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The pecking order of skin Advanced Glycation Endproducts (AGEs) as long-term markers of glycemic damage and risk factors for micro- and subclinical macrovascular disease progression in Type 1 diabetes

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Abstract

To date more than 20 glycation products were identified, of which ~15 in the insoluble human skin collagen fraction. The goal of this review is to streamline 30 years of research and ask a set of important questions: in Type 1 diabetes which glycation products correlate best with 1) past mean glycemia 2) reversibility with improved glycemic control, 2) cross-sectional severity of retinopathy, nephropathy and neuropathy and 3) the future long-term risk of progression of micro- and subclinical macrovascular disease. The trio of glycemia related glycation markers furosine (FUR)/fructose-lysine (FL), glucosepane and methylglyoxal hydroimidazolone (MG-H1) emerges as extraordinarily strong predictors of existing and future microvascular disease progression risk despite adjustment for both past and prospective A1c levels. X2 values are up to 25.1, p values generally less than 0.0001, and significance remains after adjustment for various factors such as A1c, former treatment group, log albumin excretion rate, abnormal autonomic nerve function and LDL levels at baseline. In contrast, subclinical cardiovascular progression is more weakly correlated with AGEs/glycemia with X2 values < 5.0 and p values generally < 0.05 after all adjustments. Except for future carotid intima-media thickness, which correlates with total AGE burden (MG-H1, pentosidine, fluorophore LW-1 and decreased collagen solubility), adjusted FUR and Collagen Fluorescence (CLF) are the strongest markers for future coronary artery calcium deposition, while cardiac hypertrophy is associated with LW-1 and CLF adjusted for A1c. We conclude that a robust clinical skin biopsy AGE risk panel for microvascular disease should include at least FUR/FL, glucosepane and MG-H1, while a macrovascular disease risk panel should include at least FL/FUR, MG-H1, LW-1 and CLF.

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Abbreviations

2-AAA:

2-amino adipic acid

AGE:

Advanced glycation endproducts

A1c:

Hemoglobin A1c

FL:

Fructose-lysine

FUR:

Furosine

CLF:

Collagen-linked fluorescence

CEL:

Carboxyethyl-lysine

CML:

Carboxymethyl-lysine

cMIT:

Carotid intima-medial thickening

CVD:

Cardiovascular disease

DCCT:

Diabetes Control and Complications Trial

DODIC:

Deoxyglucosone-derived imidazoline crosslink

EDIC:

Epidemiology of Diabetes Interventions and Complications

G-H1:

Glyoxal hydroimidazolone 1

GODIC:

Glyoxal-derived imidazoline crosslink

GOLD:

Glyoxal lysine dimer

IMT:

Intima media thickness

LC/MS/MS:

Liquid chromatography mass spectrometry

LW-1:

Long-wave fluorophore 1

MI:

Myocardial infarct

MG-H1:

Methylglyoxal hydroimidazolone

MODIC:

Methylglyoxal-derived imidazoline crosslink

MOLD:

Methylglyoxal lysine dimer

PWV:

Pulse wave velocity

SAF:

Skin autofluorescence

SIF:

Skin intrinsic fluorescence

SD:

Standard deviation

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Acknowledgments

This work was supported by grants from NIDDK (R21 DK-79432 to DRS, DK-101123 to VMM), JDRF (17-2010-318) and NEI (EY-07099 to VMM) and NIH and non-governmental grants to The DCCT/EDIC Research Group. We thank our colleagues from the DCCT/EDIC trial and the team of biostatisticians at the DCCT coordinating Center, Drs. Wanjie Sun, Xiaoyu Gao, Patricia A. Cleary and John M. Lachin for their help throughout the years.

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Authors and Affiliations

  1. Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA

    Vincent M. Monnier & David R. Sell

  2. Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA

    Vincent M. Monnier

  3. Department of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA

    Saul Genuth

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  1. Vincent M. Monnier
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Correspondence to Vincent M. Monnier.

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Monnier, V.M., Genuth, S. & Sell, D.R. The pecking order of skin Advanced Glycation Endproducts (AGEs) as long-term markers of glycemic damage and risk factors for micro- and subclinical macrovascular disease progression in Type 1 diabetes. Glycoconj J 33, 569–579 (2016). https://doi.org/10.1007/s10719-016-9702-2

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