**4.3 Psychological stress**

Acute psychological stress has been acknowledged for many years as a factor which favors the onset of diabetes. This is because sympathetic activation reduces the functionality of the pancreatic β cell, diminishing insulin secretion.

At the same time, in the muscle there is a decline in insulin sensitivity, glucose uptake, and glycogen deposition, all of which elevates glycemia and clinically favors the development of DM2.

Among the psychosocial factors related to this type of diabetes, depression in its different degrees has been widely studied, and a bidirectional association has been found between both disorders. It is bidirectional in the sense that depression induces DM2 and diabetics suffer from 30% more depressive states than nondiabetics [13].

The Cardiovascular Health Study demonstrated, in elderly adults, that those who reported strong depressive symptoms developed DM2 more frequently than their non-depressive peers. This association cannot be totally explained by differences in the risk factors for DM2. It is likely that both disorders have a common feature [14].

Although the intimate mechanism of this association is not known, it has been speculated that it could be related to inflammation, considering that inflammatory markers are present in diabetes and in depressive states. Some authors have found elevated C-reactive protein levels in these cases, but this has not been confirmed by others.

It has been established that depressive subjects are physically less active and that, due to their psychic disorders, also have poor eating habits, both behaviors favoring obesity, IR, and DM2. Diabetics are highly sensitive to the effects of physical stress, which is related to adrenergic stimulation that could reduce insulin secretion and glucose utilization.

In recent years, abnormal glucose metabolism has been correlated with various sleep disturbances, such as duration, fragmentation, quality, respiratory function, obstructive sleep apnea, hypoxemia, and circadian rhythm. This situation is explained by an increase in cortisol, growth hormone, inflammatory markers, and adipocyte function. There also exists a reduction in brain glucose utilization, with an increase in ghrelin, a situation that leads to obesity. This is reflected in an increase in IR and a reduction in β cell function, ultimately favoring hyperglycemia and DM2 [15].

#### **4.4 Glucotoxicity and lipotoxicity**

The concepts of glucotoxicity and lipotoxicity, related to DM2, appear in the 1990s, supported by experimental studies in animals which have been subsequently confirmed in humans. At present, glucotoxicity is defined as the adverse effects produced by chronic hyperglycemia on cell structures and functions. Hyperglycemia would cause an inhibition of the hormone synthesis through a decrease in messenger RNA for insulin; therefore, glucose would be capable of inducing damage at the level of the genetic information which is indispensable for a correct insulin synthesis [16].

Other mechanisms involved in glucotoxicity would be the lower activity of phospholipase C, an enzyme necessary for the formation of inositide phosphates which participate in insulin secretion by increasing the intracellular calcium level. Cytotoxicity to the β cell by glucose, acting as a free radical, is also possible, causing greater β cell apoptosis.

In 1963, Randle proposed that the increase in FFA, as a result of the degradation of triglycerides, causes peripheral IR. A great FFA mobilization due to greater lipolysis induces an increase in FFA oxidation in the muscle and the liver, with less glucose utilization in the former and higher hepatic gluconeogenesis; this leads to hyperglycemia plus inhibition of insulin secretion, which further elevates serum glucose levels. FFA are deposited in the muscle as triglycerides, ectopic deposits which favor IR. In the β cells, reactive oxygen species (ROS) increase, thus reducing insulin gene expression and secretion [17]. Therefore, a dual mechanism is acknowledged to lipotoxicity in the pathogenesis of DM2: it favors IR and has a direct deleterious effect on β cells. Probably, ROS produce less insulin secretion due to a lower GLUT-2 activity.

Glucotoxicity and lipotoxicity, disclosed separately for didactic reasons, coparticipate in the genesis of DM2 and interact together causing structural and functional damage in β cells and in target organs. Thus, glucotoxicity describes more accurately the reality of the chronic deleterious process. Glucolipotoxicity is capable of causing inflammation in pancreatic β cells and in the peripheral tissues where insulin acts. In the β cells, an activation of the nuclear factor kappa beta (NF-kβ) pathway occurs, increasing the production of NF-kβ which is an inflammatory cytokine. In the visceral adipose tissue, there is a decrease in adiponectin which is anti-inflammatory (insulin-sensitizing) and an increase in the proinflammatory cytokines: leptin, TNFα, and IL-6.

This chronic low-grade inflammatory state is referred to as a metainflammation [18].

#### **4.5 Oxidative stress**

ROS, generated both by hyperglycemia and increased FFA levels, would have the most important role in the onset and progression of DM2. In β cells, ROS [18] cause a

**31**

*Pathogenesis of Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.83692*

decrease in insulin synthesis and secretion; since β cells have a low antioxidant capacity, excessive ROS production results in an imbalance of the redox state, tilting the balance toward oxidation. In peripheral tissues that are targets for insulin, ROS favor inactivation of insulin signal transmission. It has also been observed that inflammation, mainly through the increase in IL-6 and TNFα, favors IR and β cell dysfunction. On the other side, the production of chemicals used worldwide in different activities including the food industry, probably through ROS generation, has increased progressively since 1940. In the USA, a direct relationship has been found between the production curves of synthetic organic chemicals and the prevalence of diabetes and other pathologies [19]. The Environmental Protection Agency has defined as endocrine-disrupting chemicals, exogenous agents that interfere with the production,

secretion, transport, metabolism, binding, action, or clearance of hormones.

The endoplasmic reticulum actively participates in protein synthesis, producing the correct folding of proteins by means of chaperones, which are helpers of this process. Activating signals such as hyperglycemia increase the demand for insulin synthesis, causing endoplasmic reticulum stress in β cells; this induces apoptotic pathways as a normal adaptive metabolic response to a metabolic load. In DM2, the endoplasmic reticulum stress caused by glucotoxicity and inflammatory cytokines

The β cell mitochondrion participates in insulin synthesis and in exocytosis. In diabetes, a mitochondrial dysfunction occurs: the mitochondrial membrane proteins are diminished, and transcriptional changes occur in their formation. Mitochondrial dysfunction, induced by glucotoxicity, results in β cell failure,

In IR, the excess of circulating fatty acids associated with the reduction in the number of mitochondria causes an increment in the level of intracellular FFA and also of diacylglycerol. These molecules activate PKC which in turn activates the serine kinase cascade, leading to an increment in the phosphorylation of the serine residues in IRS-1 and preventing the phosphorylation of tyrosine residues, which in turn inhibits PI-3 K activity, finally resulting in the suppression of insulin-induced

In recent years, a special interest has aroused for studying the influence of the diet in general and of different nutrients in particular, on the development of DM2. There is a consensus in that a healthy diet with no caloric excess and a suitable physical activity are the most effective measures for preventing DM2. There is also clinical and biological evidence that excessive sugar consumption promotes the

The effect of dietary fat on the risk for DM2 is not absolutely clarified, and some studies have even provided contradictory results; but there exists a consensus in that the quality of the fat is more important than the total amount. Dietary fat is not only a source of energy, but also fatty acids affect cell metabolism. Monounsaturated fatty acids and trans-fatty acids would not be associated with a higher incidence of DM2. In relation to dietary fats, arrives at more categorical conclusions indicating that a diet high in monounsaturated fatty acids (olive oil) and polyunsaturated fatty acids of marine origin is associated with low risk of DM2 [23]. This is confirmed by the fact that consumption of Mediterranean diet, high in monounsaturated fatty acids from vegetable oils and polyunsaturated fatty acids from fish, reduces the risk for DM2.

development of DM2 and of cardiovascular disease [22].

**4.6 Endoplasmic reticulum stress and endothelial dysfunction**

can lead to β cell dysfunction and death [20].

increase in ROS, and oxidative stress.

glucose transport [21].

**4.7 Diet and nutrients**

#### *Pathogenesis of Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.83692*

*Type 2 Diabetes - From Pathophysiology to Modern Management*

glucose utilization.

**4.4 Glucotoxicity and lipotoxicity**

greater β cell apoptosis.

cytokines: leptin, TNFα, and IL-6.

**4.5 Oxidative stress**

It has been established that depressive subjects are physically less active and that, due to their psychic disorders, also have poor eating habits, both behaviors favoring obesity, IR, and DM2. Diabetics are highly sensitive to the effects of physical stress, which is related to adrenergic stimulation that could reduce insulin secretion and

In recent years, abnormal glucose metabolism has been correlated with various sleep disturbances, such as duration, fragmentation, quality, respiratory function, obstructive sleep apnea, hypoxemia, and circadian rhythm. This situation is explained by an increase in cortisol, growth hormone, inflammatory markers, and adipocyte function. There also exists a reduction in brain glucose utilization, with an increase in ghrelin, a situation that leads to obesity. This is reflected in an increase in IR and a reduction in β cell function, ultimately favoring hyperglycemia and DM2 [15].

The concepts of glucotoxicity and lipotoxicity, related to DM2, appear in the 1990s, supported by experimental studies in animals which have been subsequently confirmed in humans. At present, glucotoxicity is defined as the adverse effects produced by chronic hyperglycemia on cell structures and functions. Hyperglycemia would cause an inhibition of the hormone synthesis through a decrease in messenger RNA for insulin; therefore, glucose would be capable of inducing damage at the level of the genetic information which is indispensable for a correct insulin synthesis [16]. Other mechanisms involved in glucotoxicity would be the lower activity of phospholipase C, an enzyme necessary for the formation of inositide phosphates which participate in insulin secretion by increasing the intracellular calcium level. Cytotoxicity to the β cell by glucose, acting as a free radical, is also possible, causing

In 1963, Randle proposed that the increase in FFA, as a result of the degradation of triglycerides, causes peripheral IR. A great FFA mobilization due to greater lipolysis induces an increase in FFA oxidation in the muscle and the liver, with less glucose utilization in the former and higher hepatic gluconeogenesis; this leads to hyperglycemia plus inhibition of insulin secretion, which further elevates serum glucose levels. FFA are deposited in the muscle as triglycerides, ectopic deposits which favor IR. In the β cells, reactive oxygen species (ROS) increase, thus reducing insulin gene expression and secretion [17]. Therefore, a dual mechanism is acknowledged to lipotoxicity in the pathogenesis of DM2: it favors IR and has a direct deleterious effect on β cells.

Probably, ROS produce less insulin secretion due to a lower GLUT-2 activity.

Glucotoxicity and lipotoxicity, disclosed separately for didactic reasons, coparticipate in the genesis of DM2 and interact together causing structural and functional damage in β cells and in target organs. Thus, glucotoxicity describes more accurately the reality of the chronic deleterious process. Glucolipotoxicity is capable of causing inflammation in pancreatic β cells and in the peripheral tissues where insulin acts. In the β cells, an activation of the nuclear factor kappa beta (NF-kβ) pathway occurs, increasing the production of NF-kβ which is an inflammatory cytokine. In the visceral adipose tissue, there is a decrease in adiponectin which is anti-inflammatory (insulin-sensitizing) and an increase in the proinflammatory

This chronic low-grade inflammatory state is referred to as a metainflammation [18].

ROS, generated both by hyperglycemia and increased FFA levels, would have the most important role in the onset and progression of DM2. In β cells, ROS [18] cause a

**30**

decrease in insulin synthesis and secretion; since β cells have a low antioxidant capacity, excessive ROS production results in an imbalance of the redox state, tilting the balance toward oxidation. In peripheral tissues that are targets for insulin, ROS favor inactivation of insulin signal transmission. It has also been observed that inflammation, mainly through the increase in IL-6 and TNFα, favors IR and β cell dysfunction.

On the other side, the production of chemicals used worldwide in different activities including the food industry, probably through ROS generation, has increased progressively since 1940. In the USA, a direct relationship has been found between the production curves of synthetic organic chemicals and the prevalence of diabetes and other pathologies [19]. The Environmental Protection Agency has defined as endocrine-disrupting chemicals, exogenous agents that interfere with the production, secretion, transport, metabolism, binding, action, or clearance of hormones.

## **4.6 Endoplasmic reticulum stress and endothelial dysfunction**

The endoplasmic reticulum actively participates in protein synthesis, producing the correct folding of proteins by means of chaperones, which are helpers of this process. Activating signals such as hyperglycemia increase the demand for insulin synthesis, causing endoplasmic reticulum stress in β cells; this induces apoptotic pathways as a normal adaptive metabolic response to a metabolic load. In DM2, the endoplasmic reticulum stress caused by glucotoxicity and inflammatory cytokines can lead to β cell dysfunction and death [20].

The β cell mitochondrion participates in insulin synthesis and in exocytosis. In diabetes, a mitochondrial dysfunction occurs: the mitochondrial membrane proteins are diminished, and transcriptional changes occur in their formation. Mitochondrial dysfunction, induced by glucotoxicity, results in β cell failure, increase in ROS, and oxidative stress.

In IR, the excess of circulating fatty acids associated with the reduction in the number of mitochondria causes an increment in the level of intracellular FFA and also of diacylglycerol. These molecules activate PKC which in turn activates the serine kinase cascade, leading to an increment in the phosphorylation of the serine residues in IRS-1 and preventing the phosphorylation of tyrosine residues, which in turn inhibits PI-3 K activity, finally resulting in the suppression of insulin-induced glucose transport [21].

#### **4.7 Diet and nutrients**

In recent years, a special interest has aroused for studying the influence of the diet in general and of different nutrients in particular, on the development of DM2.

There is a consensus in that a healthy diet with no caloric excess and a suitable physical activity are the most effective measures for preventing DM2. There is also clinical and biological evidence that excessive sugar consumption promotes the development of DM2 and of cardiovascular disease [22].

The effect of dietary fat on the risk for DM2 is not absolutely clarified, and some studies have even provided contradictory results; but there exists a consensus in that the quality of the fat is more important than the total amount. Dietary fat is not only a source of energy, but also fatty acids affect cell metabolism. Monounsaturated fatty acids and trans-fatty acids would not be associated with a higher incidence of DM2.

In relation to dietary fats, arrives at more categorical conclusions indicating that a diet high in monounsaturated fatty acids (olive oil) and polyunsaturated fatty acids of marine origin is associated with low risk of DM2 [23]. This is confirmed by the fact that consumption of Mediterranean diet, high in monounsaturated fatty acids from vegetable oils and polyunsaturated fatty acids from fish, reduces the risk for DM2.

For a long time, it was believed that free consumption of fructose had no negative effects on the body, since it does not require insulin for its metabolism. Recent studies demonstrate the exact opposite, stating that excessive intake favors metabolic syndrome. In recent years, the high fructose consumption in corn syrups in the USA is correlated with the increased prevalence of DM2, obesity, and cardiovascular disease.

The so-called fructose hypothesis postulates that a high fructose content in the diet induces activation of peroxisome proliferator-activated receptor gamma (PPAR-Ύ) responsible for IR, lipogenesis, and DM2 [24]. Besides, the fructose load with the resulting hepatic stress causes the release of proinflammatory cytokines such as TNFα that induces IR and favors the development of DM2.

The association between gluten intake and DM2 has been the subject matter of recent studies. In US healthy men and women, an inverse correlation has been found between gluten intake and incidence of DM2.

Subjects receiving a diet with high gluten content, followed up for 20–28 years, exhibit low DM2 rates [25]. The cause would be in that subjects who eat gluten-rich foods also receive an elevated supply of cereal fiber. The mechanism through which gluten reduces the risk of DM2 is unknown but is probably related to favorable changes in gut microbiota.

Presently, the effect of vitamin D supplements at pharmacological dosages in the prevention of both type 1 and type 2 diabetes is being debated. Epidemiologic studies demonstrate a relationship between vitamin D deficiency and DM2, as well as the higher frequency of this type of diabetes in areas with low sun exposure. In prospective studies of up to 20 years in humans, it has been demonstrated that the incidence of DM2 decreases by providing a daily supplement of 800 IU of vitamin D [26]. However, other studies do not show the same results; it could be concluded that supplying vitamin D to persons at risk for diabetes is an advisable measure, even though there is still not enough scientific evidence to support this position.
