, P. A., & GENUTH, S. M. (2012) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2012.10.004 · Cited by 57 · see citing works
Self-citationMuona, P., Jaakkola, S., Zhang, R. Z., Pan, T., Pelliniemi, L. J., Risteli, L., Chu, M. L., Uitto, J., & Peltonen, J. T. K. (1993) · PubMed Central · Cited by 45 · see citing works
The case for blood glucose control.
GENUTH, S. M. (1995) · PubMed · Cited by 29 · see citing works
Self-citationMolitch, M. E., Steffes, M. W., Cleary, P. A., & Nathan, D. M. (1993) · Kidney International · Cited by 13 · see citing works
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Duh, E. J., Sun, J. K., & Stitt, A. W. (2017) · JCI Insight · doi:10.1172/jci.insight.93751 · Cited by 1,057 · see citing works
Rungratanawanich, W., Qu, Y., Wang, X., Essa, M. M., & Song, B.-J. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00561-7 · Cited by 411 · see citing works
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Rabbani, N., & Thornalley, P. J. (2018) · Kidney International · doi:10.1016/j.kint.2017.11.034 · Cited by 387 · see citing works
Fishman, S. L., Sonmez, H., Basman, C., Singh, V., & Poretsky, L. (2018) · Molecular Medicine · doi:10.1186/s10020-018-0060-3 · Cited by 330 · see citing works
Dicarbonyls and glyoxalase in disease mechanisms and clinical therapeutics
Rabbani, N., Xue, M., & Thornalley, P. J. (2016) · Glycoconjugate Journal · doi:10.1007/s10719-016-9705-z · Cited by 169 · see citing works
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Li, L. H., Lee, J. C.-Y., Leung, H. H., Lam, W. C., Fu, Z., & Lo, A. C. Y. (2020) · Nutrients · doi:10.3390/nu12061721 · Cited by 152 · see citing works
Saremi, A., Howell, S., Schwenke, D. C., Bahn, G., Beisswenger, P. J., Reaven, P. D., & for the VADT Investigators (2017) · Diabetes Care · doi:10.2337/dc16-1875 · Cited by 90 · see citing works
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Hughes, M. S., Addala, A., & Buckingham, B. (2023) · New England Journal of Medicine · doi:10.1056/nejmra2215899 · Cited by 59 · see citing works
- Authors
- Genuth, S., Sun, W., Cleary, P., Gao, X., Sell, D. R., Lachin, J., The DCCT/EDIC Research Group, & Monnier, V. M.
- Affiliations
- Case Western Reserve University (US)
- George Washington University (US)
- Corresponding author
- Genuth, Saul
- Monnier, Vincent M.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2014-09-03
- Volume
- 64
- Issue
- 1
- Pages
- 266-278
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4274803
- OpenAlex
- W1965220977
- Cited by
- 146
- References
- 31
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 12 · 2023: 6 · 2022: 13 · 2021: 17 · 2020: 17 · 2019: 9 · 2018: 13 · 2017: 14 · 2016: 13 · 2015: 13 · 2014: 2
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- George Washington University
- National Institutes of Health (5u01dk094157-13, UL1TR000142)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK094176, U01-DK094157, R21DK079432, DK-79432)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- advanced glycation end products, glucosepane, skin collagen, type 1 diabetes, microvascular complications, diabetic retinopathy progression, diabetic nephropathy, diabetic neuropathy, microalbuminuria, furosine, glyoxal, metabolic memory, tight glycemic control, HbA1c
- MeSH terms
- Adult, Diabetes Mellitus, Type 1, Diabetic Angiopathies, Diabetic Nephropathies, Diabetic Retinopathy, Female, Humans, Imidazoles, Male, Pyruvaldehyde, Skin, Multivariate Analysis, Logistic Models, Glycation End Products, Advanced, Disease Progression, Microvessels, Young Adult
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