Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

Abstract

Glucose and fructose metabolism originates the highly reactive byproduct methylglyoxal (MG), which is a strong precursor of advanced glycation end products (AGE). The MG has been implicated in classical diabetic complications such as retinopathy, nephropathy, and neuropathy, but has also been recently associated with cardiovascular diseases and central nervous system disorders such as cerebrovascular diseases and dementia. Recent studies even suggested its involvement in insulin resistance and beta-cell dysfunction, contributing to the early development of type 2 diabetes and creating a vicious circle between glycation and hyperglycemia. Despite several drugs and natural compounds have been identified in the last years in order to scavenge MG and inhibit AGE formation, we are still far from having an effective strategy to prevent MG-induced mechanisms. This review summarizes the endogenous and exogenous sources of MG, also addressing the current controversy about the importance of exogenous MG sources. The mechanisms by which MG changes cell behavior and its involvement in type 2 diabetes development and complications and the pathophysiological implication are also summarized. Particular emphasis will be given to pathophysiological relevance of studies using higher MG doses, which may have produced biased results. Finally, we also overview the current knowledge about detoxification strategies, including modulation of endogenous enzymatic systems and exogenous compounds able to inhibit MG effects on biological systems.

Serum levels of advanced glycation end-products (AGEs) and the decoy soluble receptor for AGEs (sRAGE) can identify non-alcoholic fatty liver disease in age-, sex- and BMI-matched normo-glycemic adults

“…Reduced insulin sensitivity and impaired glucose and lipid metabolism [9] favour advance glycation end-products (AGEs) formation, contributing to liver damage [10]. AGEs are formed by the non-enzymatic reaction of a reducing sugar or oxidized lipid with an amino acid, resulting in alteration in the structure and function of proteins [11]. N ε -carboxyethyl-L-lysine (CEL), N ε -carboxymethyl-L-lysine (CML), and pentosidine are the most common and best characterized AGEs used as biomarkers of disease progression [12,13].…”

miR-450a-5p Eliminates MGO-Induced Insulin Resistance via Targeting CREB

“…MGO can be self-cleared by the body under normal physiological conditions, as MGO is characterized by hyper-responsiveness and short half-life, and the human body contains a variety of enzymes degrading MGO (17). In abnormal conditions, the dysfunction of MGO clearing pathway will lead to the gradual accumulation of MGO content, which can not only directly cause damage to cells, but also induce the massive generation of advanced glycation end products in the body (3). In previous studies, miRNAs such as miR-30b (18), miR-214 (19), miR-9a-3p (20) have been proved to be closely related to the content of MGO.…”

“…Methylglyoxal (MGO) plays a pivotal role in the occurrence and development of DM, which is a highly active dicarbonyl compound and a ubiquitous product of cell metabolism (2). Concretely, MGO is an inherent by-product of glycolysis with cell permeability, the aggregation of MGO is harmful, as it is the most active compound to induce glycosylation products in cells (3), and this will induce insulin resistance to further aggravate pathoglycemia and dyslipidemia, thus promoting the progress of the disease (4). In addition, MGO can easily react with proteins, fats and nucleic acids to form advanced glycation end products, leading to the occurrence of cataract, retinopathy, kidney disease, vascular disease and other diabetic complications (5)(6)(7)(8).…”

Effects of the Reactive Metabolite Methylglyoxal on Cellular Signalling, Insulin Action and Metabolism – What We Know in Mammals and What We Can Learn From Yeast

“…Increased insulin levels have been correlated with the accumulation of MG and it is believed that this insulin resistance may be a consequence of interference with insulin receptor signalling [1,24]. When studying the effects of MG accumulation on insulin signalling, it was observed in Sprague-Dawley rats treated for 9 weeks with fructose, that the development of insulin resistance was closely correlated with increased MG levels in serum and adipose tissue.…”

“…Furthermore, advanced glycation was linked to diabetic complications including macrovascular complications such as atherosclerosis [15,16] as well as microvascular complications including diabetic nephropathy [17][18][19], retinopathy [20,21] and neuropathy [22,23] in rodents. However, these macro-and microvascular complications have been reviewed elsewhere [1,15,16,24] and will not be covered here.…”