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Oxidative stress: A cause and therapeutic target of diabetic complications.

Araki E, Nishikawa T - J Diabetes Investig (2010)

Bottom Line: Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia-induced mtROS production by the induction of PPARγ coactivator-1α (PGC-1α) and MnSOD and/or activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK).We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK-PGC-1α pathway.Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00013.x, 2010).

View Article: PubMed Central - PubMed

Affiliation: Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

ABSTRACT
Oxidative stress is defined as excessive production of reactive oxygen species (ROS) in the presence of diminished anti-oxidant substances. Increased oxidative stress could be one of the common pathogenic factors of diabetic complications. However, the mechanisms by which hyperglycemia increases oxidative stress are not fully understood. In this review, we focus on the impact of mitochondrial derived ROS (mtROS) on diabetic complications and suggest potential therapeutic approaches to suppress mtROS. It has been shown that hyperglycemia increases ROS production from mitochondrial electron transport chain and normalizing mitochondrial ROS ameliorates major pathways of hyperglycemic damage, such as activation of polyol pathway, activation of PKC and accumulation of advanced glycation end-products (AGE). Additionally, in subjects with type 2 diabetes, we found a positive correlation between HbA1c and urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), which reflects mitochondrial oxidative damage, and further reported that 8-OHdG was elevated in subjects with diabetic micro- and macro- vascular complications. We recently created vascular endothelial cell-specific manganese superoxide dismutase (MnSOD) transgenic mice, and clarified that overexpression of MnSOD in endothelium could prevent diabetic retinopathy in vivo. Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia-induced mtROS production by the induction of PPARγ coactivator-1α (PGC-1α) and MnSOD and/or activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK-PGC-1α pathway. Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00013.x, 2010).

No MeSH data available.


Related in: MedlinePlus

 Proposed mechanism leading to diabetic vascular complications. Mitochondrial reactive oxygen species (ROS) could be the main cause of hyperglycemia‐induced oxidative stress. In addition, mitochondrial ROS is a causal link between hyperglycemia and each of the three main pathways responsible for hyperglycemic damage such as the activation of polyol pathway, the activation of protein kinase C (PKC) and the accumulation of advanced glycation end‐products (AGE).
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f6:  Proposed mechanism leading to diabetic vascular complications. Mitochondrial reactive oxygen species (ROS) could be the main cause of hyperglycemia‐induced oxidative stress. In addition, mitochondrial ROS is a causal link between hyperglycemia and each of the three main pathways responsible for hyperglycemic damage such as the activation of polyol pathway, the activation of protein kinase C (PKC) and the accumulation of advanced glycation end‐products (AGE).

Mentions: The main purpose of the treatment of diabetes is to prevent the onset and progression of chronic diabetic vascular complications. Oxidative stress, through the production of ROS, has been proposed as the root cause underlying the progression of long‐term diabetic complications. In the present study, we showed that hyperglycemia‐induced mitochondrial ROS production could be a key event in the development of diabetic complications (Figure 6) through the studies of subjects with type 2 diabetes, and in vascular endothelial cell‐specific MnSOD transgenic mice. In addition, we proposed that a blockade of mitochondrial ROS production through the induction of AMPK or PGC‐1α could, therefore, be useful in the design of new pharmacological approaches to prevent diabetic complications. Further clinical and basic studies will be required to clarify the benefits of reducing mitochondrial ROS production in the prevention of diabetic complications.


Oxidative stress: A cause and therapeutic target of diabetic complications.

Araki E, Nishikawa T - J Diabetes Investig (2010)

 Proposed mechanism leading to diabetic vascular complications. Mitochondrial reactive oxygen species (ROS) could be the main cause of hyperglycemia‐induced oxidative stress. In addition, mitochondrial ROS is a causal link between hyperglycemia and each of the three main pathways responsible for hyperglycemic damage such as the activation of polyol pathway, the activation of protein kinase C (PKC) and the accumulation of advanced glycation end‐products (AGE).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4008021&req=5

f6:  Proposed mechanism leading to diabetic vascular complications. Mitochondrial reactive oxygen species (ROS) could be the main cause of hyperglycemia‐induced oxidative stress. In addition, mitochondrial ROS is a causal link between hyperglycemia and each of the three main pathways responsible for hyperglycemic damage such as the activation of polyol pathway, the activation of protein kinase C (PKC) and the accumulation of advanced glycation end‐products (AGE).
Mentions: The main purpose of the treatment of diabetes is to prevent the onset and progression of chronic diabetic vascular complications. Oxidative stress, through the production of ROS, has been proposed as the root cause underlying the progression of long‐term diabetic complications. In the present study, we showed that hyperglycemia‐induced mitochondrial ROS production could be a key event in the development of diabetic complications (Figure 6) through the studies of subjects with type 2 diabetes, and in vascular endothelial cell‐specific MnSOD transgenic mice. In addition, we proposed that a blockade of mitochondrial ROS production through the induction of AMPK or PGC‐1α could, therefore, be useful in the design of new pharmacological approaches to prevent diabetic complications. Further clinical and basic studies will be required to clarify the benefits of reducing mitochondrial ROS production in the prevention of diabetic complications.

Bottom Line: Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia-induced mtROS production by the induction of PPARγ coactivator-1α (PGC-1α) and MnSOD and/or activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK).We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK-PGC-1α pathway.Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00013.x, 2010).

View Article: PubMed Central - PubMed

Affiliation: Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

ABSTRACT
Oxidative stress is defined as excessive production of reactive oxygen species (ROS) in the presence of diminished anti-oxidant substances. Increased oxidative stress could be one of the common pathogenic factors of diabetic complications. However, the mechanisms by which hyperglycemia increases oxidative stress are not fully understood. In this review, we focus on the impact of mitochondrial derived ROS (mtROS) on diabetic complications and suggest potential therapeutic approaches to suppress mtROS. It has been shown that hyperglycemia increases ROS production from mitochondrial electron transport chain and normalizing mitochondrial ROS ameliorates major pathways of hyperglycemic damage, such as activation of polyol pathway, activation of PKC and accumulation of advanced glycation end-products (AGE). Additionally, in subjects with type 2 diabetes, we found a positive correlation between HbA1c and urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), which reflects mitochondrial oxidative damage, and further reported that 8-OHdG was elevated in subjects with diabetic micro- and macro- vascular complications. We recently created vascular endothelial cell-specific manganese superoxide dismutase (MnSOD) transgenic mice, and clarified that overexpression of MnSOD in endothelium could prevent diabetic retinopathy in vivo. Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia-induced mtROS production by the induction of PPARγ coactivator-1α (PGC-1α) and MnSOD and/or activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK-PGC-1α pathway. Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00013.x, 2010).

No MeSH data available.


Related in: MedlinePlus