**3. Insulin signaling pathway**

The normal signalization of the insulin signaling pathway is vital and its dysregulation is implicated not only in T2D but also in diseases such as cancer, cardiovascular and neurodegenerative diseases. Changes in this signaling cascade as well as the consequences thereof, makes this pathway an important subject of study, considering its relevance in terms of age-related diseases.

Normally, the transport of glucose into the cells occurs through different intracellular signaling mechanisms performed in cascade, as shown in **Figure 1**. Firstly, insulin binds to its receptor, promoting tyrosine phosphorylation of IRS proteins, especially IRS-1 and 2. The tyrosine phosphorylation is critical for the

**47**

system [49, 59].

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

correct activation of the insulin pathway. Phosphorylation at serine or threonine residues is associated with the inhibition or even degradation of IRS proteins promoting downregulation of the pathway. This inhibitory effect over the pathway occurs normally via insulin-induced kinases as a way to keep the correct function of all proteins involved. However, some conditions as hyperglycemia, release of proinflammatory cytokines, oxidative stress (due to mitochondrial dysfunction), in addition to elevated fatty acids and ER stress can induce an increased serine or threonine phosphorylation, promoting the downregulation of insulin signaling and

Thus, tyrosine phosphorylation of IRS proteins, further activate PI3K (phosphatidylinositol 3-kinase) protein [36, 37], promoting in particular the translocation of glucose transporter 4 (GLUT4) to the plasma membrane enabling the entrance of glucose into the cell [38]. Among the PI3K-associated downstream proteins, here we focus especially on Akt (alpha serine/threonine-protein kinase) [39, 40]. Once activated, Akt-regulated proteins have a key role in metabolism, glycogen synthesis, autophagy, growth, cell survival, transcription and protein synthesis [41]. Akt has been described as an important downregulator of GSK3α/β proteins. These proteins are strongly associated with the formation of amyloid beta and phosphorylation of tau protein, which are the main proteins involved in Alzheimer's disease [42, 43]. Another important target of Akt are the FOXO (Forkhead box O) transcription factors, which regulates the expression of different genes related to gluconeogenesis, lipid metabolism, resistance to stress, DNA repair, cell growth, survival, differentiation, among others [41, 44, 45]. The kinase mTOR (mammalian target of rapamycin), responsible for regulating cell growth and metabolism, being a large sensor of nutrients and cellular energy, is also a target of Akt [46–48] and has a

There is evidence that changes in the expression of growth factors, IRS proteins,

IGF-1, AKT, mTOR, FOXO among others that result in downregulation of the insulin signaling pathway through nutritional restriction, for example, are implicated in the resistance to stress, induction of autophagy, extension of longevity and reduction of aging-related diseases in different species, such as worms, flies, rats, mice and some primates [47, 50–55]. The inhibition of mTOR has been widely discussed as the main protein involved in the longevity extension. Metformin, a drug commonly used to control the glycemic levels in diabetics, is able to inhibit the activity of mTOR, via activation of AMPK, a protein with role in glycolysis, fatty acid oxidation, lipogenesis reduction, gluconeogenesis and protein synthesis [52, 56, 57]. AMPK is also important in mitochondrial biogenesis, since it activates PGC1α [58], which has the ability to stimulate the mitochondrial electron transport chain and suppress ROS levels, being essential in inducing the antioxidant defense

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

exacerbating the insulin resistance condition [2, 34, 35].

major role in the mechanism of longevity extension [49].

**4. Impact of nutritional interventions in diabetes care**

Diabetes is a global health problem. Currently, the treatment of this disease has been carried out with medications, such as metformin, aiming to reduce the blood glucose levels, in an attempt to prevent a series of alterations in the cellular metabolism caused by chronic hyperglycemia. However, the success of treatments, in general, is limited, requiring other types of interventions (nutritional and regular physical activity, mainly) related to the patients' lifestyle. The majority of patients with T2D present age between 40 and 59 years, which is critical for the disease [9] and in this phase, as in the subsequent stages, with the progression of the aging process, the protein homeostasis becomes increasingly compromised,

**Figure 1.** *Insulin/insulin-like growth factor signaling pathway.*

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

correct activation of the insulin pathway. Phosphorylation at serine or threonine residues is associated with the inhibition or even degradation of IRS proteins promoting downregulation of the pathway. This inhibitory effect over the pathway occurs normally via insulin-induced kinases as a way to keep the correct function of all proteins involved. However, some conditions as hyperglycemia, release of proinflammatory cytokines, oxidative stress (due to mitochondrial dysfunction), in addition to elevated fatty acids and ER stress can induce an increased serine or threonine phosphorylation, promoting the downregulation of insulin signaling and exacerbating the insulin resistance condition [2, 34, 35].

Thus, tyrosine phosphorylation of IRS proteins, further activate PI3K (phosphatidylinositol 3-kinase) protein [36, 37], promoting in particular the translocation of glucose transporter 4 (GLUT4) to the plasma membrane enabling the entrance of glucose into the cell [38]. Among the PI3K-associated downstream proteins, here we focus especially on Akt (alpha serine/threonine-protein kinase) [39, 40]. Once activated, Akt-regulated proteins have a key role in metabolism, glycogen synthesis, autophagy, growth, cell survival, transcription and protein synthesis [41]. Akt has been described as an important downregulator of GSK3α/β proteins. These proteins are strongly associated with the formation of amyloid beta and phosphorylation of tau protein, which are the main proteins involved in Alzheimer's disease [42, 43]. Another important target of Akt are the FOXO (Forkhead box O) transcription factors, which regulates the expression of different genes related to gluconeogenesis, lipid metabolism, resistance to stress, DNA repair, cell growth, survival, differentiation, among others [41, 44, 45]. The kinase mTOR (mammalian target of rapamycin), responsible for regulating cell growth and metabolism, being a large sensor of nutrients and cellular energy, is also a target of Akt [46–48] and has a major role in the mechanism of longevity extension [49].

There is evidence that changes in the expression of growth factors, IRS proteins, IGF-1, AKT, mTOR, FOXO among others that result in downregulation of the insulin signaling pathway through nutritional restriction, for example, are implicated in the resistance to stress, induction of autophagy, extension of longevity and reduction of aging-related diseases in different species, such as worms, flies, rats, mice and some primates [47, 50–55]. The inhibition of mTOR has been widely discussed as the main protein involved in the longevity extension. Metformin, a drug commonly used to control the glycemic levels in diabetics, is able to inhibit the activity of mTOR, via activation of AMPK, a protein with role in glycolysis, fatty acid oxidation, lipogenesis reduction, gluconeogenesis and protein synthesis [52, 56, 57]. AMPK is also important in mitochondrial biogenesis, since it activates PGC1α [58], which has the ability to stimulate the mitochondrial electron transport chain and suppress ROS levels, being essential in inducing the antioxidant defense system [49, 59].
