**5. Susceptibility of T2D to Alzheimer's disease**

Alzheimer's disease (AD) is a progressive, continuous neurodegenerative disorder that affects large areas of the cerebral cortex and hippocampus. These abnormalities are usually detected for the first time in brain tissue involving the frontal and temporal lobes and then slowly advance to other areas of the neocortex at rates that vary considerably between individuals [70]. By 2018, an estimated 50 million people are living with dementia, with AD being the most prevalent form [71]. The main symptoms of AD result from the formation of beta-amyloid (Aβ) plaques and neurofibrillary tangles of the tau protein in the brain, which together lead to neuronal dysfunction and death, causing memory loss episodes which are characteristic of the pathology [70, 72]. It has been reported that similar to the toxicity caused by Aβ aggregates in the brains of patients with AD, amyloid deposits in the pancreas occur in patients with diabetes, which may induce the death of pancreatic insulin-producing β cells [73].

Recently, several studies have narrowed the relationship between T2D and dementias [74, 75], suggesting that in addition to an increase in the incidence of dementia in T2D patients, a more rapid cognitive decline may also occur, including a higher conversion rate of individuals who have mild cognitive impairment in patients with dementia [76–78]. This information has aroused interest in studying a possible association between T2D and dementia.

**49**

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

Many hypotheses have been raised about the common features that involve the two pathologies and how these can be related to each other. It has been suggested that both diseases may share common signaling pathways, although molecular and cellular mechanisms still need elucidation. There is evidence that insulin resistance in the brain, including insulin pathway dysregulation, inflammatory processes, formation of advanced glycation products, as well as oxidative stress and mitochondrial dysfunction, may be implicated in the pathogenesis of AD and T2D [79]. Insulin, besides having an essential role as regulator of energy metabolism, also exerts a role in plasticity, survival and neuronal growth, as well as learning and memory processes, contributing to the improvement of cognitive functions; their absence has been associated with cognitive decline in patients with neurological and neurodegenerative diseases, such as AD [80–82]. In fact, it has been demonstrated that brains of patients with AD present altered insulin signaling [83]. Insulin receptors are found in the central nervous system (CNS) in large number and their impairment (hence the signaling cascade) may culminate in a number of alterations mainly involving PI3K, AKT and mTOR proteins. Abnormal expression of these and other proteins and the deregulation of this pathway may contribute to the formation of Aβ aggregates, neurofibrillary tangles by hyperphosphorylation of the tau protein [84], as well as the impairment of the autophagy process regulated by mTOR [75], whose hyperexpression has been

Thus, in the same way as T2D, AD is a disease related to less efficient molecular

There is evidence that insulin plays an important role in glucose regulation in the CNS, and its additional effects on neurons include metabolic, neurotrophic, neuromodulatory and neuroendocrine actions [98]. The presence of higher levels of inflammatory mediators in the CNS seems to stimulate the formation of betaamyloid oligomers and neurofibrillary tangles, which trigger the removal of insulin receptors in neurons, making this condition common in both T2D and AD, trigger-

Besides, the lower sensitivity to insulin, in addition to being important for the progression of T2D, also appears to affect the expression and metabolism of Aβ proteins in the CNS, and consequently, an increase in oxidative stress condition [2, 100], which in turn, induces greater accumulation of Aβ oligomers [101] and the release of inflammatory mediators [88], as already mentioned. Thus, it seems

signaling in response to insulin, inflammation, oxidative stress, formation of advanced glycation end products and increased accumulation of DNA damage [87–89]. Thus, these characteristics suggest a connection between the two diseases. The presence of higher levels of inflammation has already been described both in T2D and AD patients. In T2D there is a chronic inflammatory response localized in adipose tissue and characterized by the infiltration of immune system components, mainly macrophages, which release different proinflammatory cytokines such as TNF-α and IL-6 [90, 91]. Such cytokines may lead to insulin resistance by inducing cytokine signaling suppressors (SOCS), which participate in the degradation of IRS-1 and IRS-2 [92, 93]. In addition, these cytokines also activate stress response kinases, such as JNK and NF-κβ, which in turn act on the insulin receptor, inhibiting its tyrosine kinase activity, therefore culminating in insulin resistance [94, 95]. Similar inflammatory processes probably occur in the brain and peripheral tissues. Several studies have established the presence of inflammatory markers in the brains of patients with AD, including high levels of cytokines/chemokines [96]. In addition, inflammatory mediator levels in blood as TNF-α, IL-6 and IL-1b are increased in AD patients [97]. Thus, both in the brain and in peripheral tissues, chronic inflammation becomes harmful, leading to progressive damage to tissues

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

related to T2D [85] and AD [86].

and consequently triggering degenerative diseases.

ing progression of both diseases [89, 99] (**Figure 2**).

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

Many hypotheses have been raised about the common features that involve the two pathologies and how these can be related to each other. It has been suggested that both diseases may share common signaling pathways, although molecular and cellular mechanisms still need elucidation. There is evidence that insulin resistance in the brain, including insulin pathway dysregulation, inflammatory processes, formation of advanced glycation products, as well as oxidative stress and mitochondrial dysfunction, may be implicated in the pathogenesis of AD and T2D [79].

Insulin, besides having an essential role as regulator of energy metabolism, also exerts a role in plasticity, survival and neuronal growth, as well as learning and memory processes, contributing to the improvement of cognitive functions; their absence has been associated with cognitive decline in patients with neurological and neurodegenerative diseases, such as AD [80–82]. In fact, it has been demonstrated that brains of patients with AD present altered insulin signaling [83]. Insulin receptors are found in the central nervous system (CNS) in large number and their impairment (hence the signaling cascade) may culminate in a number of alterations mainly involving PI3K, AKT and mTOR proteins. Abnormal expression of these and other proteins and the deregulation of this pathway may contribute to the formation of Aβ aggregates, neurofibrillary tangles by hyperphosphorylation of the tau protein [84], as well as the impairment of the autophagy process regulated by mTOR [75], whose hyperexpression has been related to T2D [85] and AD [86].

Thus, in the same way as T2D, AD is a disease related to less efficient molecular signaling in response to insulin, inflammation, oxidative stress, formation of advanced glycation end products and increased accumulation of DNA damage [87–89]. Thus, these characteristics suggest a connection between the two diseases.

The presence of higher levels of inflammation has already been described both in T2D and AD patients. In T2D there is a chronic inflammatory response localized in adipose tissue and characterized by the infiltration of immune system components, mainly macrophages, which release different proinflammatory cytokines such as TNF-α and IL-6 [90, 91]. Such cytokines may lead to insulin resistance by inducing cytokine signaling suppressors (SOCS), which participate in the degradation of IRS-1 and IRS-2 [92, 93]. In addition, these cytokines also activate stress response kinases, such as JNK and NF-κβ, which in turn act on the insulin receptor, inhibiting its tyrosine kinase activity, therefore culminating in insulin resistance [94, 95].

Similar inflammatory processes probably occur in the brain and peripheral tissues. Several studies have established the presence of inflammatory markers in the brains of patients with AD, including high levels of cytokines/chemokines [96]. In addition, inflammatory mediator levels in blood as TNF-α, IL-6 and IL-1b are increased in AD patients [97]. Thus, both in the brain and in peripheral tissues, chronic inflammation becomes harmful, leading to progressive damage to tissues and consequently triggering degenerative diseases.

There is evidence that insulin plays an important role in glucose regulation in the CNS, and its additional effects on neurons include metabolic, neurotrophic, neuromodulatory and neuroendocrine actions [98]. The presence of higher levels of inflammatory mediators in the CNS seems to stimulate the formation of betaamyloid oligomers and neurofibrillary tangles, which trigger the removal of insulin receptors in neurons, making this condition common in both T2D and AD, triggering progression of both diseases [89, 99] (**Figure 2**).

Besides, the lower sensitivity to insulin, in addition to being important for the progression of T2D, also appears to affect the expression and metabolism of Aβ proteins in the CNS, and consequently, an increase in oxidative stress condition [2, 100], which in turn, induces greater accumulation of Aβ oligomers [101] and the release of inflammatory mediators [88], as already mentioned. Thus, it seems

*Type 2 Diabetes - From Pathophysiology to Modern Management*

accumulation of cellular damage [51, 58, 60, 61].

reducing the incidence of aging-related diseases [62–64].

**5. Susceptibility of T2D to Alzheimer's disease**

also accompanied by a reduction in the efficiency of the DNA repair system and the antioxidant defense, besides the organism as a whole, consequently leading to the

A great number of patients with T2D are overweight or obese. Changes in the lifestyle have been shown essential in controlling the levels of blood glucose. Additionally, it was reported that T2D patients submitted to a 7-day intervention to achieve adequate blood glucose levels led to a significant decrease in DNA damage levels [26]. In particular, some nutritional interventions, as well as caloric (CR) or protein restriction, have been shown to be very effective, not only for reducing blood glucose levels, but also for having very positive benefits in terms of increased life expectancy, as demonstrated in several model organisms [52, 54], in addition to

A major recruitment study known as CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) aimed to show the effects of caloric restriction in humans. It has already been shown that in a period of 2 years, the CR is very efficient in improving insulin sensitivity [65], reducing inflammatory markers [66] and reducing oxidative stress [67]. Those features are especially significantly increased in patients with T2D, which would make this approach a valuable intervention for treatment of those patients. In fact, in a study performed in rhesus monkeys, from the 38 control animals, 16 developed high levels of blood glucose, becoming either prediabetic or diabetic. On the other hand, all the animals under caloric restriction did not present any impairment on glucose regulation [64], which may demonstrate the importance of this kind of

Although this approach has been widely discussed, the studies are still controversial regarding the best diet composition for diabetic patients. It has been hypothesized that a high intake of proteins could influence the effects of a caloric restriction [68]. In fact, there is a study showing the efficiency of a protein restriction intervention on reducing cancer incidence and extending lifespan regardless

Alzheimer's disease (AD) is a progressive, continuous neurodegenerative disorder that affects large areas of the cerebral cortex and hippocampus. These abnormalities are usually detected for the first time in brain tissue involving the frontal and temporal lobes and then slowly advance to other areas of the neocortex at rates that vary considerably between individuals [70]. By 2018, an estimated 50 million people are living with dementia, with AD being the most prevalent form [71]. The main symptoms of AD result from the formation of beta-amyloid (Aβ) plaques and neurofibrillary tangles of the tau protein in the brain, which together lead to neuronal dysfunction and death, causing memory loss episodes which are characteristic of the pathology [70, 72]. It has been reported that similar to the toxicity caused by Aβ aggregates in the brains of patients with AD, amyloid deposits in the pancreas occur in patients with diabetes, which may induce the death of pancreatic

Recently, several studies have narrowed the relationship between T2D and dementias [74, 75], suggesting that in addition to an increase in the incidence of dementia in T2D patients, a more rapid cognitive decline may also occur, including a higher conversion rate of individuals who have mild cognitive impairment in patients with dementia [76–78]. This information has aroused interest in studying a

**48**

intervention.

the intake of calories [69].

insulin-producing β cells [73].

possible association between T2D and dementia.

#### **Figure 2.**

*Relationship between increased levels of inflammatory factors and insulin sensitivity in both diseases, T2D and AD. Increased insulin resistance will lead to disease progression and the development of comorbidities in both T2D and AD.*

that all these processes are related to T2D and AD as a vicious cycle, leading to the development and progression of comorbidities in both diseases, being one of the consequences of hyperglycemia and the accumulation of Aβ oligomers, respectively.

However, both diseases seem to present less efficient DNA repair processes, which generate genomic instability and also cell death; this condition is closely related to the complications reported for patients with T2D, and also AD [24, 102]. According to Xavier et al. [103], hyperglycemic T2D patients presented induction of DNA repair pathways, probably in response to higher levels of oxidative stress, but it remains to be elucidated whether the efficacy of repair pathways are normal in non-hyperglycemic T2D patients. In the case of AD, there is evidence that repair of DNA double strand breaks is less efficient [104], as well as base excision repair pathway [105], which would be detrimental to AD individuals, considering the relevance of DNA repair mechanisms for the DNA damage repair caused by ROS [106], and also by several kinds of endogenous and exogenous agents.

## **6. Conclusions**

Insulin resistance is one of the main causes of disturbances in glucose homeostasis. In patients with T2D, long term exposure to high levels of blood glucose can lead to a number of cellular and molecular changes in the body. In this context, hyperglycemia can promote several conformational changes in mitochondria, overload of the electron transport chain, leading to the overproduction of ROS, and mitochondrial dysfunction. Furthermore, the imbalance between the prooxidant and the antioxidant defense system lead to a condition of oxidative stress, where the reactive molecules can cause damage to lipids, proteins and nucleic acids. Interestingly, there is evidence that DNA repair levels and activity of antioxidant enzymes are reduced in T2D; in the opposite, DNA damage levels as well as oxidized bases in these patients were found increased. Insulin resistance has been also associated with several metabolic pathways and induction of inflammation and stress, including ER stress. Therefore, the normal signalization of the insulin pathway is vital and its dysregulation is implicated not only in T2D but also in other diseases such as cancer, cardiovascular and neurodegenerative diseases. In the brain, there is also evidence of insulin resistance and dysregulation of insulin pathway, generating inflammatory processes, as well as oxidative stress and mitochondrial dysfunction, all of them might be implicated in the pathogenesis of T2D and AD, thus linking the two diseases.

**51**

provided the original work is properly cited.

\*Address all correspondence to: etshojo@usp.br

, Danilo J. Xavier1

Preto, University of São Paulo (USP), Ribeirão Preto, SP, Brazil

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Genetics, Ribeirão Preto Medical School, University of São Paulo

2 Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão

and Elza T. Sakamoto-Hojo1,2\*

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

Research supported by Coordination for the Improvement of Higher Education Personnel (CAPES), National Council for Scientific and Technological Development (CNPq) and São Paulo Research Foundation (FAPESP). We thank

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

CNPq for providing fellowship to J.E.B.F.Lima.

There is no conflict of interests.

**Acknowledgements**

**Conflict of interest**

**Author details**

Jessica E.B.F. Lima1

(USP), Ribeirão Preto, SP, Brazil

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