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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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AGE-induced pathways involved in β cell dysfunction according to [98,100,102,103]. Decreased insulin synthesis and reduced insulin secretion are both involved in β cell failure contributing to hyperglycemia. AGEs reduce phosphorylation (P) and induce acetylation (Ac) of FoxO1, thus, FoxO1 translocates into the nucleus and is protected against proteasomal degradation, respectively. In addition, AGEs induce PDX-1 translocation into the cytoplasm and decrease PDX-1 protein expression, finally affecting insulin gene transcription and insulin synthesis. Regarding insulin secretion, AGEs cause inhibition by activation of iNOS and consequent blocking of cytochrome c oxidase activity and ATP depletion. Moreover, AGEs decrease insulin secretion through alterations in the TCA cycle which limits ATP production. ATP depletion inhibits closure of ATP-dependent potassium channels which leads to reduced membrane depolarization and decrease of intracellular calcium concentration inhibiting insulin secretion. (Arrows illustrate direct interactions; dashed arrows illustrate possible targets of AGEs).
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biomolecules-05-00194-f004: AGE-induced pathways involved in β cell dysfunction according to [98,100,102,103]. Decreased insulin synthesis and reduced insulin secretion are both involved in β cell failure contributing to hyperglycemia. AGEs reduce phosphorylation (P) and induce acetylation (Ac) of FoxO1, thus, FoxO1 translocates into the nucleus and is protected against proteasomal degradation, respectively. In addition, AGEs induce PDX-1 translocation into the cytoplasm and decrease PDX-1 protein expression, finally affecting insulin gene transcription and insulin synthesis. Regarding insulin secretion, AGEs cause inhibition by activation of iNOS and consequent blocking of cytochrome c oxidase activity and ATP depletion. Moreover, AGEs decrease insulin secretion through alterations in the TCA cycle which limits ATP production. ATP depletion inhibits closure of ATP-dependent potassium channels which leads to reduced membrane depolarization and decrease of intracellular calcium concentration inhibiting insulin secretion. (Arrows illustrate direct interactions; dashed arrows illustrate possible targets of AGEs).

Mentions: In addition to β cell death, most of the studies showed that AGEs affect insulin secretion [95,96,97]. Further evidence for the AGE-mediated decline in insulin secretion was given by Zhao et al. [98]. They showed that AGEs block the activity of cytochrome c oxidase and production of adenosine triphosphate (ATP) in islets isolated from mice. Impaired insulin secretion increases plasma glucose levels which were accompanied by increased formation of •NO and elevated expression of inducible nitric oxide synthase (iNOS) suggesting that AGEs cause the induction of iNOS so that increasing concentrations of •NO inhibit cytochrome c oxidase activity and ATP production (Figure 4). ATP is necessary for insulin secretion as ATP causes the shutdown of ATP-sensitive potassium channels leading to membrane depolarization and the influx of Ca2+. Increased intracellular Ca2+-concentrations trigger the exocytosis of insulin granules [99]. Low ATP levels inhibit this process. More recently, Hachiya et al. tested the influence of bovine serum albumin (BSA) modified with glucose and glyceraldehyde on insulin secretion of isolated rat pancreatic islets [100]. Both, glucose-BSA and glyceraldehyde-BSA impaired insulin secretion induced by high concentrations of glucose. However, the authors were not able to detect any changes in the expression of oxidative response genes including iNOS. They concluded the impaired insulin secretion to be due to defects in the tricarboxylic acid cycle (TCA). Moreover, gene expression of the NADH (reduced nicotinamide adenine dinucleotide) shuttle enzymes malate dehydrogenase 1/2 was reduced after AGE treatment. However, as the expression of glycerol phosphate shuttle was unchanged, and inhibition of both have been linked to decreased insulin secretion [101], further investigations must clarify whether AGEs affect NADH shuttle function and thus ATP production. The different results reveal that more research to understand the causal mechanisms leading to impaired insulin secretion needs to be performed.


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

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

AGE-induced pathways involved in β cell dysfunction according to [98,100,102,103]. Decreased insulin synthesis and reduced insulin secretion are both involved in β cell failure contributing to hyperglycemia. AGEs reduce phosphorylation (P) and induce acetylation (Ac) of FoxO1, thus, FoxO1 translocates into the nucleus and is protected against proteasomal degradation, respectively. In addition, AGEs induce PDX-1 translocation into the cytoplasm and decrease PDX-1 protein expression, finally affecting insulin gene transcription and insulin synthesis. Regarding insulin secretion, AGEs cause inhibition by activation of iNOS and consequent blocking of cytochrome c oxidase activity and ATP depletion. Moreover, AGEs decrease insulin secretion through alterations in the TCA cycle which limits ATP production. ATP depletion inhibits closure of ATP-dependent potassium channels which leads to reduced membrane depolarization and decrease of intracellular calcium concentration inhibiting insulin secretion. (Arrows illustrate direct interactions; dashed arrows illustrate possible targets of AGEs).
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00194-f004: AGE-induced pathways involved in β cell dysfunction according to [98,100,102,103]. Decreased insulin synthesis and reduced insulin secretion are both involved in β cell failure contributing to hyperglycemia. AGEs reduce phosphorylation (P) and induce acetylation (Ac) of FoxO1, thus, FoxO1 translocates into the nucleus and is protected against proteasomal degradation, respectively. In addition, AGEs induce PDX-1 translocation into the cytoplasm and decrease PDX-1 protein expression, finally affecting insulin gene transcription and insulin synthesis. Regarding insulin secretion, AGEs cause inhibition by activation of iNOS and consequent blocking of cytochrome c oxidase activity and ATP depletion. Moreover, AGEs decrease insulin secretion through alterations in the TCA cycle which limits ATP production. ATP depletion inhibits closure of ATP-dependent potassium channels which leads to reduced membrane depolarization and decrease of intracellular calcium concentration inhibiting insulin secretion. (Arrows illustrate direct interactions; dashed arrows illustrate possible targets of AGEs).
Mentions: In addition to β cell death, most of the studies showed that AGEs affect insulin secretion [95,96,97]. Further evidence for the AGE-mediated decline in insulin secretion was given by Zhao et al. [98]. They showed that AGEs block the activity of cytochrome c oxidase and production of adenosine triphosphate (ATP) in islets isolated from mice. Impaired insulin secretion increases plasma glucose levels which were accompanied by increased formation of •NO and elevated expression of inducible nitric oxide synthase (iNOS) suggesting that AGEs cause the induction of iNOS so that increasing concentrations of •NO inhibit cytochrome c oxidase activity and ATP production (Figure 4). ATP is necessary for insulin secretion as ATP causes the shutdown of ATP-sensitive potassium channels leading to membrane depolarization and the influx of Ca2+. Increased intracellular Ca2+-concentrations trigger the exocytosis of insulin granules [99]. Low ATP levels inhibit this process. More recently, Hachiya et al. tested the influence of bovine serum albumin (BSA) modified with glucose and glyceraldehyde on insulin secretion of isolated rat pancreatic islets [100]. Both, glucose-BSA and glyceraldehyde-BSA impaired insulin secretion induced by high concentrations of glucose. However, the authors were not able to detect any changes in the expression of oxidative response genes including iNOS. They concluded the impaired insulin secretion to be due to defects in the tricarboxylic acid cycle (TCA). Moreover, gene expression of the NADH (reduced nicotinamide adenine dinucleotide) shuttle enzymes malate dehydrogenase 1/2 was reduced after AGE treatment. However, as the expression of glycerol phosphate shuttle was unchanged, and inhibition of both have been linked to decreased insulin secretion [101], further investigations must clarify whether AGEs affect NADH shuttle function and thus ATP production. The different results reveal that more research to understand the causal mechanisms leading to impaired insulin secretion needs to be performed.

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