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. 2022 Jan;10(1):e002667.
doi: 10.1136/bmjdrc-2021-002667.

Plasma advanced glycation end products and the subsequent risk of microvascular complications in type 1 diabetes in the DCCT/EDIC

Vincent M Monnier  1 , David R Sell  2 , Xiaoyu Gao  3 , Saul M Genuth  4 , John M Lachin  3 , Ionut Bebu  5 ; DCCT/EDIC Research Group
Affiliations

Plasma advanced glycation end products and the subsequent risk of microvascular complications in type 1 diabetes in the DCCT/EDIC

Vincent M Monnier et al. BMJ Open Diabetes Res Care. 2022 Jan.

Abstract

Introduction: To assess impact of glycemic control on plasma protein-bound advanced glycation end products (pAGEs) and their association with subsequent microvascular disease.

Research design and methods: Eleven pAGEs were measured by liquid chromatography-mass spectrometry in banked plasma from 466 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study at three time points (TPs): DCCT year 4 (TP1) and year 8 (TP2) and EDIC year 5/6 (TP3). Correlation coefficients assessed cross-sectional associations, and Cox proportional hazards models assessed associations with subsequent risk of microvascular complications through EDIC year 24.

Results: Glucose-derived glycation products fructose-lysine (FL), glucosepane (GSPN) and carboxymethyl-lysine (CML) decreased with intensive glycemic control at both TP1 and TP2 (p<0.0001) but were similar at TP3, and correlated with hemoglobin A1c (HbA1c). At TP1, the markers were associated with the subsequent risk of several microvascular outcomes. These associations did not remain significant after adjustment for HbA1c, except methionine sulfoxide (MetSOX), which remained associated with diabetic kidney disease. In unadjusted models using all 3 TPs, glucose-derived pAGEs were associated with subsequent risk of proliferative diabetic retinopathy (PDR, p<0.003), clinically significant macular edema (CSME, p<0.015) and confirmed clinical neuropathy (CCN, p<0.018, except CML, not significant (NS)). Adjusted for age, sex, body mass index, diabetes duration and mean updated HbA1c, the associations remained significant for PDR (FL: p<0.002, GSPN: p≤0.02, CML: p<0.003, pentosidine: p<0.02), CMSE (CML: p<0.03), albuminuria (FL: p<0.02, CML: p<0.03) and CCN (FL: p<0.005, GSPN : p<0.003).

Conclusions: pAGEs at TP1 are not superior to HbA1c for risk prediction, but glucose-derived pAGEs at three TPs and MetSOX remain robustly associated with progression of microvascular complications in type 1 diabetes even after adjustment for HbA1c and other factors.

Keywords: diabetic neuropathies; glycated hemoglobin A; kidney; oxidative stress.

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Conflict of interest statement

Competing interests: VMM is a member of the Scientific Advisory Board of Revel Pharmaceuticals. The other authors do not report a conflict of interest.

Figures

Figure 1
Figure 1
Effect of conventional (blue lines) and intensive (red lines) glycemic control on plasma protein advanced glycation end product (AGE) levels at three time points (TPs), that is, TP1 and TP2 at Diabetes Control and Complications Trial (DCCT) year ~4 and 8, respectively, and TP3 at Epidemiology of Diabetes Interventions and Complications (EDIC) year 5–6 (DCCT year 17). Intensive control at TP1 and TP2 significantly suppresses the glucose-derived glycation products fructose-lysine, glucosepane and carboxymethyl-lysine (CML), and o-tyrosine at TP2, but not methylglyoxal hydroimidazolone 1 (MG-H1) or other markers. Data are shown as medians with first and third quartiles. CEL, carboxyethyl-lysine; G-H1, glyoxal hydroimidazolone 1; MetSOX, methionine sulfoxide; MOLD, methylglyoxal-lysine dimer.
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