The highly reactive dicarbonyl methylglyoxal (MGO) is mainly formed as byproduct of glycolysis. Therefore, high blood glucose levels determine increased MGO accumulation. Nonetheless, MGO levels are also increased as consequence of the ineffective action of its main detoxification pathway, the glyoxalase system, of which glyoxalase 1 (Glo1) is the rate-limiting enzyme. Indeed, a physiological decrease of Glo1 transcription and activity occurs not only in chronic hyperglycaemia but also with ageing, during which MGO accumulation occurs. MGO and its advanced glycated end products (AGEs) are associated with age-related diseases including diabetes, vascular dysfunction and neurodegeneration. Endothelial dysfunction is the first step in the initiation, progression and clinical outcome of vascular complications, such as retinopathy, nephropathy, impaired wound healing and macroangiopathy. Because of these considerations, studies have been centered on understanding the molecular basis of endothelial dysfunction in diabetes, unveiling a central role of MGO-Glo1 imbalance in the onset of vascular complications. This review focuses on the current understanding of MGO accumulation and Glo1 activity in diabetes, and their contribution on the impairment of endothelial function leading to diabetes-associated vascular damage.

Dicarbonyl stress occurs when dicarbonyl metabolites (i.e., methylglyoxal, glyoxal and 3-deoxyglucosone) accumulate as a consequence of their increased production and/or decreased detoxification. This toxic condition has been associated with metabolic and age-related diseases, both of which are characterized by a pro-inflammatory and pro-oxidant state. Methylglyoxal (MGO) is the most reactive dicarbonyl and the one with the highest endogenous flux. It is the precursor of the major quantitative advanced glycated products (AGEs) in physiological systems, arginine-derived hydroimidazolones, which accumulate in aging and dysfunctional tissues. The aging process is characterized by a decline in the functional properties of cells, tissues and whole organs, starting from the perturbation of crucial cellular processes, including mitochondrial function, proteostasis and stress-scavenging systems. Increasing studies are corroborating the causal relationship between MGO-derived AGEs and age-related tissue dysfunction, unveiling a previously underestimated role of dicarbonyl stress in determining healthy or unhealthy aging. This review summarizes the latest evidence supporting a causal role of dicarbonyl stress in age-related diseases, including diabetes mellitus, cardiovascular disease and neurodegeneration.

Diabetes is a severe threat to global health. Almost 500 million people live with diabetes worldwide. Most of them have type 2 diabetes (T2D). T2D patients are at risk of developing severe and life-threatening complications, leading to an increased need for medical care and reduced quality of life. Improved care for people with T2D is essential. Actions aiming at identifying undiagnosed diabetes and at preventing diabetes in those at high risk are needed as well. To this end, biomarker discovery and validation of risk assessment for T2D are critical. Alterations of DNA methylation have recently helped to better understand T2D pathophysiology by explaining differences among endophenotypes of diabetic patients in tissues. Recent evidence further suggests that variations of DNA methylation might contribute to the risk of T2D even more significantly than genetic variability and might represent a valuable tool to predict T2D risk. In this review, we focus on recent information on the contribution of DNA methylation to the risk and the pathogenesis of T2D. We discuss the limitations of these studies and provide evidence supporting the potential for clinical application of DNA methylation marks to predict the risk and progression of T2D.

Glucose serves as a primary, and for some tissues the unique, fuel source in order to generate and maintain the biological functions. Hyperglycemia is a hallmark of type 2 diabetes and is the direct consequence of perturbations in the glucose homeostasis. Insulin resistance, referred to as a reduced response of target tissues to the hormone, contributes to the development of hyperglycemia. The molecular mechanisms responsible for the altered glucose homeostasis are numerous and not completely understood. MicroRNAs (miRNAs) are now recognized as regulators of the lipid and glucose metabolism and are involved in the onset of metabolic diseases. Indeed, these small non-coding RNA molecules operate in the RNA silencing and posttranscriptional regulation of gene expression and may modulate the levels of kinases and enzymes in the glucose metabolism. Therefore, a better characterization of the function of miRNAs and a deeper understanding of their role in disease may represent a fundamental step toward innovative treatments addressing the causes, not only the symptoms, of hyperglycemia, using approaches aimed at restoring either miRNAs or their specific targets. In this review, we outline the current understanding regarding the impact of miRNAs in the glucose metabolism and highlight the need for further research focused on altered key kinases and enzymes in metabolic diseases.