Methylglyoxal as a Potential Mediator of Metabolic Memory in Diabetes-Related Complications: From Oxidative Stress to Macromolecular Glycation and Epigenetic Remodeling
TL;DR
The role of MGO in metabolic memory is discussed, focusing on oxidative stress, protein glycation, nucleic acid damage and epigenetic remodeling, and highlights emerging therapeutic strategies targeting dicarbonyl stress to prevent the progression of diabetes-related complications.
Abstract
Diabetes-related complications often continue to progress despite improved glycemic control, a phenomenon known as metabolic memory. Increasing evidence suggests that methylglyoxal (MGO), a highly reactive dicarbonyl generated during glycolysis, may be an important mediator of this process. Hyperglycemia-induced oxidative stress promotes MGO formation, where MGO further promotes mitochondrial dysfunction and reactive oxygen species production, establishing a self-reinforcing cycle of stress. In addition, MGO modifies proteins, impairing their structure and function and promoting persistent inflammatory signaling through advanced glycation end-products. More recently, nucleic acids have emerged as important targets of dicarbonyl stress, with MGO-induced DNA and RNA glycation contributing to genomic instability and altered cellular function. Furthermore, MGO-mediated histone glycation and epigenetic remodeling may provide a mechanistic link between hyperglycemia and long-lasting changes in gene expression. These mechanisms are particularly relevant in diabetic kidney disease, where MGO contributes to inflammation, fibrosis and renal injury. However, direct evidence that MGO-induced molecular alterations and their functional consequences persist after normalization of both glucose and MGO remains limited. This review discusses the role of MGO in metabolic memory, focusing on oxidative stress, protein glycation, nucleic acid damage and epigenetic remodeling, and highlights emerging therapeutic strategies targeting dicarbonyl stress to prevent the progression of diabetes-related complications.