**4. Environmental factors of DM2**

Environmental factors are considered to be all situations that favor the development of this type of diabetes.

#### **4.1 Obesity**

General obesity, and in particular the android type, is the main environmental factor in the genesis of DM2. In our experience, at diagnosis of DM2, 80% of the patients are obese.

**29**

others.

**4.2 Aging**

susceptible subjects [12].

**4.3 Psychological stress**

the development of DM2.

tion, increasing IR and inducing DM2.

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

Historically, it was believed that fat tissue was metabolically neutral, being only an energy reservoir. In recent years, it is considered to be a real endocrine organ

The increase in visceral adipose tissue results in higher levels of FFA that activate the β isoform of protein kinase C (PKCβ) and inhibit glucose transport-4 (GLUT-4) translocation to the cell membrane, reducing glucose entry into insulin target tissues. TNFα and interleukin-6 (IL-6), by phosphorylating IRS-1 on serine/threonine residues and not on tyrosine, disrupt the correct transmission of the insulin signal. Adipose tissue also secretes several hormones known as adipocytokines; among

The influence of age on the development of DM2 is indisputable only by reviewing the universal epidemiology of this type of diabetes, which shows a progressive increment of its prevalence rates with increasing age. Glucose tolerance deteriorates with aging, which has been attributed to the loss of muscular mass and increase in adipose tissue (sarcopenia), especially in sedentary individuals, increasing IR in

It has been proposed that at an older age, mitochondrial functions decline favoring IR and, on the other side, leptin resistance rises intensifying visceral fat deposi-

Acute psychological stress has been acknowledged for many years as a factor which favors the onset of diabetes. This is because sympathetic activation reduces

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

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

the functionality of the pancreatic β cell, diminishing insulin secretion.

them we will refer, in relation to the increase in IR, to leptin, adiponectin, and resistin. DM2 patients exhibit elevated leptin levels, favoring obesity due to greater food intake and lower caloric expenditure. In humans, the defect is a resistance to leptin action at the hypothalamic receptor level, with obesity developing as these receptors become insensitive to leptin. Adiponectin is the only adipocytokine whose circulating levels are diminished in obesity. It is interesting to point out that the low adiponectin levels are observed particularly in coronary patients, constituting a risk marker for this pathology. In respect of resistin, there has been much controversy regarding its role in obesity and DM2. Its overexpression is associated to IR, dyslip-

with a huge importance in the pathogenesis of DM2 and IR [11].

idemia, and DM2, through inhibition of cell glucose uptake.

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

Historically, it was believed that fat tissue was metabolically neutral, being only an energy reservoir. In recent years, it is considered to be a real endocrine organ with a huge importance in the pathogenesis of DM2 and IR [11].

The increase in visceral adipose tissue results in higher levels of FFA that activate the β isoform of protein kinase C (PKCβ) and inhibit glucose transport-4 (GLUT-4) translocation to the cell membrane, reducing glucose entry into insulin target tissues. TNFα and interleukin-6 (IL-6), by phosphorylating IRS-1 on serine/threonine residues and not on tyrosine, disrupt the correct transmission of the insulin signal.

Adipose tissue also secretes several hormones known as adipocytokines; among them we will refer, in relation to the increase in IR, to leptin, adiponectin, and resistin. DM2 patients exhibit elevated leptin levels, favoring obesity due to greater food intake and lower caloric expenditure. In humans, the defect is a resistance to leptin action at the hypothalamic receptor level, with obesity developing as these receptors become insensitive to leptin. Adiponectin is the only adipocytokine whose circulating levels are diminished in obesity. It is interesting to point out that the low adiponectin levels are observed particularly in coronary patients, constituting a risk marker for this pathology. In respect of resistin, there has been much controversy regarding its role in obesity and DM2. Its overexpression is associated to IR, dyslipidemia, and DM2, through inhibition of cell glucose uptake.

### **4.2 Aging**

*Type 2 Diabetes - From Pathophysiology to Modern Management*

adipose tissue than in subcutaneous adipose tissue.

their clinical behavior is singular.

**3.2 Genetic defects in insulin secretion**

synthesis is lower because the messenger RNA levels are lower.

For phosphoinositide 3-kinase (PI-3 K), it has been demonstrated that in DM2 its

In the relation of obesity with DM2, correlation, among the possible genes involved, mention is made of the tumor necrosis factor alpha (TNFα) gene, a polymorphism in its promoter consisting of the substitution of guanine to adenine at position 308, which originates higher TNFα synthesis in obese IR patients. The finding regarding leptin is very interesting, in studies on thousands of cases since only five have genetic mutations for the hormone, suggesting that obesity in DM2 humans would be associated with leptin resistance at the level of its receptors. On the other side, the adiponectin gene is located on chromosome 3q27, and in this position, a locus has been found which confers susceptibility to DM2. For resistin, it has been reported that its genetic expression is four times higher in abdominal

The hereditary basis of IR in DM2 is extremely complex, moreover, when the obesity factor is included having its own polygenic component. DM2 patients have different degrees of IR with probably different genetic origins; this explains why

In DM2, the genes encoding the different protein components that participate in the mechanism of insulin synthesis and secretion are potential candidates [9, 10]. Among the most likely ones is the IRS-2 gene, which is very interesting because a polymorphism has been described which predicts anomalies both in insulin secretion and action. In 2000, a false announcement was issued regarding the discovery of the gene of DM2, referring to the calpain 10 (CAPN10) gene that encodes a family of calpain enzymes, which are calcium-activated proteases that take part in the regulation of insulin exocytosis in β cells. It was published that in Pima Indians, a specific combination of CAPN10 alleles triplicated the risk of DM2. However, in recent years, the transcription factor 7-like 2 (TCF7L2) gene has appeared to be more relevant in the genetic susceptibility to DM2, since a polymorphism of this gene has been found in several ethnic groups of DM2 patients. This factor is associated to a reduced response to glucagon-like peptide-1 (GLP-1) because GLP-1 expression in enteroendocrine cells is regulated by TCF7L2, which would have as a final consequence, a failure in β cell proliferation and in insulin secretion; thus,

variants of the TCF7L2 gene would contribute to the risk for DM2.

alterations both in insulin secretion and action.

**4. Environmental factors of DM2**

ment of this type of diabetes.

It can be said that DM2 is a polygenic disease with many susceptibility genes, each with a slight impact on its pathogenesis but giving origin to several subgroups of DM2 on account of their genetic differences. Thus, in the various individuals and in the different ethnic groups, genetic heterogeneity results in variable degrees of

Environmental factors are considered to be all situations that favor the develop-

General obesity, and in particular the android type, is the main environmental factor in the genesis of DM2. In our experience, at diagnosis of DM2, 80% of the

**28**

**4.1 Obesity**

patients are obese.

The influence of age on the development of DM2 is indisputable only by reviewing the universal epidemiology of this type of diabetes, which shows a progressive increment of its prevalence rates with increasing age. Glucose tolerance deteriorates with aging, which has been attributed to the loss of muscular mass and increase in adipose tissue (sarcopenia), especially in sedentary individuals, increasing IR in susceptible subjects [12].

It has been proposed that at an older age, mitochondrial functions decline favoring IR and, on the other side, leptin resistance rises intensifying visceral fat deposition, increasing IR and inducing DM2.
