Methylglyoxal in diabetes: link to treatment, glycaemic control and biomarkers of complications

Diabetic complications are major health problems worldwide, with the cost of caring for diabetes rising to US$245 billion in 2012 in the U.S.A. alone. It is widely recognized that non-enzymatic glycation in diabetes is a major cause of damage and dysfunction of key vascular cells. MG (methylglyoxal) is directly toxic to tissues, and is a major precursor of AGEs (advanced glycation end-products). Various propensities to diabetic complications are seen among individuals with diabetes, with accelerated rates occurring in some individuals with modest hyperglycaemia, while others never progress in spite of poor glycaemic control over many years. Since production and detoxification of MG is ultimately controlled by enzymatic mechanisms, both genetic and environmental factors could regulate tissue glycation and potentially account for these variable complication rates. Activation of pathways that determine MG levels occurs in susceptible patients, indicting an important role in pathogenesis. MG leads to formation of specific AGEs, which are likely to predict propensity to diabetic complications. We have shown recently that three specific plasma AGE biomarkers [MG-H1 (MG-derived hydroimidazolones), CEL (N^ε-carboxyethyl-lysine) and CML (N^ε-carboxymethyl-lysine)] predict biopsy-documented fast DN (diabetic nephropathy) progression. Since two of the predictive biomarkers are MG end-products, these outcomes support a role for MG in the development of DN. Our studies on MG and its end-products have also shown anti-complication effects of the drug metformin, which binds and inactivates MG, thus reducing MG-related AGEs. We have also shown that reducing post-meal glucose decreases MG levels, as well as levels of MG-related AGEs. Our clinical outcome studies have been based on the novel concept that the unique glycation products that we can measure reflect the activity of specific chemical pathways that are selectively activated by hyperglycaemia in patients that are inherently more susceptible to diabetic complications, and can be used to solve other diabetes-related medical questions.