**3. Genetic factors of DM2**

Presently, DM2 is considered to be a disease with a strong hereditary component. Thus, 35–50% of the patients have diabetic relatives, a number that is lower (15%) in subjects not having this pathology. If a survey for DM2 is conducted on the patients' parents, 10–30% of them have the disease in comparison to 1–6% in healthy controls.

**27**

**Table 1.**

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

that falls to less than 50% in fraternal twins.

the insulin secretion defect and to IR.

individuals of a same ethnic group.

**3.1 Genetic defects of IR**

**Insulin resistance genes**

1.Directly associated with lower glucose uptake

2.Explaining the obesity-type 2 diabetes relationship

• Peroxisome proliferator-activated receptor gene

• Insulin receptor substrate gene • Phosphoinositide 3-kinase gene

• β-3 adrenergic receptor gene • Tumor necrosis factor alpha gene

3.Adipocytokines in obesity

• Lipoprotein lipase gene • Fatty acid-binding protein gene 5.The thermogenesis obesity relationship

• Uncoupling protein gene **Insulin secretion genes**

• Insulin receptor substrate gene

• K+ inwardly rectifier channel gene

• Calpain 10 gene

*Candidate genes of type 2 diabetes.*

• Leptin gene • Resistin gene • Adiponectin gene 4.Lipid metabolism

In the Framingham Offspring Study, it was found that if one of the parents was diabetic, in the offspring the relative risk was 3.6; if both parents had the disease, it rose to 6.0. This study indicates that the risk for diabetes in sons or daughters of diabetic parents is similar regardless if it is the father or the mother who has the disease [5]. In monozygotic twins, there is up to 96% match for DM2, a percentage

All genes that encode enzymes or protein factors associated with insulin secretion and action are possible candidates for the disease. It has been published that the hereditary factor is stronger than the environmental factor for the secretory defect.

**Table 1** shows the most relevant candidate genes for DM2, which are related to

Each gene has been found to be altered in approximately 10% of the DM2 patients studied. Therefore, it is necessary for the individual to have at least 10 defective genes for the disease to develop. Besides, in the various populations, different genotypes involved would exist, and differences would appear also in

Genetic mutations have been found in certain protein factors and enzymes associated with the transmission of the insulin signal inside the effector cell, which would allow to partly explain the IR of DM2 [6–8]. In the insulin receptor substrate-1 (IRS-1) gene, the mutation of glycine to arginine at codon 972 is twice more prevalent in Caucasian DM2 patients than in nondiabetic controls.

In IR, genetic and environmental factors have 50% participation each.

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

*Type 2 Diabetes - From Pathophysiology to Modern Management*

DM2 is a progressive disease that develops in stages. Its natural history probably

Subsequently, and before DM2 manifests, IR is maintained, but the secretory capacity of the β cell begins to decline and glycemias rise, reaching abnormality levels for fasting glycemia and glucose intolerance, which are prediabetes stages. In these periods, chronic hyperglycemia is an important factor in the perpetuation of damage to the pancreatic β cells; as it increases and IR is maintained, glycemic levels

The insulin secretory defects observed in DM2 contribute to IR. During the evolution of DM2, the IR state is maintained, and the insulin secretory capacity gradually decreases, arriving at an insulin hyposecretion in which it will be neces-

We will now refer to the multiple factors involved in the genesis of DM2.

Hyperglycemia in DM2 not only represents the biochemical manifestation of the disease, but it is rather, in itself, a permanent factor responsible for maintaining the

Presently, DM2 is considered to be a disease with a strong hereditary component. Thus, 35–50% of the patients have diabetic relatives, a number that is lower (15%) in subjects not having this pathology. If a survey for DM2 is conducted on the patients' parents, 10–30% of them have the disease in comparison to 1–6% in healthy controls.

begins 10–20 years before its clinical onset, as a preclinical period with IR [4**].** Hyperinsulinemia is initially capable of maintaining normal fasting and postprandial glycemias. This stage would be associated with increased levels of free

progressively increase until finally clinical diabetes is established. The stages of the pathogenesis of DM2 are shown in **Figure 1**.

**2. Natural history of DM2**

fatty acids (FFA) in the obese IR patient.

sary, in some cases, to start insulin therapy.

diabetic state.

**26**

**Figure 1.**

**3. Genetic factors of DM2**

*Stages in pathogenesis of type 2 diabetes.*

In the Framingham Offspring Study, it was found that if one of the parents was diabetic, in the offspring the relative risk was 3.6; if both parents had the disease, it rose to 6.0. This study indicates that the risk for diabetes in sons or daughters of diabetic parents is similar regardless if it is the father or the mother who has the disease [5]. In monozygotic twins, there is up to 96% match for DM2, a percentage that falls to less than 50% in fraternal twins.

All genes that encode enzymes or protein factors associated with insulin secretion and action are possible candidates for the disease. It has been published that the hereditary factor is stronger than the environmental factor for the secretory defect. In IR, genetic and environmental factors have 50% participation each.

**Table 1** shows the most relevant candidate genes for DM2, which are related to the insulin secretion defect and to IR.

Each gene has been found to be altered in approximately 10% of the DM2 patients studied. Therefore, it is necessary for the individual to have at least 10 defective genes for the disease to develop. Besides, in the various populations, different genotypes involved would exist, and differences would appear also in individuals of a same ethnic group.
