title: 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.
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH vmm3@cwru.edu smg15@case.edu.
authors.forename: Saul
authors.initials: S
authors.lastname: Genuth
authors.affiliation: Biostatistics Center, The George Washington University, Rockville, MD.
authors.forename: Wanjie
authors.initials: W
authors.lastname: Sun
authors.affiliation: Biostatistics Center, The George Washington University, Rockville, MD.
authors.forename: Patricia
authors.initials: P
authors.lastname: Cleary
authors.affiliation: Biostatistics Center, The George Washington University, Rockville, MD.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: David R
authors.initials: DR
authors.lastname: Sell
authors.affiliation: Biostatistics Center, The George Washington University, Rockville, MD.
authors.forename: John
authors.initials: J
authors.lastname: Lachin
authors.affiliation: 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.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Monnier
mesh_terms: D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D003925:Diabetic Angiopathies / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D003930:Diabetic Retinopathy / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D016015:Logistic Models; D008297:Male; D055806:Microvessels / Q000378:metabolism; D015999:Multivariate Analysis; D011765:Pyruvaldehyde / Q000378:metabolism*; D012867:Skin / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D017127:Glycation End Products, Advanced; D007093:Imidazoles; C117197:imidazolone; C543060:glucosepane; D011765:Pyruvaldehyde