Vascular AGE-ing by methylglyoxal: the past, the present and the future

Abstract

Over the years, new research has elucidated the importance of the very fast formation of AGEs by the highly reactive methylglyoxal (MGO). It has become clear that MGO triggers maladaptive responses in vascular tissue. To counteract the deleterious effects of MGO, organisms have an enzymatic glyoxalase defence system in which MGO is converted to D-lactate, with glyoxalase 1 (GLO1) as the key enzyme in this system. Significant progress has been made towards the understanding of the MGO-GLO1 pathway in the pathogenesis of vascular disease in diabetes. This commentary highlights some lines of current research and future perspectives. The work conducted so far is only the starting point--in the coming 50 years, the MGO-GLO1 pathway will be the subject of intensified research, with special focus on pathophysiological pathways, the use of this system for early screening and risk prediction, and the development of intervention strategies for preventing vascular complications in people with and without diabetes. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).

Fig. 1

Biology of MGO: MGO is mainly formed as a byproduct of glycolysis. Increased levels of MGO are predominantly detoxified by GLO1, the key enzyme in the glyoxalase system, which converts MGO to d-lactate. Type 2 diabetes is associated with higher MGO incremental AUC, calculated from OGTT. MGO is involved in epigenetics and oxidative stress, and reacts, intracellularly and extracellularly, with arginine residues in proteins to produce MG-H1, the most important MGO-derived AGE. MG-H1 is cleared by lysosomal degradation. MGO modifications lead to protein inactivation, and changes in functionality and binding affinity to RAGE, resulting in maladaptive responses in vascular tissue. DHAP, dihydroxyacetone phosphate; G3P, glyceraldehyde 3-phosphate; GSH, glutathione