We previously showed that skin collagen AGEs at DCCT trial closeout were strongly associated with progression of microvascular disease even after adjustment for A1c (Glyconj. J. 33: 569, 2016). We now tested whether plasma protein AGEs are associated with subsequent progression of retinopathy, nephropathy and neuropathy.

Methods: Fourteen AGEs were measured by LC/MS/MS in banked plasmas from 466 DCCT participants at three time points (TPs): DCCT year 4 (TP1), year 8 (TP2) and EDIC year 5/6 (TP3). Data were analyzed using correlation coefficients, while associations with risk of complications used Cox proportional hazards models were determined without adjustment for multiplicity.

Results: Fructose-lysine (FL), glucosepane (GSPN) and carboxymethyl-lysine (CML) were lower in the former intensive glycemic control group at both TP1 and TP2 (P<0.0001) but notat TP3. At all 3 TPs, mean A1C was positively correlated with levels of FL (r=0.44), GSPN (r=0.33) and CML (r=0.35). In unadjusted Cox models using all three TPs, higher levels of FL, GSPN and CML were associated with subsequent risk of proliferative diabetic retinopathy (PDR, P<0.0001), clinically significant macular edema (CSME, P<0.0008) and confirmed clinical neuropathy (CCN, P<0.005). After adjustment for mean A1C, all three AGEs (FL, GSPN, CML) remained significantly associated with PDR (P<0.021), FL and GSPN remained significant for CCN (P≤0.005), and CML remained significant for CSME (P=0.033). Methylglyoxal hydroimidazolone (MG-H1) and methionine sulfoxide (MetSOX) were positively associated with sustained eGFR<60 and cardiac autonomic neuropathy before and after adjustment for A1C (P<0.05, P=0.031, respectively).

In conclusion, after adjustment for A1C, FL, GSPN, CML and MG-H1 are the plasma AGEs most strongly associated with progression of microvascular complications in type 1 diabetes.


V.M. Monnier: Consultant; Self; Juvenescence Ltd. D. Sell: None. J. Lachin: Board Member; Self; Tolerion, Inc. I. Bebu: None.


National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK101123-01)

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