Association Between Urine Free Advanced Glycation End Products (Ages) At Three Time Points During The Dcct/Edic And Subsequent Risk Of Microvascular Complications In Type 1 Diabetes

Using banked urines from 156 DCCT participants of the former skin biopsy cohort (Diabetes 48:870,1999) we tested whether free AGEs measured at DCCT year 4 (Timepoint TP1), year 8(TP2) and EDIC year 17 (TP3) are associated with risk of microvascular complications progression. Methods: Fructose-lysine(FL), glucosepane(GSPN), carboxymethyl-lysine(CML), methylglyoxal (MG-H1) and 10 other markers were measured by LC/MS/MS. Data were analyzed using correlation coefficients, while associations with risk of complications using Cox proportional hazards (PH) models without adjustment for multiplicity. Results: FL (P<0.005) and GSPN (P<0.004) were significantly lower in the intensive therapy group at TP2. At all 3 TPs, mean A1C correlated with FL (r=0.31) and GSPN (r=0.30) (P<0.0001). In unadjusted Cox PH models, higher GSPN levels were associated with sustained eGFR<60 (P=0.007), cardiac autonomic neuropathy (CAN) (P=0.008) and borderline with confirmed clinical neuropathy (CCN) (P=0.05, NS). FL and CML were associated with sustained microalbuminuria (SA) both before (P≤0.001, 0.012) and after (P≤0.034) adjustment for A1C. Upon adjustment for A1c, age and gender using all 3 TPs, methionine sulfoxide/MetSOX (P=0.001), 3-nitrotyrosine (P=0.003), and FL and G-H1 (P<0.027) were associated with PDR; pentosidine (P=0.041) with clinically significant macular edema; MetSOX (P=0.013) and GSPN (P<0.034) with sustained eGFR<60; FL (P=0.015), CML (P=0.028) and MG-H1 (P=0.042) with SA. LW-1/glucuronidine was associated with CCN both before (P<0.001) and after adjustment for A1C (P<0.001). Chi square statistics were larger than A1c for GSPN with CAN, MetSOX with sustained eGFR<60 and LW-1/glucuronidine for CCN, suggesting stronger associations. Conclusions: FL, GSPN, and CML in urine consistently emerge as the AGEs most significantly associated with risk of subsequent microvascular complications. Disclosure D. Sell: None. J. Lachin: Board Member; Self; Tolerion, Inc. I. Bebu: None. V.M. Monnier: Consultant; Self; Juvenescence Ltd. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK101123)