**8. The monogenic forms of Insulin Resistance (IR)**

A clear genotype-phenotype association is emerging following description of more than 60 mutations in insulin receptor gene which subsequently causing IR and tend to genera extreme and severe forms of IR patients. The most abundant mutations are heterozygous leading to decreased tyrosine phosphorylation of the β-subunit of the insulin receptor.


#### **8.1. Insulin gene**

member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1α expression. The deficient binding of NEUROD1 or binding of a transcriptionally inactive NEUROD1 polypeptide to target promoters in pancreatic islets leads to the develop‐ ment of T2DM in humans. In mice, two mutations in NEUROD1 in the heterozygous state were described in development of T2DM. The truncated polypeptide lacking the carboxyterminal trans-activation domain, a region that associates with the co-activators CBP and p300 is more severe clinically than mutation at Arg 111 in the DNA-binding domain, abolishes Ebox binding activity of NEUROD1 [114-125]. Other rare forms of MODY are CEL-MODY, ABCC8, KCNJ11 and UPD6 [126]. There are many factors determined the clinical presentation of various subtype of MODY including, the severity, the course of insulin secretion defect, the risk of microvascular complications and the presence of other abnormalities or defects in

Maternallyinheriteddiabetes anddeafness (MIDD)is anewsub-typeofdiabeteswithmutation in mitochondrial DNA. The mitochondrial genome is passed and inherited exclusively by maternalline.InpatientswithT2DMtherecouldbeincreaseintransmissionofinheriteddiseases by maternal line more than paternal. However, only 0.5-2.8% of patients with DM demonstrat‐ ed the frequency of adenine to guanine mutation. The adenine to guanine transition mutation at position 3243 in the dihydrouridine loop of mitochondrial tRNALeu(UUR) gene is specific to patients withaneurological syndromeMELAS (myopathy, encephalopathy,lactic acidosis and stroke like disease). There is also 3243 mutation is associated with the phenotypical distinct of MIDD sub-type. In a study of the genotype of patients with T2DM of North European extrac‐ tion with one or more features of MIDD and/or MELAS, Two patients were identified with the mutation giving a prevalence rate of 0.13% for the whole study population, and 0.45% for the sample with phenotypic features of MIDD. Other mitochondrial gene defects and mutation of

A clear genotype-phenotype association is emerging following description of more than 60 mutations in insulin receptor gene which subsequently causing IR and tend to genera extreme and severe forms of IR patients. The most abundant mutations are heterozygous leading to

**•** Type A insulin resistance syndrome, it is a heterozygous mutations in the tyrosine kinase domain of the insulin receptor gene and it is the most common phenotype. It is characterized

**•** Homozygous or compound heterozygous mutations lead to the Rabson–Mendelhall

by acanthosis nigricans and hyperandrogenism without obesity or lipoatrophy.

diabetes patients [127].

76 Treatment of Type 2 Diabetes

**7.2. Mitochondrial diabetes: A monogenic Diabetes Mellitus**

3234 are linked to the development of T2DM [128-133].

**8. The monogenic forms of Insulin Resistance (IR)**

decreased tyrosine phosphorylation of the β-subunit of the insulin receptor.

syndrome with severe impairment of insulin receptor function.

Several phenotypes, including T2DM, polycystic ovary syndrome, and birth weight are associated with tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS). A study analyzed this insulin gene class III VNTR minisatellite in 155 European T2DM parent-offspring trios from the British Diabetes Association demonstrated that variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itself at this regulatory element is a significant determinant of T2DM susceptibility. This susceptibility is exclusively mediated by paternally derived alleles [142].

#### *8.1.1. SUR-1gene*

In Dutch population, the exon 16-3t allele of the single nucleotide polymorphisms in the sulphonylurea receptor gene (SUR1) has been reported to be associated with T2DM patients compared with the control group. But there was no association between T2DM patients and the variant in exon 18 or the combination of both variants. Other studies in Caucasian popu‐ lation, strong linkage disequilibrium between the exon 16 and exon 18 variants was demon‐ strated in patients with T2DM but was not shown in the control group [143].

### *8.1.2. IRS-1gene*

The utilization of insulin receptor substrate (IRS)-proteins (IRS-1 and IRS-2) emerged many interactive proteins in the insulin signaling system. This can be amplified or attenuated independently insulin binding and tyrosine kinase activity, providing an extensible mechanism for signal transmission in multiple cellular backgrounds [144]. Patient with T2DM with IRS-1 variants did not differ in their degree of IR compared with patients without known IRS-1 polymorphisms. However, carriers of the codon 972 variant had significantly lower plasma levels of fasting insulin and C-peptide [145, 146]. Many other studies demonstrated several polymorphisms in the IRS-1 gene variant, a Gly-->Arg change at the codon 972 may contribute in impairment of insulin secretion and increased in prevalence among patients with T2DM [146].

#### *8.1.3. PC-1gene*

In Swedish and Finnish people, the Q allele of the human glycoprotein PC-1 gene is associated with surrogate measures of IR, but it may not be enough to increase the susceptibility to T2DM. An observation showed there was no difference in the Q allele frequency between the patients with T2DM and control group. There were higher fasting plasma glucose and 2 hours in QK genotype siblings with diabetes compared with carrier of KK genotype. While in sibling with QK genotype and without diabetes have higher fasting plasma glucose and insulin than KK genotype carrier [147].

#### **8.2. Glycogen synthase gene**

An Xbal polymorphism has been described in the glycogen synthase gene associated with IR [148]. More features of metabolic syndrome and increased susceptibility to T2DM were described in sibling with rare A2 allele of discordant sib-pair analysis [149]. A set of polymor‐ phic microsatellite markers that span the genome was implemented in genotyping of families with this condition to essence this approach [150].

#### *8.2.1. Calpain 10 (CAPN10) gene*

Calpain gene is cytoplasmic cystiene protease requiring calcium ions for activity. CAPN10 gene was proposed as susceptibility locus of T2DM based on the initial report of association between the T2DM and CAPN10 gene [151]. It has been reported of association with T2DM in Pima Indians [152], in African Americans [153] in Mexican Americans [154], in the Botnia area of Finland, German patients [155] and in South Indians [156].

#### *8.2.2. Foxo 1 gene*

Insulin signalling downstream of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at least in part controls glucose on β-cells mass and function. The activation of Akt is negatively affected the proliferation and metabolism of Foxo transcription factors. The changes in Foxo 1 transcriptional activity are associated with nutritional alteration of β-cells. Glucose-stimu‐ lated insulin secretion acts through its own receptor as the predominant mediator of these changes in β-cells [157]. Ghrelin increases pancreatic β-cell proliferation and survival via sequential activation of phosphatidylinositol-3 kinase (PI3K) and Akt ghrelin. It protects pancreatic β-cells from lipotoxicity by inhibiting the nuclear translocation of Foxo1 [158].

#### **8.3. Beta 3-adrenergic receptor gene**

The energy balance by increasing in lipolysis and thermogenesis could be regulated by the beta 3-adrenergic receptor (beta 3-AR) gene. The ability to gain weight and the early onset of T2DM are associated with mutation in the beta 3-AR gene (Trp64Arg). But this is not in Dutch population [159]. Many studies in different ethnic groups showed an association of beta3-AR gene polymorphism with IR, obesity and its metabolic disorders such as T2DM, coronary heart disease and hypertension [160].

#### *8.3.1. TCF7L2*

*8.1.2. IRS-1gene*

78 Treatment of Type 2 Diabetes

*8.1.3. PC-1gene*

genotype carrier [147].

**8.2. Glycogen synthase gene**

*8.2.1. Calpain 10 (CAPN10) gene*

*8.2.2. Foxo 1 gene*

prevalence among patients with T2DM [146].

with this condition to essence this approach [150].

of Finland, German patients [155] and in South Indians [156].

The utilization of insulin receptor substrate (IRS)-proteins (IRS-1 and IRS-2) emerged many interactive proteins in the insulin signaling system. This can be amplified or attenuated independently insulin binding and tyrosine kinase activity, providing an extensible mechanism for signal transmission in multiple cellular backgrounds [144]. Patient with T2DM with IRS-1 variants did not differ in their degree of IR compared with patients without known IRS-1 polymorphisms. However, carriers of the codon 972 variant had significantly lower plasma levels of fasting insulin and C-peptide [145, 146]. Many other studies demonstrated several polymorphisms in the IRS-1 gene variant, a Gly-->Arg change at the codon 972 may contribute in impairment of insulin secretion and increased in

In Swedish and Finnish people, the Q allele of the human glycoprotein PC-1 gene is associated with surrogate measures of IR, but it may not be enough to increase the susceptibility to T2DM. An observation showed there was no difference in the Q allele frequency between the patients with T2DM and control group. There were higher fasting plasma glucose and 2 hours in QK genotype siblings with diabetes compared with carrier of KK genotype. While in sibling with QK genotype and without diabetes have higher fasting plasma glucose and insulin than KK

An Xbal polymorphism has been described in the glycogen synthase gene associated with IR [148]. More features of metabolic syndrome and increased susceptibility to T2DM were described in sibling with rare A2 allele of discordant sib-pair analysis [149]. A set of polymor‐ phic microsatellite markers that span the genome was implemented in genotyping of families

Calpain gene is cytoplasmic cystiene protease requiring calcium ions for activity. CAPN10 gene was proposed as susceptibility locus of T2DM based on the initial report of association between the T2DM and CAPN10 gene [151]. It has been reported of association with T2DM in Pima Indians [152], in African Americans [153] in Mexican Americans [154], in the Botnia area

Insulin signalling downstream of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at least in part controls glucose on β-cells mass and function. The activation of Akt is negatively affected the proliferation and metabolism of Foxo transcription factors. The changes in Foxo 1 transcriptional activity are associated with nutritional alteration of β-cells. Glucose-stimu‐ lated insulin secretion acts through its own receptor as the predominant mediator of these

The risk alleles of TCF7L2 were associated with enhanced expression of this gene in human islets as well as impaired insulin secretion both in vitro and in vivo. TCF7L2 has also been linked to altered pancreatic islet morphology as exemplified by increased individual islet size and altered α and β cell ratio/distribution within human islets [161]. TCF7L2 encodes the transcription factor TCF4 which is related to Wnt signaling pathway and which plays a critical role in the pathogenesis of T2DM. The risks of alleles in TCF7L2 were associated with hepatic but not peripheral IR and enhanced the rate of hepatic glucose production in human [162]. This is indirectly disturbing beta cells function of the pancreas.

#### *8.3.2. SCL30A8*

SCL30A8 encodes the islet specific zinc transporter ZnT-8, which delivers zinc ions from cytoplasm into intracellular insulin-containing granules and is implicated in insulin matura‐ tion and/or storage processes in β-cells [163]. The expression level of ZnT-8 was remarkably down regulated in the pancreas of db/db and Akitamice in the early stage of diabetes. Global SCL30A8 knockout mice demonstrated reduced plasma insulin, impaired glucose –stimulated insulin secretion, and markedly reduced islet zinc content [164].

#### **8.4. Others genetic syndromes associated with diabetes**

Down syndrome, Klinefelter syndrome, Turner syndrome, Wolfram syndrome, Friedreicha‐ taxia, Huntington chorea, Laurence-Moon-Biedlsyndrome, Myotonicdystrophy, Porphyria and Prader-Willi syndrome.
