**5. Deficit in insulin secretion**

In DM2 patients, deficit in insulin secretion is the building block of its pathogenesis. It has been found that the disturbances caused are both quantitative and qualitative and are present in variable degrees in the patients.

When the secretory disorder appears, hyperglycemia manifests. It has been demonstrated that, in general, individuals exhibiting the most severe hyposecretion have the highest glycemias. The graphic relationship of fasting and postprandial glycemias versus insulinemias is very well known and gives origin to the inverted U or Starling curve; at low glucose values, insulinemias are also low and then the relationship is inverse, and at higher glycemias, there are lower insulinemias [27].

In DM2 patients, the lack of insulin response to glucose worsens with the years of evolution of the disease and is accentuated with the persistent hyperglycemias (glucotoxicity). Once glycemia rises, a vicious circle is produced because glucose on its own causes changes in β cells, paradoxically slowing down insulin secretion [28].

DM2 patients exhibit changes in the biphasic insulin secretion curve under a stimulus of intravenous glucose; the first phase is lost, the second phase shows less elevation and is more prolonged in time than in the normal curve. These alterations, which are present since the prediabetes state, reduce the effectiveness of insulin. Besides, in DM2 patients, there are a lower number of pulses of insulin secretion under glucose stimulus [29]. Similar to other hormones, insulin is more effective when secreted in pulses that released continuously.

**33**

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

favoring β cell apoptosis [31].

or precedes the diagnosis of DM2.

**6. Insulin resistance**

other is characteristic of DM2.

in the different individuals.

**6.1 IR in the liver**

At the anatomical level, in the pancreas of DM2 patients, there is a 40% reduction of the β cell mass, which on its own does not explain the hyposecretion. In this respect, the theory of low birth weight, also called the theory of the thrifty gene or of feast and famine, is very attractive. In those patients, their reduced pancreas does not allow to compensate the insulin demand when they are obese, subsequently developing DM2 [30]. The reduction in β cell mass could be due to an increase in apoptosis and autophagy that would exceed the islet regenerative capacity.

In DM2, a morphological change that has been extensively studied is the amyloid deposition in the islets of Langerhans, a disturbance that may lead to accelerated death of β cells with the consequent decrease of insulin secretion. It has been reported that the presence of amyloid coincides with or precedes hyperglycemia,

Amyloid is constituted by a peptide initially named amylin and presently referred to as islet amyloid polypeptide (IAPP), normally produced by β cells. This amyloid forms fibrils that are cytotoxic to these cells through an oxidative stress mechanism; IAPP overexposure would favor DM2 development. It has not yet been clarified whether the excess of amyloid deposition is caused by the hyperglycemia

At present, epigenetics is considered to be a factor of DM2 and other diseases; these are interactions between genes and environment that occur in individuals through small chemical modifications that are capable of regulating the expression

IR, defined as a lower biological activity of the hormone in its different metabolic actions for a certain concentration, is the first abnormality detected in the

both disorders having genetic bases that have been extensively studied but not well defined to date, influenced by epigenetic factors that can act since intrauterine life. IR, obesity, and DM2 are highly interrelated. In 95% of the cases, IR presents in subjects with excess weight or obesity will subsequently develop DM2. Although IR is present in almost all patients with DM2, the degrees of IR are very variable in different individuals; besides, a proportion of IR comes from obesity itself, and the

IR plays a main role in DM2 development together with the insulin secretion defect,

IR is expressed in the liver, muscle, and adipose tissue with different intensities

A positive correlation has been demonstrated between fasting glucose and hepatic gluconeogenesis, such that as the latter descends, basal glycemia levels also descend. Therefore, the hepatic gluconeogenesis that produces glucose in an environment of elevated glycemia levels is abnormal and of very important in maintaining fasting hyperglycemia in DM2 patients. The mechanism through which hepatic glucose production increases would be an elevated supply of FFA from adipose tissue, which

In DM2 due to IR, hyperglycemia occurs through three mechanisms: excessive hepatic production of glucose (gluconeogenesis), decrease in its uptake by peripheral tissues (muscle and adipose tissue), and increase in FFA resulting from a greater lipolysis in the adipocytes. FFA competes with glucose as a source of energy contributing to increase glycemia and inhibit glucose entry through the cell membrane [3].

of the DM2 genes especially related to insulin secretion [32].

evolution of DM2 and is already present in the prediabetes state.

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

*Type 2 Diabetes - From Pathophysiology to Modern Management*

vascular disease.

changes in gut microbiota.

support this position.

**5. Deficit in insulin secretion**

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 cardio-

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

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

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

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

In DM2 patients, deficit in insulin secretion is the building block of its pathogenesis. It has been found that the disturbances caused are both quantitative and

When the secretory disorder appears, hyperglycemia manifests. It has been demonstrated that, in general, individuals exhibiting the most severe hyposecretion have the highest glycemias. The graphic relationship of fasting and postprandial glycemias versus insulinemias is very well known and gives origin to the inverted U or Starling curve; at low glucose values, insulinemias are also low and then the relationship is inverse, and at higher glycemias, there are lower insulinemias [27]. In DM2 patients, the lack of insulin response to glucose worsens with the years of evolution of the disease and is accentuated with the persistent hyperglycemias (glucotoxicity). Once glycemia rises, a vicious circle is produced because glucose on its own causes changes in β cells, paradoxically slowing down insulin secretion [28]. DM2 patients exhibit changes in the biphasic insulin secretion curve under a stimulus of intravenous glucose; the first phase is lost, the second phase shows less elevation and is more prolonged in time than in the normal curve. These alterations, which are present since the prediabetes state, reduce the effectiveness of insulin. Besides, in DM2 patients, there are a lower number of pulses of insulin secretion under glucose stimulus [29]. Similar to other hormones, insulin is more effective

qualitative and are present in variable degrees in the patients.

when secreted in pulses that released continuously.

such as TNFα that induces IR and favors the development of DM2.

found between gluten intake and incidence of DM2.

**32**

At the anatomical level, in the pancreas of DM2 patients, there is a 40% reduction of the β cell mass, which on its own does not explain the hyposecretion. In this respect, the theory of low birth weight, also called the theory of the thrifty gene or of feast and famine, is very attractive. In those patients, their reduced pancreas does not allow to compensate the insulin demand when they are obese, subsequently developing DM2 [30]. The reduction in β cell mass could be due to an increase in apoptosis and autophagy that would exceed the islet regenerative capacity.

In DM2, a morphological change that has been extensively studied is the amyloid deposition in the islets of Langerhans, a disturbance that may lead to accelerated death of β cells with the consequent decrease of insulin secretion. It has been reported that the presence of amyloid coincides with or precedes hyperglycemia, favoring β cell apoptosis [31].

Amyloid is constituted by a peptide initially named amylin and presently referred to as islet amyloid polypeptide (IAPP), normally produced by β cells. This amyloid forms fibrils that are cytotoxic to these cells through an oxidative stress mechanism; IAPP overexposure would favor DM2 development. It has not yet been clarified whether the excess of amyloid deposition is caused by the hyperglycemia or precedes the diagnosis of DM2.

At present, epigenetics is considered to be a factor of DM2 and other diseases; these are interactions between genes and environment that occur in individuals through small chemical modifications that are capable of regulating the expression of the DM2 genes especially related to insulin secretion [32].
