**3.1 Genetic defects of IR**

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.

#### **Insulin resistance genes**

1.Directly associated with lower glucose uptake

	- β-3 adrenergic receptor gene
	- Tumor necrosis factor alpha gene
	- Peroxisome proliferator-activated receptor gene
	- Leptin gene
	- Resistin gene
	- Lipoprotein lipase gene
	- Uncoupling protein gene

#### **Insulin secretion genes**


#### **Table 1.** *Candidate genes of type 2 diabetes.*

For phosphoinositide 3-kinase (PI-3 K), it has been demonstrated that in DM2 its synthesis is lower because the messenger RNA levels are lower.

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 adipose tissue than in subcutaneous adipose tissue.

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 their clinical behavior is singular.

#### **3.2 Genetic defects in insulin secretion**

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.

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 alterations both in insulin secretion and action.
