Review
Where does plasma methylglyoxal originate from?

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Abstract

The elevation of plasma methylglyoxal levels in diabetic humans is widely observed, but it is unknown to what extent different sources of methylglyoxal contribute to its plasma concentration. A retrospective analysis of clinical findings has been undertaken. There is controversy about the correlation of plasma methylglyoxal concentrations with fasting or postprandial glucose levels, and the relationship with HbA1c. There is only one study in which plasma ketone body levels have been monitored in parallel with methylglyoxal and a positive correlation between plasma methylglyoxal and β-hydroxybutyrate was observed. There are no reports on plasma aminoacetone levels and methylglyoxal in diabetic humans. This paper suggests that although there is a close association between methylglyoxal and carbohydrate metabolism, the presence of this 1,2-dicarbonyl in the plasma is mainly due to other mechanisms. Protein glycation and aminoacetone degradation are proposed to be the major and the minor sources of plasma methylglyoxal under normal conditions.

Introduction

Diabetes mellitus is common affecting about 8% of the world population and carries large health and social consequences [1]. Its incidence and prevalence are further increasing, particularly type 2 diabetes, which accounts for about 90% of diabetic cases. People with diabetes have premature mortality [2] and significant morbidity associated with diabetes-related complications.

Scientific endeavors have focused attention on several molecules with a potential role in the development of diabetes complications. One of these candidate molecules is methylglyoxal [3] and its potential role has been highlighted as a result of elevated levels found by direct measurements in the plasma of people with diabetes [4], [5]. The well-known link between glycolysis and methylglyoxal production seemingly explains the elevated plasma levels of methyglyoxal in people with diabetes. On the one hand, the core biochemical feature of diabetes is hyperglycemia, and on the other hand, glucose breakdown includes 0.1–0.4% of triose-phosphates being directed to the methylglyoxal pathway [6], [7]. Hence, it is plausible and has become standard dogma that methylglyoxal detected in the plasma originates from or at least is related to glycolysis, despite the fact that the sources of plasma methylglyoxal have never been correctly evaluated.

There are several pathways involved in methylglyoxal production and breakdown, and there are several compartments in which these reactions occur. However, there is a lack of publications that would have addressed where plasma methylglyoxal originates from.

In this paper, the origin of plasma methylglyoxal is investigated. The events leading to methylglyoxal production from the different body compartments are taken into account to dispute current dogma on the origin of plasma methylglyoxal which argue against the source of plasma methylglyoxal being glycolysis.

Section snippets

Possible sources of plasma methylglyoxal

Theoretically, there are only three possible internal sources of plasma methylglyoxal. First, it is formed in situ in the plasma. The second and the third possibilities are its release from cells or its outflow from injured cells, respectively. External sources of plasma methylglyoxal cannot be excluded. Foodstuffs, coffee and alcoholic beverages contain methylglyoxal [5], [8].

Eq. (1) describes the biochemical situation:mgaplasma=mgainsituformed+mgareleasedfromthecells+mgaoutflownfrom

Compartments and reactions of methylglyoxal formation and breakdown

Methylglyoxal is produced in the course of carbohydrate, lipid and amino acid metabolisms, and involves both enzyme-catalyzed steps and non-enzymatic reactions (Fig. 1) [9]. Methylglyoxal formation linked to carbohydrate metabolism depends on the generation of triose-phosphates, which are converted to methylglyoxal either enzymatically or non-enzymatically [9]. However, the extent of the triose-phosphate pool is not exclusively dependent on the rate of glycolysis, as other pathways of glucose

Methylglyoxal formation in the plasma

Although increased levels of methylglyoxal has been reported in both blood (plasma) and urine of people with diabetes, controversy remains about correlating methylglyoxal production to fasting or postprandial glucose levels generating concerns about the role of glucose breakdown in its production (Table 1). It should be noted that data are variable with regard to methylglyoxal values, probably reflecting at least two factors. The first factor is a technical issue. Deproteinization of the

Methylglyoxal release from the cells

For this purpose, two important cell types need to be considered, red blood cells and endothelial cells (Fig. 2).

Mature human erythrocytes have lost all cellular organelles and produce ATP from glycolysis that ends with l-lactic acid production [42]. Glucose breakdown in red blood cells influences methylglyoxal formation by at least four mechanisms: (i) by phosphorylating glycolysis, (ii) by pentose-phosphate shunt, (iii) by sorbitol pathway and (iv) by glucoxidation (Fig. 1).

Although the

Methylglyoxal outflow from already injured cells

Increased levels of methylglyoxal are detected in blood samples of people with diabetes (Table 1.). In the majority of cases, plasma (serum) methylglyoxal concentrations have been measured and found to be elevated compared with controls [13], [15], [16], [17], [18], [21], [22], [23], [51], [68]. In other cases, either the whole blood methylglyoxal content (cell and medium together) or the amount of methylglyoxal in red blood cells have been measured [27], [28], [29].

There are only two papers

Methylglyoxal from external sources

Since methylglyoxal is present in foodstuffs, alcoholic beverages, cigarette smoke and urban atmosphere, its intake occurs every day [3], [5], [8].

The effects of externally added methylglyoxal in animals were investigated for its effects on genotoxicity, modulation of blood glutathione and glucose, and kidney collagen accumulation [9].

All in all, methylglyoxal originating from external sources exerts effects in the body, suggesting uptake and transport. However, it seems unlikely that it

Conclusion

Methylglyoxal production occurs in different ways and its various sources are not evenly present in the blood and tissues (Fig. 2, Table 2). In this report, four possible sources of plasma methylglyoxal have been identified in a deductive manner (Table 3).

With our present knowledge, it is concluded that the source of plasma methylglyoxal cannot be glycolysis. Rather it is generated in the plasma mainly via the interaction between glucose and proteins, and to a lesser extent via aminoacetone

Conflict of interest

The author declares that he has no conflict of interest.

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