Glyoxalase I is a novel target for the prevention of metabolic derangement

Abstract

Obesity prevalence in the US has nearly tripled since 1975 and a parallel increase in prevalence of type 2 diabetes (T2D). Obesity promotes a myriad of metabolic derangements with insulin resistance (IR) being perhaps the most responsible for the development of T2D and other related diseases such as cardiovascular disease. The precarious nature of IR development is such that it provides a valuable target for the prevention of further disease development. However, the mechanisms driving IR are numerous and complex making the development of viable interventions difficult. The development of metabolic derangement in the context of obesity promotes accumulation of reactive metabolites such as the reactive alpha-dicarbonyl methylglyoxal (MG). MG accumulation has long been appreciated as a marker of disease progression in patients with T2D as well as the development of diabetic complications. However, recent evidence suggests that the accumulation of MG occurs with obesity prior to T2D onset and may be a primary driving factor for the development of IR and T2D. Further, emerging evidence also suggests that this accumulation of MG with obesity may be a result in a loss of MG detoxifying capacity of glyoxalase I. In this review, we will discuss the evidence that posits MG accumulation because of GLO1 attenuation is a novel target mechanism of the development of metabolic derangement. In addition, we will also explore the regulation of GLO1 and the strategies that have been investigated so far to target GLO1 regulation for the prevention and treatment of metabolic derangement.

Keywords: Advanced glycation; Carbonyl; Dicarbonyl; diabetes; insulin resistance; obesity.