ReviewWhere does plasma methylglyoxal originate from?
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:
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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