**2. Oxidative stress and mitochondrial dysfunction**

Changes in glucose homeostasis represent a critical factor for the development of metabolic diseases. Normally, to maintain optimal levels of blood glucose, the pancreas secretes two hormones. In response to high glucose levels, pancreatic β cells secrete insulin, which promote the uptake of glucose by peripheral tissues, reduce gluconeogenesis and decrease glycogen and triglyceride breakdown. However, when glucose levels are reduced in the blood, α-cells release glucagon, which will reverse the above process.

Overall, insulin resistance is one of the main causes of disturbances in glucose homeostasis; when insulin receptors do not respond to the amount of insulin produced, the consequence is a deficiency of the body in the glucose uptake and absorption. As a compensatory mechanism, pancreatic β cells increase the release of insulin, but if the glucose levels remain high due to the inability of insulin to achieve body's demand, it may occur the onset of T2D. Insulin resistance persists in patients since pre-diabetes, a stage in which individuals show glucose levels above the normal values, but not so high for the diagnosis of the disease. It should be mention that at this stage, a healthy nutritional style, physical exercises and weight control may allow the individuals to recover normal glucose levels.

At a long term, high levels of blood glucose can lead to a number of cellular and molecular changes in the body, especially due to the production of reactive oxygen species (ROS) [10]. It is well known that mitochondria are the main source of ROS; these highly dynamic organelles constantly undergo structural changes, responding rapidly to the physiological alterations in the environment. Exposure of cells to hyperglycemic conditions is associated with several mitochondrial alterations. There is evidence that the number and morphology of mitochondria are essential

**45**

*Oxidative Stress, DNA Damage and Repair Pathways in Patients with Type 2 Diabetes Mellitus*

for the maintenance of cellular function. Hyperglycemia in this context is reported as an inducer of glucose metabolism, which can promote several conformational changes in mitochondria, overload of the electron transport chain, leading to the

It has been reported [15] that patients with pre-diabetes presented an increase in the mitochondrial mass, suggesting that the initial increase in blood glucose levels may induce an adaptative response in order to increase mitochondrial biogenesis to maintain homeostasis. These results are associated with an increase in mitophagy, raising evidence that during pre-diabetes state there may be an elimination of compromised mitochondria in an attempt to reduce mitochondrial oxidative stress

ROS are normal byproducts of aerobic respiration, consisting of non-radicals, as hydrogen peroxide (H2O2) and free radicals, as hydroxyl radical (OH) and superox-

catalase and superoxide dismutase) are able to eliminate ROS and maintain the homeostasis of the organism. However, in a hyperglycemic state, the mitochondria electron transport chain becomes hyperactive, thus inducing an excessive production of ROS that surpasses the antioxidant defense system [17]. The imbalance between the prooxidants and the antioxidant defense system lead to a condition called oxidative stress, where the reactive molecules can cause damage to lipids,

Among DNA damage caused by ROS, the major oxidized base modifications generated are 8-oxoguanine (8-oxoG) and 8-oxodesoxyguanosine (8-oxodG), which could occur in both DNA and the nucleotide pool, the latter can be incorporated into the DNA during replication or repair [19, 20]. The repair of 8-oxoG in DNA is performed by the base excision repair mechanism (BER), in which the DNA glycosylase OGG1 recognizes the 8oxoG and together with APE1 enzyme, polymerase complex β and DNA ligase I promote DNA repair [21, 22]; the removal of 8-oxo-dG from the nucleotide pool is performed by the enzyme hMTH1 (human MutT homolog), which hydrolyses 8-oxo-dGTP to transport this molecule to the cytosol, preventing its incorporation into the DNA [23]. For different types of DNA lesions, other DNA repair processes, such as nucleotide excision, homologous recombination, non-homologous end-joining, and mismatch repair may also occur. In diabetes, there is evidence that DNA repair levels and activity of antioxidant enzymes are reduced [24, 25], as well as DNA damage levels and oxidized bases in

The oxidative stress promoted by chronic hyperglycemia causes cellular damage mainly in the pancreatic β cells, which present low levels of antioxidant enzymes, and are more susceptible to damages caused by ROS. This stress is also responsible for releasing inflammatory mediators, which in turn culminate in a vicious cycle leading to β-cell dysfunction, insulin resistance and metabolic decline, which are

In diabetes, high glucose levels may also induce endoplasmic reticulum (ER) stress. Since the ER is the main responsible for protein maturation and folding, in particular proinsulin, in a hyperglycemic state, this molecule tends to be excessively synthesized and can overload the ER, leading to the accumulation of misfolded proteins, thus generating a stress condition. This stress may lead to the activation of the unfolded protein response pathway, which may restore ER homeostasis or induce cell death. The latter may lead to β-cell dysfunction, and consequently, to the

Several metabolic pathways are involved in insulin resistance and induction of inflammation and stress, including the JNK (JUN N-terminal kinase) and IKKβ (IκB kinase-β) pathways, both of them can be activated by ER stress [32]. IKKβ is

reduction of insulin secretion and chronic hyperglycemia [28–31].

<sup>−</sup>). In normal situations, antioxidant enzymes (glutathione peroxidase,

overproduction of ROS, and mitochondrial dysfunction [11–14].

*DOI: http://dx.doi.org/10.5772/intechopen.85438*

[15, 16].

ide anion (O2

proteins and nucleic acids [18].

these patients were found increased [26, 27].

critical for the development of T2D [28].

#### *Oxidative Stress, DNA Damage and Repair Pathways in Patients with Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.85438*

for the maintenance of cellular function. Hyperglycemia in this context is reported as an inducer of glucose metabolism, which can promote several conformational changes in mitochondria, overload of the electron transport chain, leading to the overproduction of ROS, and mitochondrial dysfunction [11–14].

It has been reported [15] that patients with pre-diabetes presented an increase in the mitochondrial mass, suggesting that the initial increase in blood glucose levels may induce an adaptative response in order to increase mitochondrial biogenesis to maintain homeostasis. These results are associated with an increase in mitophagy, raising evidence that during pre-diabetes state there may be an elimination of compromised mitochondria in an attempt to reduce mitochondrial oxidative stress [15, 16].

ROS are normal byproducts of aerobic respiration, consisting of non-radicals, as hydrogen peroxide (H2O2) and free radicals, as hydroxyl radical (OH) and superoxide anion (O2 <sup>−</sup>). In normal situations, antioxidant enzymes (glutathione peroxidase, catalase and superoxide dismutase) are able to eliminate ROS and maintain the homeostasis of the organism. However, in a hyperglycemic state, the mitochondria electron transport chain becomes hyperactive, thus inducing an excessive production of ROS that surpasses the antioxidant defense system [17]. The imbalance between the prooxidants and the antioxidant defense system lead to a condition called oxidative stress, where the reactive molecules can cause damage to lipids, proteins and nucleic acids [18].

Among DNA damage caused by ROS, the major oxidized base modifications generated are 8-oxoguanine (8-oxoG) and 8-oxodesoxyguanosine (8-oxodG), which could occur in both DNA and the nucleotide pool, the latter can be incorporated into the DNA during replication or repair [19, 20]. The repair of 8-oxoG in DNA is performed by the base excision repair mechanism (BER), in which the DNA glycosylase OGG1 recognizes the 8oxoG and together with APE1 enzyme, polymerase complex β and DNA ligase I promote DNA repair [21, 22]; the removal of 8-oxo-dG from the nucleotide pool is performed by the enzyme hMTH1 (human MutT homolog), which hydrolyses 8-oxo-dGTP to transport this molecule to the cytosol, preventing its incorporation into the DNA [23]. For different types of DNA lesions, other DNA repair processes, such as nucleotide excision, homologous recombination, non-homologous end-joining, and mismatch repair may also occur. In diabetes, there is evidence that DNA repair levels and activity of antioxidant enzymes are reduced [24, 25], as well as DNA damage levels and oxidized bases in these patients were found increased [26, 27].

The oxidative stress promoted by chronic hyperglycemia causes cellular damage mainly in the pancreatic β cells, which present low levels of antioxidant enzymes, and are more susceptible to damages caused by ROS. This stress is also responsible for releasing inflammatory mediators, which in turn culminate in a vicious cycle leading to β-cell dysfunction, insulin resistance and metabolic decline, which are critical for the development of T2D [28].

In diabetes, high glucose levels may also induce endoplasmic reticulum (ER) stress. Since the ER is the main responsible for protein maturation and folding, in particular proinsulin, in a hyperglycemic state, this molecule tends to be excessively synthesized and can overload the ER, leading to the accumulation of misfolded proteins, thus generating a stress condition. This stress may lead to the activation of the unfolded protein response pathway, which may restore ER homeostasis or induce cell death. The latter may lead to β-cell dysfunction, and consequently, to the reduction of insulin secretion and chronic hyperglycemia [28–31].

Several metabolic pathways are involved in insulin resistance and induction of inflammation and stress, including the JNK (JUN N-terminal kinase) and IKKβ (IκB kinase-β) pathways, both of them can be activated by ER stress [32]. IKKβ is

*Type 2 Diabetes - From Pathophysiology to Modern Management*

but this approach is still a major challenge for researchers.

**2. Oxidative stress and mitochondrial dysfunction**

may allow the individuals to recover normal glucose levels.

of insulin resistance and T2D [9].

the above process.

modifications in histones and DNA methylation may influence the heritability of T2D [3, 4]. Due to the complexity of the interaction of different factors involved in this disease, genome-wide association studies (GWAS) have been performed in an

In 2007, the first GWAS was performed in France in patients with T2D [5]; At present, at least 75 associated loci have been identified, including the *TCF7L2* transcription factor, which is the most common gene found, in addition to *PPARG, KCNJ11, FTO, CDKN2A/2B, CDKAL1, IGFBP2* among others [6]. Since then, similar studies showed that the loci presenting greater association with T2D vary as regards the relative risk between different ethnicities [7]. Besides, these variants explain only a low percentage of the disease heritability, most of which are found in intergenic or intronic regions [6]. Furthermore, DNA methylation patterns may contribute to genetic susceptibility to T2D. There is evidence of an increased risk of T2D development associated with distinct methylation patterns in some loci [8],

While obesity and overweight have been considered an important cause of T2D, a poor diet and lack of physical activity significantly contribute to an increased risk

Changes in glucose homeostasis represent a critical factor for the development of metabolic diseases. Normally, to maintain optimal levels of blood glucose, the pancreas secretes two hormones. In response to high glucose levels, pancreatic β cells secrete insulin, which promote the uptake of glucose by peripheral tissues, reduce gluconeogenesis and decrease glycogen and triglyceride breakdown. However, when glucose levels are reduced in the blood, α-cells release glucagon, which will reverse

Overall, insulin resistance is one of the main causes of disturbances in glucose

At a long term, high levels of blood glucose can lead to a number of cellular and molecular changes in the body, especially due to the production of reactive oxygen species (ROS) [10]. It is well known that mitochondria are the main source of ROS; these highly dynamic organelles constantly undergo structural changes, responding rapidly to the physiological alterations in the environment. Exposure of cells to hyperglycemic conditions is associated with several mitochondrial alterations. There is evidence that the number and morphology of mitochondria are essential

homeostasis; when insulin receptors do not respond to the amount of insulin produced, the consequence is a deficiency of the body in the glucose uptake and absorption. As a compensatory mechanism, pancreatic β cells increase the release of insulin, but if the glucose levels remain high due to the inability of insulin to achieve body's demand, it may occur the onset of T2D. Insulin resistance persists in patients since pre-diabetes, a stage in which individuals show glucose levels above the normal values, but not so high for the diagnosis of the disease. It should be mention that at this stage, a healthy nutritional style, physical exercises and weight control

One of the greatest concerns regarding the poor glycemic control in patients with T2D is related to the micro and macrovascular complications of diabetes. Since the onset of T2D did not present specific acute symptoms, 50% of adults with T2D do not know that they have the disease [9]. Chronic hyperglycemia induces a series of complications, such as retinopathy, neuropathy and nephropathy. In a long term, the high blood glucose levels may also induce endothelial dysfunction, which contributes to the increased risk for the development of cardiovascular diseases.

attempt to identify genetic variants related to the increased risk of T2D.

**44**

a protein responsible for mediating the activation of NF-κβ (nuclear factor-κB), which in turn stimulates the proinflammatory cytokines, TNF-α (tumor necrosis factor-alpha) and interleukin 1β (IL-1β), that can promote inhibition of the insulin receptor substrate (IRS) protein phosphorylation or reduce their transcriptional expression, compromising the insulin pathway and contributing to insulin resistance [25, 28].

Obesity is another critical factor that results in oxidative stress and insulin resistance [33], generating a chronic inflammatory condition in adipose tissue, causing the recurrent release of pro-inflammatory cytokines, such as those previously mentioned, in addition to interleukin 6 (IL-6), which together lead to pancreatic β-cell dysfunction, decreased insulin secretion, and consequently hyperglycemia and thus triggering T2D [28].
