scholarly journals Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

2020 ◽  
Vol 100 (1) ◽  
pp. 407-461 ◽  
Author(s):  
C. G. Schalkwijk ◽  
C. D. A. Stehouwer

The formation and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis of type 2 diabetes, vascular complications of diabetes, and several other age-related chronic inflammatory diseases such as cardiovascular disease, cancer, and disorders of the central nervous system. MGO is mainly formed as a byproduct of glycolysis and, under physiological circumstances, detoxified by the glyoxalase system. MGO is the major precursor of nonenzymatic glycation of proteins and DNA, subsequently leading to the formation of advanced glycation end products (AGEs). MGO and MGO-derived AGEs can impact on organs and tissues affecting their functions and structure. In this review we summarize the formation of MGO, the detoxification of MGO by the glyoxalase system, and the biochemical pathways through which MGO is linked to the development of diabetes, vascular complications of diabetes, and other age-related diseases. Although interventions to treat MGO-associated complications are not yet available in the clinical setting, several strategies to lower MGO have been developed over the years. We will summarize several new directions to target MGO stress including glyoxalase inducers and MGO scavengers. Targeting MGO burden may provide new therapeutic applications to mitigate diseases in which MGO plays a crucial role.

2015 ◽  
Vol 128 (12) ◽  
pp. 839-861 ◽  
Author(s):  
Dionne E.M. Maessen ◽  
Coen D.A. Stehouwer ◽  
Casper G. Schalkwijk

The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO-associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.


2004 ◽  
Vol 5 (2) ◽  
pp. 163-169 ◽  
Author(s):  
A. E. Buchs ◽  
A. Kornberg ◽  
M. Zahavi ◽  
D. Aharoni ◽  
C. Zarfati ◽  
...  

The aim of the study was to determine the correlation between the expression of tissue factor (TF) and the receptor for advanced glycation end products (RAGEs) and vascular complications in patients with longstanding uncontrolled type 2 diabetes (T2D). TF and RAGE mRNAs as well as TF antigen and activity were investigated in 21 T2D patients with and without vascular complications. mRNA expression was assessed by reverse transcriptase–polymerase chain reaction (RT-PCR) in nonstimulated and advanced glycation end product (AGE) albumin–stimulated peripheral blood mononuclear cells (PBMCs). TF antigen expression was determined by enzyme-linked immunosorbent assay (ELISA) and TF activity by a modified prothrombin time assay. Basal RAGE mRNA expression was 0.2 ± 0.06 in patients with complications and 0.05 ± 0.06 patients without complications (P= .004). Stimulation did not cause any further increase in either group. TF mRNA was 0.58 ± 0.29 in patients with complications and 0.21 ± 0.18 in patients without complications (P= .003). Stimulation resulted in a nonsignificant increase in both groups. Basal TF activity (U/106PBMCs) was 18.4 ± 13.2 in patients with complications and 6.96 ± 5.2 in patients without complications (P= .003). It increased 3-fold in both groups after stimulation (P= .001). TF antigen (pg/106PBMCs) was 33.7 ± 28.6 in patients with complications, 10.4 ± 7.8 in patients without complications (P= .02). Stimulation tripled TF antigen in both groups of patients (P= .001). The RAGE/TF axis is up-regulated inT2Dpatients with vascular complications as compared to patients without complications. This suggests a role for this axis in the pathogenesis of vascular complications in T2D.


2020 ◽  
Vol 3 (5) ◽  
pp. 01-04
Author(s):  
Abdullah Ghouth

The Background and Purpose: to assess the prevalence of hypertension and micro-vascular complications among type 2 diabetic patients registered in primary health care center in Mukalla city at eastern Yemen. Methods: A Cross-sectional study was conducted in a randomly selected eligible patients from the diabetic registry of the AL Noor Charity Center (ACC), Mukalla city in Yemen. Results: Prevalence of hypertension in the T2DM patients were 46.7% (56/120). Retinopathy is the most micro-vascular complications among the adults having T2DM (73/120, 60.8%) while nephropathy is the least prevalence (13/120, 10.8%), prevalence of neuropathy was 49.2% (59/120). a high prevalence of retinopathy in males (66%) than females (55.7%) and a high prevalence of neuropathy in male adults (52.2%) than females (46%).No statistical significant difference were exit related to gender for any studied complications. Similar findings were observed regarding age related variations. Conclusion: A high prevalence of hypertension, retinopathy and neuropathy were reported among T2DM patients in Mukalla. Adopting effective and safe treatment strategies are highly recommended to prevent premature death and complications due to DM.


2008 ◽  
Vol 90 (1) ◽  
pp. 29-29
Author(s):  
Waquar Yusef

There are nearly 2.3 million individuals with diagnosed diabetes in the UK. Cardiovascular disease is the cause of death in up to 75 per cent of patients with type 2 diabetes. Often these deaths are premature.


2021 ◽  
Vol 98 (9-10) ◽  
pp. 699-708
Author(s):  
T. A. Meleshkevich ◽  
I. A. Kurnikova ◽  
A. E. Mitichkin ◽  
E. I. Luchina ◽  
M. E. Shevchenko ◽  
...  

Issues of the formation and progression of late complications of diabetes mellitus remain interesting and foreground today, especially in cases of type 2 diabetes mellitus (dm) combined with other endocrine diseases. The pathogenetic relation between the mechanisms leading to blood vessels and nerves damage against the background of diabetes mellitus, and, for example, mechanisms of autoimmune thyroid abnormality (ait), is far from being unambiguous, but the very fact of its existence cannot be denied.Purpose: to determine the predominant type of comorbidity (trans-syndromal, trans-nosological or chronological) and the level of comorbidity according to the disease rating scale (cirs) in patients with type 2 diabetes and ait, to study the structure of later complications of diabetes mellitus in this group of patients and to assess the contribution of certain factors to increased risk of complications.Methods. 428 patients were examined in a specialized endocrinology department, and two groups were formed: an observation group — 213 people with diagnosed type 2 diabetes and ait, and a comparison group — 215 people with a diagnosis of type 2 diabetes. These groups were comparable in age, the duration of diabetes, body mass index, correction of the disease. The analysis included clinical and laboratory parameters, the results of hormones level studies (tsh, free t4, insulin, c-peptide) and antibodies (at-tpo), thyroid ultrasonography, calculation of the insulin resistance index (homa) and the comorbidity index (cirs — cumulative illness rating scale) followed by a correlation-regression analysis of statistical data. The state of the peripheral nervous system was evaluated with the use of electromyography in patients of both groups, and the severity of diabetic neuropathy was evaluated with the use of the neuropathy disability score and vas (visual analogue scale) scales. The state of the vascular system was studied according to the data of ultrasound examination of the vessels of the lower extremities, echocardiography, and ophthalmoscopy.Results. The obtained data made it possible to determine the factors infl uencing the risk of type 2 diabetes complications developement, and to establish that neuropathic complications begin and progress faster in patients with comorbid endocrine pathology, however, there is no such dependence for vascular complications. According to the linear regression equation of the dependence of total complications on the duration of the disease, it was revealed that the development of vascular complications in patients with combined endocrinopathy occurs even more slowly than in patients with diabetes. The contribution of diabetes compensation and identifi ed risk factors to the progression of diabetic complications was less important for patients with endocrinopathies. As for evaluating the contribution of individual parameters, the most signifi cant were the duration of diabetes mellitus, albuminuria, atherosclerosis of the vessels of the lower extremities.Conclusion. In addition to the known risk factors for the development and progression of vascular complications, in patients with overlapping endocrinopathy, the preservation of residual insulin secretion and renal function (chronic kidney disease, proteinuria) were important. the prevalence of “total” Complications in the group of patients with combined endocrine pathology was lower, however, neuropathic complications in the same group were observed more often,т which indicates the primary eff ect of thyroid dysfunction on the structure of the nervous tissue.


Author(s):  
Claudia Borsa ◽  
Daniela Gradinaru ◽  
Denisa Margina ◽  
Gabriel Ioan Prada ◽  
Catalina Pena

The interaction of Advanced Glycation End products (AGEs) and their specific receptor, Receptor for Advanced Glycation End products (RAGE) play an important role in diabetes and vascular complications. Engagement of RAGE by AGEs leads to activation of cellular signaling pathways and vascular dysfunction. The soluble RAGE (sRAGE) acts as a decoy receptor for AGEs. The aim of this study was to evaluate the soluble RAGE in elderly subjects with T2DM and its relationships with glycoxidative, inflammatory and cardiovascular risk markers. The serum AGEs, sRAGE, interleukine- 6 (IL-6), lipid profile, glycemic status, uric acid, creatinine and cardiovascular risk markers were determined in elderly subjects with type 2 diabetes mellitus (T2DM, N=72, 75±4 years old) and aged-match healthy subjects (N=15, 76±3 years old). Significant higher levels of AGEs and AGEs/sRAGE ratio concomitantly with significant lower levels of sRAGE were pointed out in elderly subjects with T2DM as compared to control. The values of AGEs/sRAGE ratio were significantly positively associated (P<0.05) with atherogenic, inflammatory and cardiovascular risk markers and significantly negatively with anti-atherogenic lipoproteins (P<0.05). The multivariate regression analyses showed that atherogenic index was an independent predictor of sRAGE levels and AGEs/sRAGE ratio values. The associations of soluble RAGE and the AGEs/sRAGE ratio with atherogenic and inflammatory markers could reflect the protective role of soluble variants of RAGE in atherosclerosis and diabetes vascular complications.


Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1062 ◽  
Author(s):  
Gemma Aragonès ◽  
Sheldon Rowan ◽  
Sarah G Francisco ◽  
Wenxin Yang ◽  
Jasper Weinberg ◽  
...  

Hyperglycemia, a defining characteristic of diabetes, combined with oxidative stress, results in the formation of advanced glycation end products (AGEs). AGEs are toxic compounds that have adverse effects on many tissues including the retina and lens. AGEs promote the formation of reactive oxygen species (ROS), which, in turn, boost the production of AGEs, resulting in positive feedback loops, a vicious cycle that compromises tissue fitness. Oxidative stress and the accumulation of AGEs are etiologically associated with the pathogenesis of multiple diseases including diabetic retinopathy (DR). DR is a devastating microvascular complication of diabetes mellitus and the leading cause of blindness in working-age adults. The onset and development of DR is multifactorial. Lowering AGEs accumulation may represent a potential therapeutic approach to slow this sight-threatening diabetic complication. To set DR in a physiological context, in this review we first describe relations between oxidative stress, formation of AGEs, and aging in several tissues of the eye, each of which is associated with a major age-related eye pathology. We summarize mechanisms of AGEs generation and anti-AGEs detoxifying systems. We specifically feature the potential of the glyoxalase system in the retina in the prevention of AGEs-associated damage linked to DR. We provide a comparative analysis of glyoxalase activity in different tissues from wild-type mice, supporting a major role for the glyoxalase system in the detoxification of AGEs in the retina, and present the manipulation of this system as a therapeutic strategy to prevent the onset of DR.


2003 ◽  
Vol 31 (6) ◽  
pp. 1400-1402 ◽  
Author(s):  
M. Bourajjaj ◽  
C.D.A. Stehouwer ◽  
V.W.M. van Hinsbergh ◽  
C.G. Schalkwijk

Various theories have been proposed to explain the hyperglycaemia-induced pathogenesis of vascular complications of diabetes, including detrimental effects of AGEs (advanced glycation end products) on vascular tissues. Increased formation of the very reactive dicarbonyl compound MGO (methylglyoxal), one of the side-products of glycolysis, and MGO-derived AGEs seem to be implicated in the development of diabetic vascular complications. Although the exact role of MGO and MGO adducts in the development of vascular complications is unknown, receptor-mediated activation of vascular cells by the MGO–arginine adduct hydroimidazolone, as well as intracellular modifications of protein by MGO, seem to be involved. The aim of this mini-review is to assess to what extent MGO is related to vascular complications in diabetes.


Sign in / Sign up

Export Citation Format

Share Document