**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,

*Type 2 Diabetes - From Pathophysiology to Modern Management*

tance [25, 28].

and thus triggering T2D [28].

**3. Insulin signaling pathway**

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 resis-

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

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,

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

considering its relevance in terms of age-related diseases.

**46**

**Figure 1.**

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

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

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

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 intervention.

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 the intake of calories [69].
