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Review
. 2017 May 5;18(5):984.
doi: 10.3390/ijms18050984.

Dicarbonyls and Advanced Glycation End-Products in the Development of Diabetic Complications and Targets for Intervention

Sebastian Brings  1   2 , Thomas Fleming  3   4   5 , Marc Freichel  6 , Martina U Muckenthaler  7 , Stephan Herzig  8   9 , Peter P Nawroth  10   11   12   13
Affiliations
Review

Dicarbonyls and Advanced Glycation End-Products in the Development of Diabetic Complications and Targets for Intervention

Sebastian Brings et al. Int J Mol Sci. .

Abstract

Advanced glycation end-products (AGEs) are non-enzymatic protein and amino acid adducts as well as DNA adducts which form from dicarbonyls and glucose. AGE formation is enhanced in diabetes and is associated with the development of diabetic complications. In the current review, we discuss mechanisms that lead to enhanced AGE levels in the context of diabetes and diabetic complications. The methylglyoxal-detoxifying glyoxalase system as well as alternative pathways of AGE detoxification are summarized. Therapeutic approaches to interfere with different pathways of AGE formation are presented.

Keywords: 3-deoxyglucosone; advanced glycation end-products; aldose reductase; diabetes; glyoxal; glyoxalase; methylglyoxal.

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Conflict of interest statement

Sebastian Brings, Thomas Fleming and Peter P. Nawroth are named as inventors in a pending patent that discloses the use of scavenger peptides for the treatment of MG induced complications.

Figures

Figure 1
Figure 1
Shown are the major precursors for the advanced glycation end-products (AGEs) identified in vivo. 3DG-H1: 3-Deoxyglucosone-hydroimidazolone 1; CML: Nε-(carboxymethyl)-lysine; G-H1; Glyoxal-derived hydroimidazolone 1; MG-H1: Methyglyoxal-derived hydroimidazolone 1.
Figure 2
Figure 2
The main AGEs that have been quantified in vivo are shown. AGE structures are given as AGE free adducts.
Figure 3
Figure 3
Influence of protein half-life, chemical stability of AGEs and precursor level on the accumulation of AGE protein adducts over time. AGE formation under normal precursor conditions are shown in (A). Proteins with short half-life do not show long-term protein–AGE accumulation but AGE free adducts are released upon proteolysis. Stable AGEs such as CML accumulate over time on proteins with long half-life. The effect of an elevation of precursor levels as it is found in diabetes is shown in (B).
Figure 4
Figure 4
Pathways of dicarbonyl detoxification. MG reacts with glutathione to yield hemithioacetal, the substrate for glyoxalase 1 (GLO1). (A) The product, S-d-lactoylglutathione, is hydrolyzed by glyoxalase 2 (GLO2) to yield d-lactate and reduced glutathione. Glyoxal is also metabolized via this pathway and results in glycolate production (not shown). Aldose reductases (B) catalyze the NADPH (nicotinamide adenine dinucleotide phosphate)-dependent reduction of MG which yield hydroxyacetone (major product) and lactaldehyde (minor product) in the absence of reduced glutathione (GSH). Lactaldehyde may be further reduced to propanediol. In the presence of GSH (C) aldose reductase acts on the hemithioacetal which results in a shift towards lactaldehyde production. Products of 3-DG and glyoxal metabolism of aldose reductase are 3-deoxyfructose and glycolaldehyde respectively (not shown). Aldehyde dehydrogenase (D) oxidizes dicarbonyls and is of potential importance for 3-DG metabolism with the resulting product being 2-keto-3-deoxygluconic acid. Products of MG and glyoxal oxidation are pyruvate and glyoxylate, respectively (not shown).
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References

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