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Advanced glycation end products and oxidative stress in type 2 diabetes mellitus.

Nowotny K, Jung T, Höhn A, Weber D, Grune T - Biomolecules (2015)

Bottom Line: Thus, AGEs contribute at least partly to chronic stress conditions in diabetes.As AGEs are not only formed endogenously, but also derive from exogenous sources, i.e., food, they have been assumed as risk factors for T2DM.However, the role of AGEs in the pathogenesis of T2DM and diabetic complications-if they are causal or simply an effect-is only partly understood.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. Kerstin.Nowotny@dife.de.

ABSTRACT
Type 2 diabetes mellitus (T2DM) is a very complex and multifactorial metabolic disease characterized by insulin resistance and β cell failure leading to elevated blood glucose levels. Hyperglycemia is suggested to be the main cause of diabetic complications, which not only decrease life quality and expectancy, but are also becoming a problem regarding the financial burden for health care systems. Therefore, and to counteract the continually increasing prevalence of diabetes, understanding the pathogenesis, the main risk factors, and the underlying molecular mechanisms may establish a basis for prevention and therapy. In this regard, research was performed revealing further evidence that oxidative stress has an important role in hyperglycemia-induced tissue injury as well as in early events relevant for the development of T2DM. The formation of advanced glycation end products (AGEs), a group of modified proteins and/or lipids with damaging potential, is one contributing factor. On the one hand it has been reported that AGEs increase reactive oxygen species formation and impair antioxidant systems, on the other hand the formation of some AGEs is induced per se under oxidative conditions. Thus, AGEs contribute at least partly to chronic stress conditions in diabetes. As AGEs are not only formed endogenously, but also derive from exogenous sources, i.e., food, they have been assumed as risk factors for T2DM. However, the role of AGEs in the pathogenesis of T2DM and diabetic complications-if they are causal or simply an effect-is only partly understood. This review will highlight the involvement of AGEs in the development and progression of T2DM and their role in diabetic complications.

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Influence of methylglyoxal-modified collagen on cellular functions relevant to diabetic complications, according to [113,116,119,120]. Cells were cultured on methylglyoxal-modified collagen and the effect of AGE-collagen on cellular functions was studied. Dermal fibroblasts grown on modified collagen increase collagen synthesis. Methylglyoxal-modified collagen reduces cell adhesion and migration of mesangial cells, cardiac fibroblast are less adherent. Myofibroblast differentiation is stimulated in cardiac fibroblasts cultured on modified collagen and modifications of basement membrane collagen causes detachment, cell death and reduced angiogenesis of vascular endothelial cells.
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biomolecules-05-00194-f005: Influence of methylglyoxal-modified collagen on cellular functions relevant to diabetic complications, according to [113,116,119,120]. Cells were cultured on methylglyoxal-modified collagen and the effect of AGE-collagen on cellular functions was studied. Dermal fibroblasts grown on modified collagen increase collagen synthesis. Methylglyoxal-modified collagen reduces cell adhesion and migration of mesangial cells, cardiac fibroblast are less adherent. Myofibroblast differentiation is stimulated in cardiac fibroblasts cultured on modified collagen and modifications of basement membrane collagen causes detachment, cell death and reduced angiogenesis of vascular endothelial cells.

Mentions: One main target of increased concentrations of reducing sugars and dicarbonyl compounds found in diabetes is collagen. There are a few studies which investigated the effect of modified collagen on cell functions. According to the subsequent studies, a simplified scheme describing which cell functions are affected by methylglyoxal-modified collagen, contributing to diabetes-related changes related to diabetic complications, is illustrated in Figure 5. Firstly, it was reported that modification of basement membrane collagen type IV by methylglyoxal reduces attachment of vascular endothelial cells and angiogenesis [113]. AGEs such as MG-H1 were found on integrin-binding sites of collagen and were assumed to cause decreased cell attachment. As demonstrated by Chong et al., methylglyoxal modifications of arginine residues in the integrin-binding sequence also reduce collagen binding so that collagen degradation by phagocytosis is impaired, thus, promoting fibrosis [114]. Regarding the collagen turnover, it was shown that collagen modified with glyoxal and methylglyoxal is per se less degradable by proteases due to the formation of cross-links [115]. Yuen et al. observed that methylglyoxal-modified collagen type I inhibits cell adhesion of cardiac fibroblasts while stimulating myofibroblast differentiation and their migration [116]. Further investigations of Talior-Volodarsky et al. reported that myofibroblast differentiation is stimulated by upregulation of α11 integrin expression which was found to be induced by transforming growth factor (TGF) β2/Smad3 signaling [117,118].


Advanced glycation end products and oxidative stress in type 2 diabetes mellitus.

Nowotny K, Jung T, Höhn A, Weber D, Grune T - Biomolecules (2015)

Influence of methylglyoxal-modified collagen on cellular functions relevant to diabetic complications, according to [113,116,119,120]. Cells were cultured on methylglyoxal-modified collagen and the effect of AGE-collagen on cellular functions was studied. Dermal fibroblasts grown on modified collagen increase collagen synthesis. Methylglyoxal-modified collagen reduces cell adhesion and migration of mesangial cells, cardiac fibroblast are less adherent. Myofibroblast differentiation is stimulated in cardiac fibroblasts cultured on modified collagen and modifications of basement membrane collagen causes detachment, cell death and reduced angiogenesis of vascular endothelial cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384119&req=5

biomolecules-05-00194-f005: Influence of methylglyoxal-modified collagen on cellular functions relevant to diabetic complications, according to [113,116,119,120]. Cells were cultured on methylglyoxal-modified collagen and the effect of AGE-collagen on cellular functions was studied. Dermal fibroblasts grown on modified collagen increase collagen synthesis. Methylglyoxal-modified collagen reduces cell adhesion and migration of mesangial cells, cardiac fibroblast are less adherent. Myofibroblast differentiation is stimulated in cardiac fibroblasts cultured on modified collagen and modifications of basement membrane collagen causes detachment, cell death and reduced angiogenesis of vascular endothelial cells.
Mentions: One main target of increased concentrations of reducing sugars and dicarbonyl compounds found in diabetes is collagen. There are a few studies which investigated the effect of modified collagen on cell functions. According to the subsequent studies, a simplified scheme describing which cell functions are affected by methylglyoxal-modified collagen, contributing to diabetes-related changes related to diabetic complications, is illustrated in Figure 5. Firstly, it was reported that modification of basement membrane collagen type IV by methylglyoxal reduces attachment of vascular endothelial cells and angiogenesis [113]. AGEs such as MG-H1 were found on integrin-binding sites of collagen and were assumed to cause decreased cell attachment. As demonstrated by Chong et al., methylglyoxal modifications of arginine residues in the integrin-binding sequence also reduce collagen binding so that collagen degradation by phagocytosis is impaired, thus, promoting fibrosis [114]. Regarding the collagen turnover, it was shown that collagen modified with glyoxal and methylglyoxal is per se less degradable by proteases due to the formation of cross-links [115]. Yuen et al. observed that methylglyoxal-modified collagen type I inhibits cell adhesion of cardiac fibroblasts while stimulating myofibroblast differentiation and their migration [116]. Further investigations of Talior-Volodarsky et al. reported that myofibroblast differentiation is stimulated by upregulation of α11 integrin expression which was found to be induced by transforming growth factor (TGF) β2/Smad3 signaling [117,118].

Bottom Line: Thus, AGEs contribute at least partly to chronic stress conditions in diabetes.As AGEs are not only formed endogenously, but also derive from exogenous sources, i.e., food, they have been assumed as risk factors for T2DM.However, the role of AGEs in the pathogenesis of T2DM and diabetic complications-if they are causal or simply an effect-is only partly understood.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. Kerstin.Nowotny@dife.de.

ABSTRACT
Type 2 diabetes mellitus (T2DM) is a very complex and multifactorial metabolic disease characterized by insulin resistance and β cell failure leading to elevated blood glucose levels. Hyperglycemia is suggested to be the main cause of diabetic complications, which not only decrease life quality and expectancy, but are also becoming a problem regarding the financial burden for health care systems. Therefore, and to counteract the continually increasing prevalence of diabetes, understanding the pathogenesis, the main risk factors, and the underlying molecular mechanisms may establish a basis for prevention and therapy. In this regard, research was performed revealing further evidence that oxidative stress has an important role in hyperglycemia-induced tissue injury as well as in early events relevant for the development of T2DM. The formation of advanced glycation end products (AGEs), a group of modified proteins and/or lipids with damaging potential, is one contributing factor. On the one hand it has been reported that AGEs increase reactive oxygen species formation and impair antioxidant systems, on the other hand the formation of some AGEs is induced per se under oxidative conditions. Thus, AGEs contribute at least partly to chronic stress conditions in diabetes. As AGEs are not only formed endogenously, but also derive from exogenous sources, i.e., food, they have been assumed as risk factors for T2DM. However, the role of AGEs in the pathogenesis of T2DM and diabetic complications-if they are causal or simply an effect-is only partly understood. This review will highlight the involvement of AGEs in the development and progression of T2DM and their role in diabetic complications.

Show MeSH
Related in: MedlinePlus