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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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Formation of reactive dicarbonyls and AGEs, modified according to [29]. Reactive dicarbonyls including methylglyoxal, glyoxal and 3-deoxyglucosone are formed through several pathways: the Maillard reaction, the polyol pathway, glycolysis, lipid peroxidation or glucose autoxidation. Dicarbonyl compounds react further to form irreversible products, the so-called AGEs.
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biomolecules-05-00194-f002: Formation of reactive dicarbonyls and AGEs, modified according to [29]. Reactive dicarbonyls including methylglyoxal, glyoxal and 3-deoxyglucosone are formed through several pathways: the Maillard reaction, the polyol pathway, glycolysis, lipid peroxidation or glucose autoxidation. Dicarbonyl compounds react further to form irreversible products, the so-called AGEs.

Mentions: The first link between glycated proteins and diabetes was made in 1968 with the discovery of an altered form of hemoglobin (meanwhile known as HbA1c) in red blood cells of patients with diabetes [11]. It became clear, that glycation occurs predominantly on the N-terminal valine of the β chain and that this Amadori product is formed non-enzymatically in a reaction which was before only known to take place in food [12,13]. In this so-called Maillard reaction, the carbonyl group of a reducing sugar reacts with the amino group of a protein, lipid or nucleic acid generating Schiff bases which rearrange to Amadori products (Figure 2). However, Amadori products are relatively unstable so that further consecutive and parallel reactions occur, eventually leading to the formation of irreversible AGEs. The Maillard reaction is the most common pathway known to form AGEs. Not only during all stages of the Maillard reaction, but also as intermediates or byproducts of glucose autoxidation, lipid peroxidation or the polyol pathway, high reactive carbonyl compounds, including glyoxal, methylglyoxal or 3-deoxyglucosone are formed [14,15,16]. Increased concentrations of glyoxal, methylglyoxal as well as 3-deoxyglucosone have been found in plasma of patients with T2DM [17]. Glyoxal, for example, causes the formation of Nε-(carboxymethyl) lysine (CML) [18] which is at present the best characterized AGE. Further AGEs formed by glyoxal are glyoxal-derived lysyl dimer (GOLD) [19], Nω-(carboxymethyl) arginine (CMA) [20] or S-carboxymethylcysteine [21]. Methylglyoxal causes the generation of, for example, Nε-(carboxyethyl) lysine (CEL) [22], methylglyoxal-derived lysyl dimer (MOLD) [23], argpyrimidine [24] or methylglyoxal-derived hydroimidazolone MG-H1 [25] whereas 3-deoxyglucosone leads to the formation of pyrraline [26], pentosidine [27], imidazolone or also CML [28].


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

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

Formation of reactive dicarbonyls and AGEs, modified according to [29]. Reactive dicarbonyls including methylglyoxal, glyoxal and 3-deoxyglucosone are formed through several pathways: the Maillard reaction, the polyol pathway, glycolysis, lipid peroxidation or glucose autoxidation. Dicarbonyl compounds react further to form irreversible products, the so-called AGEs.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00194-f002: Formation of reactive dicarbonyls and AGEs, modified according to [29]. Reactive dicarbonyls including methylglyoxal, glyoxal and 3-deoxyglucosone are formed through several pathways: the Maillard reaction, the polyol pathway, glycolysis, lipid peroxidation or glucose autoxidation. Dicarbonyl compounds react further to form irreversible products, the so-called AGEs.
Mentions: The first link between glycated proteins and diabetes was made in 1968 with the discovery of an altered form of hemoglobin (meanwhile known as HbA1c) in red blood cells of patients with diabetes [11]. It became clear, that glycation occurs predominantly on the N-terminal valine of the β chain and that this Amadori product is formed non-enzymatically in a reaction which was before only known to take place in food [12,13]. In this so-called Maillard reaction, the carbonyl group of a reducing sugar reacts with the amino group of a protein, lipid or nucleic acid generating Schiff bases which rearrange to Amadori products (Figure 2). However, Amadori products are relatively unstable so that further consecutive and parallel reactions occur, eventually leading to the formation of irreversible AGEs. The Maillard reaction is the most common pathway known to form AGEs. Not only during all stages of the Maillard reaction, but also as intermediates or byproducts of glucose autoxidation, lipid peroxidation or the polyol pathway, high reactive carbonyl compounds, including glyoxal, methylglyoxal or 3-deoxyglucosone are formed [14,15,16]. Increased concentrations of glyoxal, methylglyoxal as well as 3-deoxyglucosone have been found in plasma of patients with T2DM [17]. Glyoxal, for example, causes the formation of Nε-(carboxymethyl) lysine (CML) [18] which is at present the best characterized AGE. Further AGEs formed by glyoxal are glyoxal-derived lysyl dimer (GOLD) [19], Nω-(carboxymethyl) arginine (CMA) [20] or S-carboxymethylcysteine [21]. Methylglyoxal causes the generation of, for example, Nε-(carboxyethyl) lysine (CEL) [22], methylglyoxal-derived lysyl dimer (MOLD) [23], argpyrimidine [24] or methylglyoxal-derived hydroimidazolone MG-H1 [25] whereas 3-deoxyglucosone leads to the formation of pyrraline [26], pentosidine [27], imidazolone or also CML [28].

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