The Critical Role of Methylglyoxal and Glyoxalase 1 in Diabetic Nephropathy

Rabbani, Naila; Thornalley, Paul J.

doi:10.2337/db13-1606

Cited by 132 publications

(88 citation statements)

References 21 publications

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“…Of these, reactive a-dicarbonyls like MG are among the most important (6). Reactive a-dicarbonyls are the major source of intra-and extracellular AGEs (11), which contribute to the development and progression of diabetic vascular complications (5), including accelerated atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…A number of metabolic and hemodynamic factors contribute to accelerated atherosclerosis in the setting of diabetes. One key pathway is the increased production of reactive dicarbonyls generated from triose phosphate intermediates of glycolysis, glycerol and ketone peroxidation, overactivation of the polyol pathway, and the degradation of glycated proteins (3)(4)(5)(6). In experimental diabetes, circulating and tissue levels of methylglyoxal (MG) are three to five times higher than in the nondiabetic state (7,8).…”

mentioning

confidence: 99%

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Dicarbonyl Stress in the Absence of Hyperglycemia Increases Endothelial Inflammation and Atherogenesis Similar to That Observed in Diabetes

et al. 2014

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The deleterious effects of high glucose levels and enhanced metabolic flux on the vasculature are thought to be mediated by the generation of toxic metabolites, including reactive dicarbonyls like methylglyoxal (MG). In this article, we demonstrate that increasing plasma MG to levels observed in diabetic mice either using an exogenous source (1% in drinking water) or generated following inhibition, its primary clearance enzyme, glyoxalase-1 (with 50 mg/kg IP bromobenzyl-glutathione cyclopentyl diester every second day), was able to increase vascular adhesion and augment atherogenesis in euglycemic apolipoprotein E knockout mice to a similar magnitude as that observed in hyperglycemic mice with diabetes. The effects of MG appear partly mediated by activation of the receptor for advanced glycation end products (RAGE), as deletion of RAGE was able to reduce inflammation and atherogenesis associated with MG exposure. However, RAGE deletion did not completely prevent inflammation or vascular damage, possibly because the induction of mitochondrial oxidative stress by dicarbonyls also contributes to inflammation and atherogenesis. Such data would suggest that a synergistic combination of RAGE antagonism and antioxidants may offer the greatest utility for the prevention and management of diabetic vascular complications.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Dicarbonyl Stress in the Absence of Hyperglycemia Increases Endothelial Inflammation and Atherogenesis Similar to That Observed in Diabetes

et al. 2014

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“…Another study shows that urine d-lactate, a downstream metabolite of MGO, is higher in DMN subjects than healthy subjects [35][36][37]. These clinical data suggest MGO is crucial for progression of diabetic nephropathy [4,38].…”

Section: Methylglyoxal Generation Metabolism and Damagementioning

confidence: 93%

“…Methylglyoxal is up to 20,000-fold more reactive than glucose in glycation processes [2]. In diabetic patients, MGO and MGO-related advanced end products (AGEs) are responsible for many diabetes-related complications [3][4][5]. Recent studies have shown that the impacts of MGO reach far beyond blood sugar level, as we had previously assumed.…”

Section: Introductionmentioning

confidence: 94%

Evolving Evidence of Methylglyoxal and Dicarbonyl Stress Related Diseases from Diabetic to Non-Diabetic Models

Wang¹,

Lee²,

Chou³

2015

Pharm Anal Acta

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Methylglyoxal (MGO), a byproduct of sugar and lipid metabolic processes, is a major glycating agent. This metabolite reacts with basic residues of proteins and promotes the formation of advanced glycation end products (AGEs). Although MGO and AGEs are widely discussed in the context of diabetes, until recently, MGO was thought to result from insufficient blood sugar control. A new report reveals that plasma MGO, and not blood sugar, distinguishes diabetic patients with no pain from those with pain. This ability brings to MGO a new applicability to disease diagnosis.Diseases with normal sugar conditions, such as hypertension, sepsis, and renal disease, are increasingly recognized as MGO-related. We review the role of MGO in drug-induced nephropathy, induction of hypertension by oral administration, and as a biomarker of sepsis. We also discuss the measurement of MGO and its stable metabolite d-lactate.The metabolism and pathogenic mechanisms of MGO need investigation in diverse disease models. Whether MGO can be considered as an individual pathological factor will be an interesting topic.

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“…Inhibition of glycolysis will increase the residence time of glyceraldehyde 3-p and increase its chances to spontaneously degrade to methylglyoxal. It can be expected that similar problems will occur in gut microbes exposed to glyphosate, as well as human cells, and this may explain the increased levels of methylglyoxal observed in association with diabetes [74]. A study comparing rats fed a high-fructose compared to a high-glucose diet revealed that those rats fed fructose experienced a significant increase in body weight, liver mass and fat mass compared to the glucosefed rats [75].…”

Section: Glyoxal Methylglyoxal and Glyoxylatementioning

confidence: 99%