Dicarbonyl Stress in Diabetic Vascular Disease

Abstract

Late vascular complications play a prominent role in the diabetes-induced increase in morbidity and mortality. Diabetes mellitus is recognised as a risk factor driving atherosclerosis and cardiovascular mortality; even after the normalisation of blood glucose concentration, the event risk is amplified-an effect called "glycolytic memory". The hallmark of this glycolytic memory and diabetic pathology are advanced glycation end products (AGEs) and reactive glucose metabolites such as methylglyoxal (MGO), a highly reactive dicarbonyl compound derived mainly from glycolysis. MGO and AGEs have an impact on vascular and organ structure and function, contributing to organ damage. As MGO is not only associated with hyperglycaemia in diabetes but also with other risk factors for diabetic vascular complications such as obesity, dyslipidaemia and hypertension, MGO is identified as a major player in the development of vascular complications in diabetes both on micro- as well as macrovascular level. In diabetes mellitus, the detoxifying system for MGO, the glyoxalase system, is diminished, accounting for the increased MGO concentration and glycotoxic load. This overview will summarise current knowledge on the effect of MGO and AGEs on vascular function.

Keywords: advanced glycation end products; atherosclerotic disease; cardiovascular risk; endothelial dysfunction; glycotoxic load; methylglyoxal.

Figure 1

Reactions/sources that lead to the formation and degradation of MGO. MGO is formed via the spontaneous degradation of the triosephosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyd 3-phosphate (G3P) originating from glycolysis. Other sources of MGO are exogenous sources like food and beverages, glycated proteins, threonine, or ketone bodies (acetoacetate). The glyoxalase system detoxifies MGO, in the first step, MGO forms a hemithioacetal with reduced glutathione (GSH). This serves as a substrate for glyoxalase 1 (GLO1). GLO1 catalyses the conversion of the hemithioacetal to S-D-lactoylglutathione. In the next step, glyoxalase 2 (GLO2) catalyses the hydrolysis of S-D-lactoylglutathione, forming D-lactate and recycling GSH. Minor degradation pathways of MGO involve aldehyde dehydrogenases (ALDHs) and aldose reductases (AKRs) yielding in pyruvate or hydroxyacetone, respectively; adapted from [9].

Figure 2

Imbalance of glyoxalase 1 activity and MGO concentration provoke endothelial dysfunction preceding atherosclerotic events, overflow with MGO exceeds the detoxifying capacity of GLO1 and results in endothelial dysfunction and further late complications.

Figure 3

The unifying hypothesis comprises mechanisms by which glucose at each level of glycolysis contributes to the generation of late diabetic complications. Under physiological conditions, glucose is metabolised through the glycolytic pathway. Increase in intracellular glucose leads to increased flux of glucose to sorbitol via the polyol pathway, to an increase in the hexosamine pathway, to activation of protein kinase C (PKC), and to formation of advanced glycation end products (AGEs) in endothelial cells. AKR = aldose reductase, SDH = sorbitol dehydrogenase, GFAT = glutamine: fructose-6-phosphate amidotransferase, GlcNAc = N-Acetylglucosamin, DAG = diaclyglycerol, PKC = proteinkinase C, G3P = glyceraldehyd 3-phosphate, DHAP = dihydroxyacetone phosphate.

Figure 4

Effector pathways (red) and possible solutions (therapeutic options) (green) to overcome negative effects in reactive dicarbonyl and AGE generation, RCS = reactive carbonyl species, CNS = central nervous system, PNS = peripheral nervous system.