**Acknowledgements**

*Type 2 Diabetes - From Pathophysiology to Modern Management*

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,

*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* 

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

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

**50**

two diseases.

respectively.

**Figure 2.**

*T2D and AD.*

exogenous agents.

**6. Conclusions**

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