Section 3 Diabetes Mellitus

*Cellular Metabolism and Related Disorders*

KL, et al. Lactate uptake by the injured human brain: Evidence from an arteriovenous gradient and cerebral microdialysis study. Journal of

Neurotrauma. 2013;**30**:2031-2037. DOI:

[63] Bouzat P, Sala N, Suys T, Zerlauth JB, Marques-Vidal P, Feihl F, et al. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. Intensive Care Medicine.

2014;**40**:412-421. DOI: 10.1007/

10.3389/fnins.2014.00408

10.1089/neu.2014.3483

fnins.2015.00112

[66] Carpenter KLH, Jalloh I, Hutchinson PJ. Glycolysis and the significance of lactate in traumatic brain injury. Frontiers in Neuroscience. 2015;**9**:112. DOI: 10.3389/

[67] Hyder F, Herman P, Bailey CJ, Møller A, Globinsky R, Fulbright RK, et al. Uniform distributions of glucose oxidation and oxygen extraction in gray matter of normal human brain: No evidence of regional differences of aerobic glycolysis. Journal of Cerebral Blood Flow & Metabolism. 2016;**36**:903-916. DOI:

10.1177/0271678X15625349

[64] Brooks GA, Martin NA. Cerebral metabolism following traumatic brain injury: New discoveries with implications for treatment. Frontiers in Neuroscience. 2015;**8**:408. DOI:

[65] Glenn TC, Martin NA, Hovda DA, Vespa P, Johnson ML, Horning MA, et al. Lactate; brain fuel following traumatic brain injury. Journal of Neurotrauma. 2015;**32**:820-832. DOI:

10.1089/neu.2013.2947

s00134-013-3203-6

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**51**

LADA

**1. Introduction**

**2. Diabetes mellitus type 1**

**Chapter 4**

**Abstract**

Diabetes Mellitus: A Group of

*Lilian Sanhueza, Pilar Durruty, Cecilia Vargas,* 

*Paulina Vignolo and Karina Elgueta*

Genetic-Based Metabolic Diseases

Diabetes mellitus (DM) is a disease characterized by defects in action and/or secretion of insulin that results in chronic hyperglycemia and long-term severe vascular complications. The main clinical presentations with the proven genetic base are covered. Type 1 diabetes (DM1) is an autoimmune, heterogeneous, multifactorial, and polygenic-based disease. Selectively destroys 90% of beta cells of the pancreas, mediated by activated T lymphocytes in patients with haplotypes linked to major histocompatibility complex (MHC). Genetic and genomic studies have been carried out in family groups, demonstrating up to 15 affected chromosomal regions. Type 2 diabetes (DM2) presents genes with various polymorphisms which, together with post-genomic and environmental factors, make it more complex to understand the pathogenesis. Monogenic diabetes comprises neonatal diabetes (ND), maturity onset diabetes in young (MODY), an autosomal dominant transmission which is inherited directly in three successive generations, and the very rare mitochondrial diabetes. Latent autoimmune diabetes in adults (LADA) mainly affects patients with normal weight and initially diagnosed as DM2. Its characteristics are low levels of C-peptide in both fasting and post-glucagon tests. They present MHC alleles of susceptibility and positive autoantibodies: Anti-decarboxylase glutamic acid.

**Keywords:** diabetes mellitus type 1, diabetes mellitus type 2, monogenic diabetes,

Diabetes mellitus (DM) is a group of metabolic diseases of different etiologies characterized by chronic hyperglycemia resulting from a deficit in both the secretion and the action of insulin hormone. Now-a-days, there is a genetic basis of these clinical manifestations. In this chapter, we describe the most important ones such as diabetes mellitus type 1 (DM1), diabetes mellitus type 2 (DM2), monogenic

DM1 is characterized by autoimmune destruction of the beta cells of the pancreatic islets, which leads to an extreme insulinopenia. The character of autoimmunity confirm the presence of islet cell antibodies (ICA), insulin auto antibodies (IAA),

diabetes, and latent autoimmune diabetes in adults (LADA).

#### **Chapter 4**

## Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases

*Lilian Sanhueza, Pilar Durruty, Cecilia Vargas, Paulina Vignolo and Karina Elgueta*

#### **Abstract**

Diabetes mellitus (DM) is a disease characterized by defects in action and/or secretion of insulin that results in chronic hyperglycemia and long-term severe vascular complications. The main clinical presentations with the proven genetic base are covered. Type 1 diabetes (DM1) is an autoimmune, heterogeneous, multifactorial, and polygenic-based disease. Selectively destroys 90% of beta cells of the pancreas, mediated by activated T lymphocytes in patients with haplotypes linked to major histocompatibility complex (MHC). Genetic and genomic studies have been carried out in family groups, demonstrating up to 15 affected chromosomal regions. Type 2 diabetes (DM2) presents genes with various polymorphisms which, together with post-genomic and environmental factors, make it more complex to understand the pathogenesis. Monogenic diabetes comprises neonatal diabetes (ND), maturity onset diabetes in young (MODY), an autosomal dominant transmission which is inherited directly in three successive generations, and the very rare mitochondrial diabetes. Latent autoimmune diabetes in adults (LADA) mainly affects patients with normal weight and initially diagnosed as DM2. Its characteristics are low levels of C-peptide in both fasting and post-glucagon tests. They present MHC alleles of susceptibility and positive autoantibodies: Anti-decarboxylase glutamic acid.

**Keywords:** diabetes mellitus type 1, diabetes mellitus type 2, monogenic diabetes, LADA

#### **1. Introduction**

Diabetes mellitus (DM) is a group of metabolic diseases of different etiologies characterized by chronic hyperglycemia resulting from a deficit in both the secretion and the action of insulin hormone. Now-a-days, there is a genetic basis of these clinical manifestations. In this chapter, we describe the most important ones such as diabetes mellitus type 1 (DM1), diabetes mellitus type 2 (DM2), monogenic diabetes, and latent autoimmune diabetes in adults (LADA).

#### **2. Diabetes mellitus type 1**

DM1 is characterized by autoimmune destruction of the beta cells of the pancreatic islets, which leads to an extreme insulinopenia. The character of autoimmunity confirm the presence of islet cell antibodies (ICA), insulin auto antibodies (IAA),

glutamic acid decarboxylase auto antibodies (GAD65), protein tyrosine phosphatase 2 (IA-2), and zinc transporter gene ZnT8 [1]. There is an interaction between genetic and environmental factors in the development of DM1 (**Figure 1**).

#### **2.1 Genetic factors of DM1**

DM1 is a polygenic disease, with at least 15 associated chromosomal regions. The leading group of genes that predispose to type 1 diabetes is located on human chromosome 6 specifically at 6p21, and this chromosomal region contains a group of genes called major histocompatibility complex (MHC), responsible for the immune response and the antigen presentation of the beta cell to T lymphocytes [2]. The classic histocompatibility genes are extremely polymorphic (amino acid sequence differs among individuals) and include MHC-A, B, and C molecules (class I histocompatibility antigens) and the immune-response genes DP, DQ, and DR (class II histocompatibility antigens). Numbers (DR3, DR4; A1, A2; B1, B8) are given to distinguish different alleles of any given gene. The designation w (workshop) with numbers is given for provisionally named alleles (DQw8, DQw7) [3]. DM1 has been associated mainly with allelic variants of MHC-DR (DR3/DR4). The MHC locus is a genetic factor of great importance in DM1, and it was first shown in an association study that revealed that about 95% of all patients with DM1 were heterozygous for MHC-DR3/DR4. The majority of type 1 diabetics have the MHC-DR3, MHC-DR4 haplotype, or both [4]. Susceptibility to DM type 1 is associated with these linked DQ alleles that are often in linkage disequilibrium with DR. The closest association in DM1 occurs with the haplotypes DQA1\*0301, DQB1\*0302, DQA1\*501, and DQB1\*0201. It has been shown that the beta DQ chains of those affected have valine, alanine, or serine at position 57; near the peptide-binding gap, presence of aspartic acid is normal [5] Factors involved in the pathophysiology of DM1 are shown in (**Figures 2** and **3**).

However, there are exceptions to this association, which indicates that amino acids other than Asp57 at position 57 of the beta chain play an essential but not exclusive role in the susceptibility to DM1 [5]. There is an interaction between genetic and environmental factors in the development of DM1.

#### **2.2 Heritage in type 1 DM**

The inheritance of DM1 is unknown. Several hypotheses have been suggested, such as that of dominant inheritance, but it is ruled out by the rarity of DM1 in relatives, children, and descendants. The possibility of recessive inheritance was also

**53**

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases*

*Etiology of type 1 diabetes. MHC-DQ B antigen amino acid sequence.*

considered, however, invalidated because in homozygotes for the DR3 or DR4 alleles, the susceptibility to the disease is not increased. The observation that heterozygosis DR3/DR4 increases the risk for diabetes, compared with that presented by homozygotes from other high-risk alleles, suggests a polygenic way of inheritance. The diabetogenic MHC haplotype is necessary for the susceptibility to DM1, but must be positively or negatively influenced by genes not linked to MHC, such as the gene located close to the repeated DNA sequence minisatellite, in the promoter region of the gene of the insulin (chromosome 11p15); one gene on chromosome 11q and another on chromosome 6q [6]. Some genes seem to confer protection against the development of the disease. For example, the DQA1\*0102 and DQB1\*0602 haplotypes are present in 20% of the United States population but is extremely rare in individuals with DM1 (<1%). This situation indicates that several genes are interacting to determine the DM1 phenotype, so this disease presents genetic heterogeneity (**Figure 4**). DM1 is uncommon in Chile and usually does not occur in native Chilean families. A study of a family with an affected female child was carried out in a Mapuche community in the Southern (VIII region). This case is a unique and sporadic DM1 case with Mapuche heritage. Genetic analysis by PCR was done

*DOI: http://dx.doi.org/10.5772/intechopen.89924*

**Figure 2.**

**Figure 3.**

*Pathophysiology of type 1 diabetes.*

**Figure 2.** *Etiology of type 1 diabetes. MHC-DQ B antigen amino acid sequence.*

**Figure 3.**

*Cellular Metabolism and Related Disorders*

**2.1 Genetic factors of DM1**

shown in (**Figures 2** and **3**).

**2.2 Heritage in type 1 DM**

glutamic acid decarboxylase auto antibodies (GAD65), protein tyrosine phosphatase 2 (IA-2), and zinc transporter gene ZnT8 [1]. There is an interaction between

DM1 is a polygenic disease, with at least 15 associated chromosomal regions. The leading group of genes that predispose to type 1 diabetes is located on human chromosome 6 specifically at 6p21, and this chromosomal region contains a group of genes called major histocompatibility complex (MHC), responsible for the immune response and the antigen presentation of the beta cell to T lymphocytes [2]. The classic histocompatibility genes are extremely polymorphic (amino acid sequence differs among individuals) and include MHC-A, B, and C molecules (class I histocompatibility antigens) and the immune-response genes DP, DQ, and DR (class II histocompatibility antigens). Numbers (DR3, DR4; A1, A2; B1, B8) are given to distinguish different alleles of any given gene. The designation w (workshop) with numbers is given for provisionally named alleles (DQw8, DQw7) [3]. DM1 has been associated mainly with allelic variants of MHC-DR (DR3/DR4). The MHC locus is a genetic factor of great importance in DM1, and it was first shown in an association study that revealed that about 95% of all patients with DM1 were heterozygous for MHC-DR3/DR4. The majority of type 1 diabetics have the MHC-DR3, MHC-DR4 haplotype, or both [4]. Susceptibility to DM type 1 is associated with these linked DQ alleles that are often in linkage disequilibrium with DR. The closest association in DM1 occurs with the haplotypes DQA1\*0301, DQB1\*0302, DQA1\*501, and DQB1\*0201. It has been shown that the beta DQ chains of those affected have valine, alanine, or serine at position 57; near the peptide-binding gap, presence of aspartic acid is normal [5] Factors involved in the pathophysiology of DM1 are

However, there are exceptions to this association, which indicates that amino acids other than Asp57 at position 57 of the beta chain play an essential but not exclusive role in the susceptibility to DM1 [5]. There is an interaction between

The inheritance of DM1 is unknown. Several hypotheses have been suggested, such as that of dominant inheritance, but it is ruled out by the rarity of DM1 in relatives, children, and descendants. The possibility of recessive inheritance was also

genetic and environmental factors in the development of DM1.

genetic and environmental factors in the development of DM1 (**Figure 1**).

**52**

**Figure 1.**

*Pathogenesis of type 1 diabetes.*

*Pathophysiology of type 1 diabetes.*

considered, however, invalidated because in homozygotes for the DR3 or DR4 alleles, the susceptibility to the disease is not increased. The observation that heterozygosis DR3/DR4 increases the risk for diabetes, compared with that presented by homozygotes from other high-risk alleles, suggests a polygenic way of inheritance. The diabetogenic MHC haplotype is necessary for the susceptibility to DM1, but must be positively or negatively influenced by genes not linked to MHC, such as the gene located close to the repeated DNA sequence minisatellite, in the promoter region of the gene of the insulin (chromosome 11p15); one gene on chromosome 11q and another on chromosome 6q [6]. Some genes seem to confer protection against the development of the disease. For example, the DQA1\*0102 and DQB1\*0602 haplotypes are present in 20% of the United States population but is extremely rare in individuals with DM1 (<1%). This situation indicates that several genes are interacting to determine the DM1 phenotype, so this disease presents genetic heterogeneity (**Figure 4**).

DM1 is uncommon in Chile and usually does not occur in native Chilean families. A study of a family with an affected female child was carried out in a Mapuche community in the Southern (VIII region). This case is a unique and sporadic DM1 case with Mapuche heritage. Genetic analysis by PCR was done

**Figure 4.**

*Interaction of genetic and environmental factors about the immune response in type 1 diabetes.*

to detect class I and II HLA genes by reverse dot blot. The proband, her mother, and sister had positive islet cell antibodies (ICA). Her father and brother were negative. All the family was positive for anti-glutamic decarboxylase antibodies (GAD65). All subjects had HLA-DRB1 0407/0407 and HLA-DQB1 0302/0302 alleles. The index case and her father were homozygotes for the HLA-A1: A\*68012/A\*68012 allele. No evidence of viral infections such as rubella, mumps, or measles was found in this family. All genotypes were compared with the European population, where the diabetogenic combination DR4/DQB1\*0302 is the most prevalent [5]. Finally, despite of the high relative risk of DM1 in subjects with certain MHC class II alleles, it does not develop in the majority of people who inherit these alleles, which also suggests that environmental factors influence development of the disease [1] (**Figure 4**).

#### **2.3 Clinical manifestations of type 1 diabetes**

The onset of DM1 is usually abrupt, with severe symptoms attributable to hyperglycemia maintained for days or weeks, such as polyuria, polydipsia, polyphagia, asthenia, and progressive weight loss, and manifests as diabetic ketoacidosis. Two pathophysiological situations must be present to establish this condition: extreme insulinopenia and increase of counterregulatory hormones, principally glucagon. DM1 is observed mainly in children, adolescents, and young adults, generally under 30 years, although it can also appear in individuals of more advanced ages.

#### **3. Diabetes mellitus type 2**

DM2 has an important genetic component in its pathogenesis. There are multiple genes involved in different metabolic pathways that contribute to the pathogenesis of the disease, in addition to environmental factors such as obesity, an unhealthy diet, and a sedentary lifestyle. These genes have various polymorphisms, which added to post-genomic factors related to their expression and inhibition are responsible for this complex disease, as seen in **Figure 5**.

#### **3.1 Heritage in type 2 diabetes**

The genetic nature of DM2 has been based on high heritability, estimated at 30–70% and high prevalence in some ethnic groups; 39% of patients with DM2 have at least one relative with the disease. There are 1.5–3 times higher risk of presenting

**55**

mined by genetic factors.

**Figure 5.**

*Pathogenesis of type 2 diabetes.*

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases*

DM2 if there is a history of the disease in the family; if the affected one is the mother or the brother, the risk is of 2 and 3 times greater, respectively. The heritability described is mainly in middle-aged people (35–60 years) decreasing markedly in larger groups [6]. First-degree relatives of people with DM2 show early defects in insulin withdrawal and action [7]. If other factors such as obesity and impaired fasting glycemia are added to the family history, the risk of presenting the disease is 16 times higher. The presentation of DM2 involves genes that code for proteins or related enzymes in the process of pancreatic formation, synthesis, sectioning, and insulin action. Genome-wide association studies (GWAS) have shown more than 100 locus susceptible to DM2, most related to insulin sequestration, suggesting that this alteration, essential for the presentation of the disease, is more strongly deter-

The genetic susceptibility given by the presence of risk variants is responsible for about 10% of the family aggregation of the disease. There is a considerable percentage of "missing heritability" that could be explained by: frequent variants of low power, others of low frequency but powerful effect, interaction between gene–gene,

The genetic variants associated with the action of insulin and DM2 are related to the transcription of the intracellular signal of insulin. Due directly to protein mutations of the signaling cascade intracellularly or indirectly due to mutations in genes associated with metabolic syndrome, such as those related to obesity and lipid metabolism. Yaghootkar et al. evolved cluster of 17 genetic variables associated with insulin resistance related to the development of DM2 [8]. Some of the genes that are

Located on chromosome 2, it encodes peptides related to the insulin signaling cascade. Arg972Gly mutation, a common variant of IRS-1, is more prevalent in Caucasian DM2 than in non DM2, and in obese adults, it has been associated with

gene–environment interaction, epigenetic factors, and others.

**3.2 Genetic defects in the action of insulin**

most related to DM2 appear in **Table 1** [9].

*3.2.1 Insulin receptor substrate-1 gene (IRS-1)*

increased insulin resistance.

*DOI: http://dx.doi.org/10.5772/intechopen.89924*

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases DOI: http://dx.doi.org/10.5772/intechopen.89924*

*Cellular Metabolism and Related Disorders*

development of the disease [1] (**Figure 4**).

**2.3 Clinical manifestations of type 1 diabetes**

sible for this complex disease, as seen in **Figure 5**.

to detect class I and II HLA genes by reverse dot blot. The proband, her mother, and sister had positive islet cell antibodies (ICA). Her father and brother were negative. All the family was positive for anti-glutamic decarboxylase antibodies (GAD65). All subjects had HLA-DRB1 0407/0407 and HLA-DQB1 0302/0302 alleles. The index case and her father were homozygotes for the HLA-A1:

*Interaction of genetic and environmental factors about the immune response in type 1 diabetes.*

A\*68012/A\*68012 allele. No evidence of viral infections such as rubella, mumps, or measles was found in this family. All genotypes were compared with the European population, where the diabetogenic combination DR4/DQB1\*0302 is the most prevalent [5]. Finally, despite of the high relative risk of DM1 in subjects with certain MHC class II alleles, it does not develop in the majority of people who inherit these alleles, which also suggests that environmental factors influence

The onset of DM1 is usually abrupt, with severe symptoms attributable to hyperglycemia maintained for days or weeks, such as polyuria, polydipsia, polyphagia, asthenia, and progressive weight loss, and manifests as diabetic ketoacidosis. Two pathophysiological situations must be present to establish this condition: extreme insulinopenia and increase of counterregulatory hormones, principally glucagon. DM1 is observed mainly in children, adolescents, and young adults, generally under 30 years, although it can also appear in individuals of more

DM2 has an important genetic component in its pathogenesis. There are multiple genes involved in different metabolic pathways that contribute to the pathogenesis of the disease, in addition to environmental factors such as obesity, an unhealthy diet, and a sedentary lifestyle. These genes have various polymorphisms, which added to post-genomic factors related to their expression and inhibition are respon-

The genetic nature of DM2 has been based on high heritability, estimated at 30–70% and high prevalence in some ethnic groups; 39% of patients with DM2 have at least one relative with the disease. There are 1.5–3 times higher risk of presenting

**54**

advanced ages.

**Figure 4.**

**3. Diabetes mellitus type 2**

**3.1 Heritage in type 2 diabetes**

DM2 if there is a history of the disease in the family; if the affected one is the mother or the brother, the risk is of 2 and 3 times greater, respectively. The heritability described is mainly in middle-aged people (35–60 years) decreasing markedly in larger groups [6]. First-degree relatives of people with DM2 show early defects in insulin withdrawal and action [7]. If other factors such as obesity and impaired fasting glycemia are added to the family history, the risk of presenting the disease is 16 times higher. The presentation of DM2 involves genes that code for proteins or related enzymes in the process of pancreatic formation, synthesis, sectioning, and insulin action. Genome-wide association studies (GWAS) have shown more than 100 locus susceptible to DM2, most related to insulin sequestration, suggesting that this alteration, essential for the presentation of the disease, is more strongly determined by genetic factors.

The genetic susceptibility given by the presence of risk variants is responsible for about 10% of the family aggregation of the disease. There is a considerable percentage of "missing heritability" that could be explained by: frequent variants of low power, others of low frequency but powerful effect, interaction between gene–gene, gene–environment interaction, epigenetic factors, and others.

#### **3.2 Genetic defects in the action of insulin**

The genetic variants associated with the action of insulin and DM2 are related to the transcription of the intracellular signal of insulin. Due directly to protein mutations of the signaling cascade intracellularly or indirectly due to mutations in genes associated with metabolic syndrome, such as those related to obesity and lipid metabolism. Yaghootkar et al. evolved cluster of 17 genetic variables associated with insulin resistance related to the development of DM2 [8]. Some of the genes that are most related to DM2 appear in **Table 1** [9].

#### *3.2.1 Insulin receptor substrate-1 gene (IRS-1)*

Located on chromosome 2, it encodes peptides related to the insulin signaling cascade. Arg972Gly mutation, a common variant of IRS-1, is more prevalent in Caucasian DM2 than in non DM2, and in obese adults, it has been associated with increased insulin resistance.


**Table 1.** *Candidate genes of DM2 for insulin resistance.*

#### *3.2.2 Peroxisome proliferator-activated receptor gamma 2 gene (PPARG)*

Located on chromosome 3, it codes for the peroxisome proliferator-activated receptor. It has a key role in adipocyte differentiation. The presence of a type of polymorphism is associated with 1.25 odds ratio (OR) for DM2.

#### *3.2.3 Protein tyrosine phosphatase receptor type D gene (PTPRD)*

Located on chromosome 9, it is encoded for PTPRD. Its overexpression in the skeletal muscle generates insulin resistance. Diabetes-related polymorphism has been evidenced in Chinese with an OR 1.57.

#### *3.2.4 β-3 adrenergic receptor gene*

It regulates lipolysis of visceral fat and is related to thermogenesis. It is associated with risk of obesity and early presentation of DM2.

#### *3.2.5 Adiponectin gene*

It is located in chromosome 3q27. Low levels of adiponectin have a role in the pathogenesis of insulin resistance and obesity. Insulinosensitivity is a consistent and independent predictor factor of DM2. Variants in the genes that code for adiponectin receptor have proven to be a risk factor for presenting DM2 in some populations.

#### *3.2.6 Leptin gene*

Mutations related to this gene are involved with the pathogenesis of obesity and glucose metabolism, thereby decreasing insulin sensitivity and inhibiting the expression of the pre-proinsulin gene in the pancreatic β-cells. Recent evidence suggests that high circulating levels of leptin probably independent of adiposity are associated with an increased risk of type 2 diabetes in men.

#### **3.3 Genetic defects in insulin secretion**

There are multiple loci associated with this defect that have been found in GWAS studies. Among them most relevant are those presented in **Table 2** [9].

#### *3.3.1 Calpain 10 gene (CAPN10)*

Encodes a family of calpain enzymes, it was one of the first to study in linkage, but it is currently known that the risk of this association is low OR 1.17 [10].

**57**

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases*

*DOI: http://dx.doi.org/10.5772/intechopen.89924*

• Transcription factor 7-like 2 (TCF7L2) • Potassium voltage gated channel subfamily

*Candidate genes of DM2 for insulin secretion.*

**Insulin secretion genes** • Calpain 10 gene (CAPN10)

• Q member 1 (KCNQ1) • J member 11 (KCNJ11)

**Table 2.**

*3.3.2 Transcription factor 7-like 2 gene (TCF7L2)*

*3.3.3 Potassium voltage-gated channel subfamily*

with decreased insulin sequestration [12].

**3.4 Epigenetics in DM2**

arteriosclerosis, and retinopathy.

matory signaling pathway.

gene expression.

*3.4.1 Methylation and histone-modification*

*3.4.2 Non-coding RNAs (ncRNAs) and chromatin remodeling*

metabolism.

2.5 for homozygous variable [11].

It 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. The increased expression of the gene in the pancreatic beta cell causes secretion alteration due to a decrease in the incretin effect. In liver and adipose tissue, it generates insulin resistance. The risk of DM is consistent with an OR up to

Q member 1 (KCNQ1) located on chromosome 11, it codes for the same name channel present in the cell membrane. There are four variants associated with DM2 in various populations. Studies suggest that the effect linked to DM2 is related to epigenetic modifications. J Member 11 (KCNJ11): code for Kir6.2 ATP-sensitive potassium channel. Variant E23K increases the risk of DM2 by 1.2 times associated

Epigenetics or genetic modifications not associated to nucleotide mutations that influence the expression of a gene play a key role in the pathogenesis and T2DM complications. There are prenatal factors that induce epigenetic changes that increase the risk of T2DM by altering the secretion and sensitivity of insulin, hepatic glucose production, and the release of hormones involved in glucose

The sustained activation of inflammatory-related genes in T2DM patients by epigenetic mechanisms contribute to the progression of vascular complications,

Types of epigenetic modifications and relation to DM2 are shown in **Figure 6**.

These are the epigenetic modifications most associated to vascular complications related to DM2. Both hypomethylations and hypermethylations generate persistent activation of proaterogenic genes such as NF-kB-dependent oxidative and inflam-

Non-coding nRNAs play an essential role in post-transcriptional regulation of


#### **Table 2.**

*Cellular Metabolism and Related Disorders*

• Insulin receptor substrate gene-1 (IRS-1)

• Peroxisome proliferator-activating receptor gene (PPARΎ) • Protein tyrosine phosphatase receptor type D (PTPRD)

**Insulin resistance genes**

• Adiponectin gene • Leptin gene

**Table 1.**

• β-3 adrenergic receptor gene

*Candidate genes of DM2 for insulin resistance.*

*3.2.2 Peroxisome proliferator-activated receptor gamma 2 gene (PPARG)*

polymorphism is associated with 1.25 odds ratio (OR) for DM2.

*3.2.3 Protein tyrosine phosphatase receptor type D gene (PTPRD)*

ated with risk of obesity and early presentation of DM2.

associated with an increased risk of type 2 diabetes in men.

**3.3 Genetic defects in insulin secretion**

*3.3.1 Calpain 10 gene (CAPN10)*

been evidenced in Chinese with an OR 1.57.

*3.2.4 β-3 adrenergic receptor gene*

*3.2.5 Adiponectin gene*

*3.2.6 Leptin gene*

Located on chromosome 3, it codes for the peroxisome proliferator-activated receptor. It has a key role in adipocyte differentiation. The presence of a type of

Located on chromosome 9, it is encoded for PTPRD. Its overexpression in the skeletal muscle generates insulin resistance. Diabetes-related polymorphism has

It regulates lipolysis of visceral fat and is related to thermogenesis. It is associ-

It is located in chromosome 3q27. Low levels of adiponectin have a role in the pathogenesis of insulin resistance and obesity. Insulinosensitivity is a consistent and independent predictor factor of DM2. Variants in the genes that code for adiponectin receptor have proven to be a risk factor for presenting DM2 in some populations.

Mutations related to this gene are involved with the pathogenesis of obesity and glucose metabolism, thereby decreasing insulin sensitivity and inhibiting the expression of the pre-proinsulin gene in the pancreatic β-cells. Recent evidence suggests that high circulating levels of leptin probably independent of adiposity are

There are multiple loci associated with this defect that have been found in GWAS studies. Among them most relevant are those presented in **Table 2** [9].

Encodes a family of calpain enzymes, it was one of the first to study in linkage,

but it is currently known that the risk of this association is low OR 1.17 [10].

**56**

*Candidate genes of DM2 for insulin secretion.*

#### *3.3.2 Transcription factor 7-like 2 gene (TCF7L2)*

It 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. The increased expression of the gene in the pancreatic beta cell causes secretion alteration due to a decrease in the incretin effect. In liver and adipose tissue, it generates insulin resistance. The risk of DM is consistent with an OR up to 2.5 for homozygous variable [11].

#### *3.3.3 Potassium voltage-gated channel subfamily*

Q member 1 (KCNQ1) located on chromosome 11, it codes for the same name channel present in the cell membrane. There are four variants associated with DM2 in various populations. Studies suggest that the effect linked to DM2 is related to epigenetic modifications. J Member 11 (KCNJ11): code for Kir6.2 ATP-sensitive potassium channel. Variant E23K increases the risk of DM2 by 1.2 times associated with decreased insulin sequestration [12].

#### **3.4 Epigenetics in DM2**

Epigenetics or genetic modifications not associated to nucleotide mutations that influence the expression of a gene play a key role in the pathogenesis and T2DM complications. There are prenatal factors that induce epigenetic changes that increase the risk of T2DM by altering the secretion and sensitivity of insulin, hepatic glucose production, and the release of hormones involved in glucose metabolism.

The sustained activation of inflammatory-related genes in T2DM patients by epigenetic mechanisms contribute to the progression of vascular complications, arteriosclerosis, and retinopathy.

Types of epigenetic modifications and relation to DM2 are shown in **Figure 6**.

#### *3.4.1 Methylation and histone-modification*

These are the epigenetic modifications most associated to vascular complications related to DM2. Both hypomethylations and hypermethylations generate persistent activation of proaterogenic genes such as NF-kB-dependent oxidative and inflammatory signaling pathway.

#### *3.4.2 Non-coding RNAs (ncRNAs) and chromatin remodeling*

Non-coding nRNAs play an essential role in post-transcriptional regulation of gene expression.

**Figure 6.**

*DM2 epigenetic factors.*

The most extensively studied are short nucleotide sequences (18–25) called MicroRNA (miRNA) and represent the principal epigenetic regulators of gene expression.

Deregulation in epithelial cells is correlated to the risk of developing vascular complications in DM2.

There are miRNAs associated with inflammation; for example, miR-155, which is associated to the progression of kidney disease in DM2 patients and miR-126, that when inhibited in pre-diabetes patients is correlated with the increase of activation of the NF-kb pathway in endothelial cells.

Long non-coding RNAs (lncRNAs) have been associated with pancreatic B cell damage, increase of inflammatory processes, alterations in the immune response, and insulin resistance in TSDM. Chromatin remodeling that regulates gene expression, such as p66Shc, has been linked with insulin resistance, increase of vascular risk in DM2, and obesity [13].

DM2 is a polygenic disease, of high heritability, which involves genes related to insulin and action, in addition to those that code for the components of the metabolic syndrome. What has been discovered so far is broad but only accounts for a part of the complex relationship of genetics and its phenotypic expression in DM2. The study of epigenetics in DM2 has opened the possibility to find pathogenetic markers at the onset of the disease and during the development of chronic complications, which will allow early screening and individualized treatment in the near future.

#### **4. Monogenic diabetes**

It is caused by one or more defects in a single gene. The disease can be inherited within a family by the genetic transmission of a dominant or recessive nature and not Mendelian. It can also be presented as a spontaneous case due to a de novo mutation [14]. Monogenic diabetes includes neonatal diabetes, maturity onset diabetes young (MODY), and mitochondrial diabetes (**Figure 7**).

#### **4.1 Neonatal diabetes**

It is defined as diabetes that appears before 6 months of age and is subdivided into transitory (TNDM) and permanent (PNDM). TNDM develops in the first weeks of life and resolves within a few months, but 50% have a relapse in adolescence or adulthood. TNDM is most frequently caused by abnormalities

**59**

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases*

in the imprinted region of chromosome 6q24 (spanning two candidate genes PLAGL1 and HYMAI), thereby leading to overexpression of paternally derived genes. Activating mutations in either the KCNJ11 or ABCC8 genes encoding the two subunits (Kir6.2 and SUR1, respectively) of the adenosine triphosphatesensitive potassium channel on the beta-cell membrane prevent insulin secretion in response to hyperglycemia and can cause both PNDM and TNDM. Diabetes caused by mutations in KCNJ11 and ABCC8 often responds to sulfonylureas. Mutations in other genes critical to beta-cell function and regulation, and in the insulin gene itself, also cause PNDM. Heterozygous coding mutations in the preproinsulin gene (INS) are the second common cause of PNDM after KATP channel

Described in 1975 by Tattersall and named in 1976 by Fajans, MODY is recognized as a form of mild-presenting family diabetes that is diagnosed during adolescence or early adulthood. Currently, other types are identified with a less classic presentation [4, 5]. It is estimated that its prevalence is underestimated, and

It is presented in 3.6% of the population with diabetes under 30 years [4]. MODY is a heterogeneous group of disorders caused by mutations in genes essential for beta-cell development, function and regulation, glucose sensing, and in the insulin gene itself. Although at least 14 genes are associated with MODY, we describe the four most frequent types (**Table 3**). Mutations in HNF-1α, HNF-4α, HNF-1β, and GCK genes account for over 80% of all known

Heterozygous mutations in three of them are responsible for the majority of cases of this type of diabetes: glucokinase gene (GCK); two genes encoding hepatocyte nuclear factor (HNF) transcription factors HNF-1α and HNF-4α. Most MODYcausative genes, except GCK, encode transcription factors expressed in pancreatic beta-cells (**Table 4**). The majority of patients with MODY exhibit isolated diabetes or stable mild fasting hyperglycemia, but some MODY subtypes have additional features, such as renal abnormalities (MODY 5) and pancreatic exocrine dysfunc-

GCK, a glucose sensor expressed in pancreatic beta-cells, is a key enzyme in glucose metabolism that catalyzes the conversion of glucose to glucose-6-phosphate and thus controls glucose-mediated insulin secretion. As such, GCK serves to facilitate insulin release that is both appropriate and proportional to the blood glucose concentration. Heterozygous inactivating mutations in GCK (MODY 2) increase the set point for insulin secretion in response to increased blood sugar, thereby causing stable, mild fasting hyperglycemia. More than 600 mutations have been

it would correspond about 5% of DM2 and a similar percentage in DM1.

*DOI: http://dx.doi.org/10.5772/intechopen.89924*

mutations [15, 16].

**4.2 MODY**

**Figure 7.**

*Subtypes of monogenic diabetes.*

MODY cases.

tion (MODY 6) [17–20].

*4.2.1 MODY 2 (GCK)*

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases DOI: http://dx.doi.org/10.5772/intechopen.89924*

#### **Figure 7.**

*Cellular Metabolism and Related Disorders*

expression.

**Figure 6.**

*DM2 epigenetic factors.*

complications in DM2.

risk in DM2, and obesity [13].

**4. Monogenic diabetes**

**4.1 Neonatal diabetes**

of the NF-kb pathway in endothelial cells.

The most extensively studied are short nucleotide sequences (18–25) called MicroRNA (miRNA) and represent the principal epigenetic regulators of gene

Deregulation in epithelial cells is correlated to the risk of developing vascular

There are miRNAs associated with inflammation; for example, miR-155, which is associated to the progression of kidney disease in DM2 patients and miR-126, that when inhibited in pre-diabetes patients is correlated with the increase of activation

Long non-coding RNAs (lncRNAs) have been associated with pancreatic B cell damage, increase of inflammatory processes, alterations in the immune response, and insulin resistance in TSDM. Chromatin remodeling that regulates gene expression, such as p66Shc, has been linked with insulin resistance, increase of vascular

DM2 is a polygenic disease, of high heritability, which involves genes related to insulin and action, in addition to those that code for the components of the metabolic syndrome. What has been discovered so far is broad but only accounts for a part of the complex relationship of genetics and its phenotypic expression in DM2. The study of epigenetics in DM2 has opened the possibility to find pathogenetic markers at the onset of the disease and during the development of chronic complications, which will allow early screening and individualized treatment in the near

It is caused by one or more defects in a single gene. The disease can be inherited within a family by the genetic transmission of a dominant or recessive nature and not Mendelian. It can also be presented as a spontaneous case due to a de novo mutation [14]. Monogenic diabetes includes neonatal diabetes, maturity onset

It is defined as diabetes that appears before 6 months of age and is subdivided into transitory (TNDM) and permanent (PNDM). TNDM develops in the first weeks of life and resolves within a few months, but 50% have a relapse in adolescence or adulthood. TNDM is most frequently caused by abnormalities

diabetes young (MODY), and mitochondrial diabetes (**Figure 7**).

**58**

future.

*Subtypes of monogenic diabetes.*

in the imprinted region of chromosome 6q24 (spanning two candidate genes PLAGL1 and HYMAI), thereby leading to overexpression of paternally derived genes. Activating mutations in either the KCNJ11 or ABCC8 genes encoding the two subunits (Kir6.2 and SUR1, respectively) of the adenosine triphosphatesensitive potassium channel on the beta-cell membrane prevent insulin secretion in response to hyperglycemia and can cause both PNDM and TNDM. Diabetes caused by mutations in KCNJ11 and ABCC8 often responds to sulfonylureas. Mutations in other genes critical to beta-cell function and regulation, and in the insulin gene itself, also cause PNDM. Heterozygous coding mutations in the preproinsulin gene (INS) are the second common cause of PNDM after KATP channel mutations [15, 16].

#### **4.2 MODY**

Described in 1975 by Tattersall and named in 1976 by Fajans, MODY is recognized as a form of mild-presenting family diabetes that is diagnosed during adolescence or early adulthood. Currently, other types are identified with a less classic presentation [4, 5]. It is estimated that its prevalence is underestimated, and it would correspond about 5% of DM2 and a similar percentage in DM1.

It is presented in 3.6% of the population with diabetes under 30 years [4]. MODY is a heterogeneous group of disorders caused by mutations in genes essential for beta-cell development, function and regulation, glucose sensing, and in the insulin gene itself. Although at least 14 genes are associated with MODY, we describe the four most frequent types (**Table 3**). Mutations in HNF-1α, HNF-4α, HNF-1β, and GCK genes account for over 80% of all known MODY cases.

Heterozygous mutations in three of them are responsible for the majority of cases of this type of diabetes: glucokinase gene (GCK); two genes encoding hepatocyte nuclear factor (HNF) transcription factors HNF-1α and HNF-4α. Most MODYcausative genes, except GCK, encode transcription factors expressed in pancreatic beta-cells (**Table 4**). The majority of patients with MODY exhibit isolated diabetes or stable mild fasting hyperglycemia, but some MODY subtypes have additional features, such as renal abnormalities (MODY 5) and pancreatic exocrine dysfunction (MODY 6) [17–20].

#### *4.2.1 MODY 2 (GCK)*

GCK, a glucose sensor expressed in pancreatic beta-cells, is a key enzyme in glucose metabolism that catalyzes the conversion of glucose to glucose-6-phosphate and thus controls glucose-mediated insulin secretion. As such, GCK serves to facilitate insulin release that is both appropriate and proportional to the blood glucose concentration. Heterozygous inactivating mutations in GCK (MODY 2) increase the set point for insulin secretion in response to increased blood sugar, thereby causing stable, mild fasting hyperglycemia. More than 600 mutations have been


#### **Table 3.**

*Frequent types of MODY and its pathophysiological alteration.*


#### **Table 4.**

*Clinical characteristics of most common MODY subtypes.*

reported. Patients with MODY 2 are usually asymptomatic, and they do not require treatment. In pregnancy, insulin may be required to prevent fetal complications, such as high birth weight and neonatal hypoglycemia. These neonatal complications are dependent on whether the mutation is inherited.

In 2018, a MODY family study was published in Chile [21]. The case is about a 17-year-old woman with DM, fasting blood glucose 130 mg/dl, without ketosis or weight loss, and BMI 18 kg/m<sup>2</sup> . No signs of insulin resistance were seen, C-peptide 2.3 ng/ml (normal) and negative DM1 autoantibodies. In a family study, diabetic father and brother with impaired fasting blood glucose (**Figure 8**). The geneticmolecular analysis of the GKC gene, the patient, the father, and the brother presented a mutation at position 1343 of exon 10 corresponding to a heterozygous exchange of guanine for adenine (1343 G > A). The change is not synonymous and determines that at position 448 of the GKC enzyme, the amino acid glycine is substituted by aspartic acid. Diagnosis of MODY 2 was confirmed, and it was established that the mutation was by paternal line.

#### *4.2.2 MODY 3 (HNF-1α)*

The transcription factor HNF-1α is expressed in the liver, kidney, intestine, and pancreatic beta-cells. Heterozygous HNF-1α mutations result in progressive beta-cell dysfunction that leads to diabetes in early adult life.

**61**

in Europe and the US.

**Figure 8.**

*4.2.3 MODY 1 (HNF-4α)*

*Chilean family inheritance pattern MODY 2.*

(apoAII, apoCIII, and apoB).

*4.2.4 MODY 5 (HNF-1β)*

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases*

According to studies, a total of 414 different HNF-1α mutations were identified in 1200 families, where a mutation (P291fsinsC) in exon 4 was the most common. Hyperglycemia associated with MODY 3 may be severe, and the risk of microvascular and macrovascular complications is similar to DM1 and DM2. Because of this, patients require strict glycemic control and close monitoring of possible complications. There is a defect in the renal resorption of glucose, characterized by a decreased glucose threshold for glycosuria and reduced tubular reabsorption of glucose. Patients are sensitive to sulfonylurea therapy, but most of them eventually progress to insulin treatment. This subtype of MODY is the most frequent

This MODY was the first described. The transcription factor HNF-4α is expressed in the liver, kidney, and pancreatic beta-cells. HNF-4α gene encodes a transcription factor important for pancreatic development and beta-cell differentiation and function. Heterozygous HNF-4α mutations cause a similar clinical phenotype observed in MODY 3. Most patients have a progressive insulin deficiency, diabetes onset before age 25 years, and a response to relative low-dose sulfonylurea therapy. Fetal HNF-4α heterozygosity results in macrosomia due to hyperinsulinemia in utero and subsequent neonatal hyperinsulinemic hypoglycemia, which is responsive to diazoxide. MODY 1 is associated with triglyceride metabolism, and mutation carriers may exhibit reduced levels of apoproteins

The transcription factor HNF-1β is involved in the organogenesis of the kidney, genitourinary tract, liver, lungs, gut, and pancreas. Patients with heterozygous

*DOI: http://dx.doi.org/10.5772/intechopen.89924*

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases DOI: http://dx.doi.org/10.5772/intechopen.89924*

#### **Figure 8.**

*Cellular Metabolism and Related Disorders*

**Age at the onset of diabetes (years)**

*Frequent types of MODY and its pathophysiological alteration.*

*GCK, glucokinase; HNF, hepatocyte nuclear factor.*

1 17 (5–18) High Neonatal diabetes,

2 10 (0–18) Mild Mild fasting long-term

3 |4 (4–18) High Glycosuria—very low

5 <25 Variable Renal malformations, genital

**MODY subtypes**

**Table 3.**

**Table 4.**

reported. Patients with MODY 2 are usually asymptomatic, and they do not require treatment. In pregnancy, insulin may be required to prevent fetal complications, such as high birth weight and neonatal hypoglycemia. These neonatal complications

In 2018, a MODY family study was published in Chile [21]. The case is about a 17-year-old woman with DM, fasting blood glucose 130 mg/dl, without ketosis or

2.3 ng/ml (normal) and negative DM1 autoantibodies. In a family study, diabetic father and brother with impaired fasting blood glucose (**Figure 8**). The geneticmolecular analysis of the GKC gene, the patient, the father, and the brother presented a mutation at position 1343 of exon 10 corresponding to a heterozygous exchange of guanine for adenine (1343 G > A). The change is not synonymous and determines that at position 448 of the GKC enzyme, the amino acid glycine is substituted by aspartic acid. Diagnosis of MODY 2 was confirmed, and it was

The transcription factor HNF-1α is expressed in the liver, kidney, intestine, and pancreatic beta-cells. Heterozygous HNF-1α mutations result in progressive beta-cell dysfunction that leads to diabetes in early adult life.

. No signs of insulin resistance were seen, C-peptide

**Hyperglycemia Other clinical features Possible treatment**

**Gene Frequency % Physiopathology**

**MODY 2** GCK 15–20 Glucose sensing defect **MODY 3** HNF-1α 30–50 Insulin secretion deficit **MODY 1** HNF-4α 5 Insulin secretion deficit **MODY 5** HNF-1β 5 Beta cell dysfunction

> neonatal hyperinsulinemic hypoglycemia, low triglycerides

stability asymptomatic

C-reactive protein of <0.5 mg/ dl

anomalies, pancreatic hypoplasia, low birth weight

Sensitive to sulphonylureas

Diet no medication

Sensitive to sulphonylureas

Insulin

are dependent on whether the mutation is inherited.

*Clinical characteristics of most common MODY subtypes.*

established that the mutation was by paternal line.

weight loss, and BMI 18 kg/m<sup>2</sup>

*4.2.2 MODY 3 (HNF-1α)*

**60**

*Chilean family inheritance pattern MODY 2.*

According to studies, a total of 414 different HNF-1α mutations were identified in 1200 families, where a mutation (P291fsinsC) in exon 4 was the most common. Hyperglycemia associated with MODY 3 may be severe, and the risk of microvascular and macrovascular complications is similar to DM1 and DM2. Because of this, patients require strict glycemic control and close monitoring of possible complications. There is a defect in the renal resorption of glucose, characterized by a decreased glucose threshold for glycosuria and reduced tubular reabsorption of glucose. Patients are sensitive to sulfonylurea therapy, but most of them eventually progress to insulin treatment. This subtype of MODY is the most frequent in Europe and the US.

#### *4.2.3 MODY 1 (HNF-4α)*

This MODY was the first described. The transcription factor HNF-4α is expressed in the liver, kidney, and pancreatic beta-cells. HNF-4α gene encodes a transcription factor important for pancreatic development and beta-cell differentiation and function. Heterozygous HNF-4α mutations cause a similar clinical phenotype observed in MODY 3. Most patients have a progressive insulin deficiency, diabetes onset before age 25 years, and a response to relative low-dose sulfonylurea therapy. Fetal HNF-4α heterozygosity results in macrosomia due to hyperinsulinemia in utero and subsequent neonatal hyperinsulinemic hypoglycemia, which is responsive to diazoxide. MODY 1 is associated with triglyceride metabolism, and mutation carriers may exhibit reduced levels of apoproteins (apoAII, apoCIII, and apoB).

#### *4.2.4 MODY 5 (HNF-1β)*

The transcription factor HNF-1β is involved in the organogenesis of the kidney, genitourinary tract, liver, lungs, gut, and pancreas. Patients with heterozygous

mutations in HNF-1β rarely present with isolated diabetes. By contrast, patients usually have renal disorders (especially renal cyst and renal dysplasia). Urogenital tract abnormalities and atrophy of pancreas may also occur. The sensitivity to sulphonylureas is absent, and early insulin therapy is required. At least 50% of HNF-1β MODY cases are due to microdeletion of chromosome 17 (17q12) involving between 15 and 29 genes, including HNF1β. De novo mutations are frequent (up to 50% of cases) and hence family may be absent.

#### **4.3 Mitochondrial diabetes**

This disease is a mitochondrial disorder characterized by maternally transmitted diabetes and sensorineural deafness. The most common form is caused by an exchange between an adenine for guanine (3243A/G) in DNA. This mutation also causes a severe neuromuscular disease syndrome called MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke). Diabetes onset is usually insidious, but 20% of patients have an acute presentation, even in diabetic ketoacidosis. It usually occurs in the third to fourth decades of life in non-obese individuals [14].

#### **5. Diagnostic algorithm of diabetes in young adult**

**Figure 9** shows a diagnostic algorithm for diabetes in patients under 30 years of age.

**63**

diagnosis [25].

**6.1 Epidemiology**

which keep the debate open.

clinical suspicion should be high.

**6.2 Pathophysiology**

*6.2.1 Genetics*

with LADA [31].

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases*

Diabetes is a complex disease, which makes its classification difficult. DM1 is caused by autoimmune destruction of the beta cell, which leads to absolute insulin deficiency. DM2 is secondary to the progressive loss of insulin secretion by the beta cell, in the context of insulin resistance. Other types of diabetes are gestational diabetes, MODY, post-transplant, and exocrine, among others [22]. DM1 is a heterogeneous disease, the incidence of which is higher in children and adolescents, characterized by the presence of specific immunological markers. However, no less than a percentage of adults experience the disease; so, the term latent adult diabetes (LADA) has been coined. In this case, the disease is even more heterogeneous, since there is a variable proportion of destruction of the beta cell, with the presence of immunological markers, but zero or deficient initial insulin requirements, so they can initially be misclassified as DM2 [23]. These patients probably have pathophysiological processes similar to DM1, but with differences in genetic penetrance and immune factors. The term LADA was introduced in the 90s, to define a subgroup of patients with diabetes initially not requiring insulin, but with immunological markers of DM1 detectable in the serum [24]. In 2015, the Immunology of Diabetes Society proposed three diagnostic criteria for LADA: age of onset>30 years, presence of any DM1 marker antibody, and lack of need for insulin treatment for at least 6 months from

Currently, the American Association of Diabetes (ADA) does not recognize this entity, but instead classifies it within the group of patients with DM1, but every day there is more information about its clinical and pathophysiological characteristics,

The available data show that the prevalence of LADA is higher than previously recognized. About 40% of cases of DM1 occur in adults over 30 years [26]. Scandinavian studies show that 7.5–10% of the population with apparent DM2 have circulating antibodies against the beta cell (ICA or GAD 65) [27]. The Action LADA study, conducted in Europe, which evaluated 6000 adults attended in primary and secondary care centers, reported a frequency of 9.7% of LADA [28]. A Chinese study, LADA China study reported a 5.9% positive antibody in adults previously diagnosed with DM2 [29]. The prevalence of LADA is, therefore generally underestimated, due to the lack of study with antibodies in adult patients; so, the level of

In genotype analysis, patients with LADA have been shown to share genetic characteristics with DM1 (HLA, INS VNTR, CTLA4, and PTPN22) and DM2 (TCF7L2) [30], which might suggest that LADA is a spectrum of insulin deficiency between DM1 and DM2. The HLA-DRB1\*04-DQB1\*0302 and HLA-DRB1\*0301DQB1\*0201 haplotypes, which confer high susceptibility to DM1, and decrease progressively with increasing age, have been further diminished in elderly DM1 patients and have been described less frequently even in patients

**6. LADA: Latent autoimmune diabetes adult**

*DOI: http://dx.doi.org/10.5772/intechopen.89924*

#### **Figure 9.**

*Diagnostic algorithm of diabetes in young adult.*

#### **6. LADA: Latent autoimmune diabetes adult**

Diabetes is a complex disease, which makes its classification difficult. DM1 is caused by autoimmune destruction of the beta cell, which leads to absolute insulin deficiency. DM2 is secondary to the progressive loss of insulin secretion by the beta cell, in the context of insulin resistance. Other types of diabetes are gestational diabetes, MODY, post-transplant, and exocrine, among others [22]. DM1 is a heterogeneous disease, the incidence of which is higher in children and adolescents, characterized by the presence of specific immunological markers. However, no less than a percentage of adults experience the disease; so, the term latent adult diabetes (LADA) has been coined. In this case, the disease is even more heterogeneous, since there is a variable proportion of destruction of the beta cell, with the presence of immunological markers, but zero or deficient initial insulin requirements, so they can initially be misclassified as DM2 [23]. These patients probably have pathophysiological processes similar to DM1, but with differences in genetic penetrance and immune factors. The term LADA was introduced in the 90s, to define a subgroup of patients with diabetes initially not requiring insulin, but with immunological markers of DM1 detectable in the serum [24]. In 2015, the Immunology of Diabetes Society proposed three diagnostic criteria for LADA: age of onset>30 years, presence of any DM1 marker antibody, and lack of need for insulin treatment for at least 6 months from diagnosis [25].

Currently, the American Association of Diabetes (ADA) does not recognize this entity, but instead classifies it within the group of patients with DM1, but every day there is more information about its clinical and pathophysiological characteristics, which keep the debate open.

#### **6.1 Epidemiology**

*Cellular Metabolism and Related Disorders*

cases) and hence family may be absent.

**5. Diagnostic algorithm of diabetes in young adult**

**Figure 9** shows a diagnostic algorithm for diabetes in patients under

**4.3 Mitochondrial diabetes**

individuals [14].

30 years of age.

mutations in HNF-1β rarely present with isolated diabetes. By contrast, patients usually have renal disorders (especially renal cyst and renal dysplasia). Urogenital tract abnormalities and atrophy of pancreas may also occur. The sensitivity to sulphonylureas is absent, and early insulin therapy is required. At least 50% of HNF-1β MODY cases are due to microdeletion of chromosome 17 (17q12) involving between 15 and 29 genes, including HNF1β. De novo mutations are frequent (up to 50% of

This disease is a mitochondrial disorder characterized by maternally transmitted diabetes and sensorineural deafness. The most common form is caused by an exchange between an adenine for guanine (3243A/G) in DNA. This mutation also causes a severe neuromuscular disease syndrome called MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke). Diabetes onset is usually insidious, but 20% of patients have an acute presentation, even in diabetic ketoacidosis. It usually occurs in the third to fourth decades of life in non-obese

**62**

**Figure 9.**

*Diagnostic algorithm of diabetes in young adult.*

The available data show that the prevalence of LADA is higher than previously recognized. About 40% of cases of DM1 occur in adults over 30 years [26]. Scandinavian studies show that 7.5–10% of the population with apparent DM2 have circulating antibodies against the beta cell (ICA or GAD 65) [27]. The Action LADA study, conducted in Europe, which evaluated 6000 adults attended in primary and secondary care centers, reported a frequency of 9.7% of LADA [28]. A Chinese study, LADA China study reported a 5.9% positive antibody in adults previously diagnosed with DM2 [29]. The prevalence of LADA is, therefore generally underestimated, due to the lack of study with antibodies in adult patients; so, the level of clinical suspicion should be high.

#### **6.2 Pathophysiology**

#### *6.2.1 Genetics*

In genotype analysis, patients with LADA have been shown to share genetic characteristics with DM1 (HLA, INS VNTR, CTLA4, and PTPN22) and DM2 (TCF7L2) [30], which might suggest that LADA is a spectrum of insulin deficiency between DM1 and DM2. The HLA-DRB1\*04-DQB1\*0302 and HLA-DRB1\*0301DQB1\*0201 haplotypes, which confer high susceptibility to DM1, and decrease progressively with increasing age, have been further diminished in elderly DM1 patients and have been described less frequently even in patients with LADA [31].

#### **6.3 Autoimmunity**

DM1 is a known autoimmune disease, mediated by cells. The presence of T lymphocytes that are reactive to islet cells, in LADA, gives us some evidence that there is a cell-mediated immune response as well [32]. Adult autoimmune diabetes has a "lower genetic load," characterized by lower circulating antibodies than early-onset DM1 in childhood or adolescence, which correlates with less intense beta cell destruction and lower HLA genetic susceptibility. Many studies have compared circulating antibodies in early DM1 in childhood with LADA, finding ICA, AAI, IA-2, and anti ZnT8 more frequently in children than in adults, while anti GAD and IA-2 were found with similar frequency in both ages [33]. Anti-GAD is the antibody most frequently found in patients with LADA, up to 90% positive, also being the most persistent over time. The beta cell function in early DM1 in childhood and adolescence is severely compromised since diagnosis, a difference in LADA in that the deficit is less severe. It has also been found that there is a correlation between age of diagnosis and fasting C-peptide levels, which is related to the latest age of LADA. To explain the later and less aggressive presentation compared to DM1, several theories are postulated, among others: intermittent crisis of autoimmune aggression (**Figure 10**) or greater capacity to regenerate beta cells and protection against the apoptotic process.

#### **6.4 Clinical characteristics**

Patients with LADA are a heterogeneous group, with antibody titers and body mass index (BMI). In general, the appearance of the condition is 35 years later, with cases described since the age of 25. Patients with LADA tend to have a BMI higher than DM1, but less than DM2. The existence of other autoimmune comorbidity or their family history is common, mainly thyroid disease. A higher frequency of antiperoxidase antibodies (TPO) has been seen, in up to 27% of patients, compared to those with anti-GAD negative, which makes it necessary to monitor thyroid function and perform screening for other autoimmune diseases. The initial response to oral therapy is satisfactory, progressing in varying degrees to insulin requirements, from 6 months to several years, depending mainly on antibody titers (**Table 5**).

#### **Figure 10.**

*The destruction of beta cell and the appearance of DM1 according to the age of onset and the putative pathogenetic mechanisms.*

**65**

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases*

adolescence rare adulthood

Insulin resistance No modifications Increased or

Body mass index Low or normal Normal or

**Clinical features DM1 LADA DM2**

Start Acute Rare acute Slow

Ketosis Frequently Rare Rare

Autoimmunity Greatly increased Increased No modifications

Beta cell function Very reduced Reduced Increased or unchanged

From the diagnostic >6 months from

MHC susceptibility Severely increased Increased No changes

without changes

the diagnostic

overweight

>30 years Adulthood, rare childhood,

and adolescence

Severely increased

Years from the diagnostic

Overweight or obesity

High titers of anti-GAD compared to low ones, have lower BMI, less endogenous insulin secretion, and faster progression to insulin-dependence. The presence of anti-GAD antibodies (or ICA) may be useful to identify patients with a previous diagnosis of DM2, who respond partially to treatment with oral antidiabetics and who quickly require insulin therapy. Regarding the metabolic profile, patients with LADA have advantages regarding DM2 with a better profile, that is, lower triglyceride levels, higher levels of HDL, lower BMI, and lower waist circumference. There are no specific guidelines for the treatment of patients with LADA. However, the metabolic goals are the same as for DM1 and DM2 patients, so you should try to achieve HbA1c <7%. The diet and exercise recommendations do not show differences with the classic presentations. Despite the extensive use of oral antidiabetics in DM2, especially metformin, there are no studies of this drug in patients with LADA. Glibenclamide and insulin were compared in LADA patients, finding that the group that used GBC had worse metabolic control and faster deterioration of CP secretion at a follow-up of 30 months. Therefore, the use of sulfonylureas as a firstline drug in this type of diabetes is not recommended. TZD combined with insulin show preservation of beta cell function in a small group of Chinese patients. The use of other agents such as insulin sensitizers could be used in combination with insulin in patients who share characteristics with DM2, that is, BMI >30 kg/m<sup>2</sup>

signs of insulin resistance. The role of the iDPP4 is not established. Patients with LADA treated with insulin glargine, the effect of adding sitagliptin or placebo was compared, the group with sitagliptin had a minimal decrease in C-peptide at oneyear follow-up, compared to placebo. However, more studies support this evidence.

Today, evidence indicates that early insulin therapy, along with changes in lifestyle, is the therapy of choice in patients with LADA when metabolic control is impaired primarily in young patients with elevated antibody titers since this treatment slows the deterioration of beta cell function, controls hyperglycemia, and prevents glucotoxicity [34]. TZD combined with insulin shows preservation of beta cell function in a small group of Chinese patients. The use of other agents such as insulin sensitizers could be used in combination with insulin in patients who share

We should keep in mind, like DM1 and DM2, patients.

and

*DOI: http://dx.doi.org/10.5772/intechopen.89924*

Age at diagnosis Childhood and

Insulin requirements

*Adapted to [35].*

*LADA, DM1, and DM2 clinical features.*

**Table 5.**

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases DOI: http://dx.doi.org/10.5772/intechopen.89924*


#### **Table 5.**

*Cellular Metabolism and Related Disorders*

DM1 is a known autoimmune disease, mediated by cells. The presence of T lymphocytes that are reactive to islet cells, in LADA, gives us some evidence that there is a cell-mediated immune response as well [32]. Adult autoimmune diabetes has a "lower genetic load," characterized by lower circulating antibodies than early-onset DM1 in childhood or adolescence, which correlates with less intense beta cell destruction and lower HLA genetic susceptibility. Many studies have compared circulating antibodies in early DM1 in childhood with LADA, finding ICA, AAI, IA-2, and anti ZnT8 more frequently in children than in adults, while anti GAD and IA-2 were found with similar frequency in both ages [33]. Anti-GAD is the antibody most frequently found in patients with LADA, up to 90% positive, also being the most persistent over time. The beta cell function in early DM1 in childhood and adolescence is severely compromised since diagnosis, a difference in LADA in that the deficit is less severe. It has also been found that there is a correlation between age of diagnosis and fasting C-peptide levels, which is related to the latest age of LADA. To explain the later and less aggressive presentation compared to DM1, several theories are postulated, among others: intermittent crisis of autoimmune aggression (**Figure 10**) or greater capacity

to regenerate beta cells and protection against the apoptotic process.

Patients with LADA are a heterogeneous group, with antibody titers and body mass index (BMI). In general, the appearance of the condition is 35 years later, with cases described since the age of 25. Patients with LADA tend to have a BMI higher than DM1, but less than DM2. The existence of other autoimmune comorbidity or their family history is common, mainly thyroid disease. A higher frequency of antiperoxidase antibodies (TPO) has been seen, in up to 27% of patients, compared to those with anti-GAD negative, which makes it necessary to monitor thyroid function and perform screening for other autoimmune diseases. The initial response to oral therapy is satisfactory, progressing in varying degrees to insulin requirements, from 6 months to several years, depending mainly on antibody titers (**Table 5**).

*The destruction of beta cell and the appearance of DM1 according to the age of onset and the putative* 

**6.3 Autoimmunity**

**6.4 Clinical characteristics**

**64**

**Figure 10.**

*pathogenetic mechanisms.*

*LADA, DM1, and DM2 clinical features.*

High titers of anti-GAD compared to low ones, have lower BMI, less endogenous insulin secretion, and faster progression to insulin-dependence. The presence of anti-GAD antibodies (or ICA) may be useful to identify patients with a previous diagnosis of DM2, who respond partially to treatment with oral antidiabetics and who quickly require insulin therapy. Regarding the metabolic profile, patients with LADA have advantages regarding DM2 with a better profile, that is, lower triglyceride levels, higher levels of HDL, lower BMI, and lower waist circumference. There are no specific guidelines for the treatment of patients with LADA. However, the metabolic goals are the same as for DM1 and DM2 patients, so you should try to achieve HbA1c <7%. The diet and exercise recommendations do not show differences with the classic presentations. Despite the extensive use of oral antidiabetics in DM2, especially metformin, there are no studies of this drug in patients with LADA. Glibenclamide and insulin were compared in LADA patients, finding that the group that used GBC had worse metabolic control and faster deterioration of CP secretion at a follow-up of 30 months. Therefore, the use of sulfonylureas as a firstline drug in this type of diabetes is not recommended. TZD combined with insulin show preservation of beta cell function in a small group of Chinese patients. The use of other agents such as insulin sensitizers could be used in combination with insulin in patients who share characteristics with DM2, that is, BMI >30 kg/m<sup>2</sup> and signs of insulin resistance. The role of the iDPP4 is not established. Patients with LADA treated with insulin glargine, the effect of adding sitagliptin or placebo was compared, the group with sitagliptin had a minimal decrease in C-peptide at oneyear follow-up, compared to placebo. However, more studies support this evidence. We should keep in mind, like DM1 and DM2, patients.

Today, evidence indicates that early insulin therapy, along with changes in lifestyle, is the therapy of choice in patients with LADA when metabolic control is impaired primarily in young patients with elevated antibody titers since this treatment slows the deterioration of beta cell function, controls hyperglycemia, and prevents glucotoxicity [34]. TZD combined with insulin shows preservation of beta cell function in a small group of Chinese patients. The use of other agents such as insulin sensitizers could be used in combination with insulin in patients who share

characteristics with DM2, that is, BMI >30 kg/m<sup>2</sup> and signs of insulin resistance. The role of the iDPP4 is not established. Patients with LADA treated with insulin glargine, the effect of adding sitagliptin or placebo was compared, the group with sitagliptin had a minimal decrease in C-peptide at one-year follow-up, compared to placebo. However, more studies support this evidence. We should keep in mind, like DM1 and DM2, patients with LADA require a multidisciplinary approach to proper treatment.

#### **6.5 Clinical features of DM1, LADA, and DM2**

This Table summarizes major clinical features of DM1, LADA, and DM2.

#### **Acknowledgements**

Special thanks to Miss Macarena Darby for her contribution in the translation of the chapter.

### **Author details**

Lilian Sanhueza1,2\*, Pilar Durruty3,4, Cecilia Vargas4 , Paulina Vignolo5,6 and Karina Elgueta1,7

1 Diabetes Unit, Internal Medicine Service, San Juan de Dios Hospital, Santiago, Chile

2 Department of Medicine, Faculty of Medical Sciences, University of Santiago of Chile, Santiago, Chile

3 Diabetes Unit, Department of Medicine, Faculty of Medicine, San Juan de Dios Hospital, University of Chile, Santiago, Chile

4 Endocrinonology and Diabetes Section, Department of Medicine, Faculty of Medicine, Clinical Hospital University of Chile, Santiago, Chile

5 Diabetes Unit, Department of Internal Medicine, Padre Hurtado Hospital, Santiago, Chile

6 Faculty of Medicine, Development University, Santiago, Chile

7 Adult Diabetes Unit, Department of Internal Medicine Las Condes Clinic, Santiago, Chile

\*Address all correspondence to: lilianllay@yahoo.es

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**67**

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases*

In: García de los Ríos M, Durruty P, editors. Diabetes Mellitus. Santiago, Chile: Ed Mediterráneo; 2003. pp. 42-55

[10] Weedon MN, Schwarz PE, Horikawa Y, et al. Meta-analysis and a large association study confirm a role for calpain-10 variation in type 2 diabetes susceptibility. American Journal of Human Genetics. 2003;**73**:1208-1212

[11] Sale MM, Smith SG,

2007;**56**(10):2638-2642

Mychaleckyj JC, et al. Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African–American population enriched for nephropathy. Diabetes.

[12] Gloyn AL, Weedon MN, Owen KR, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir62 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23 K variant is associated with type 2 diabetes. Diabetes. 2003;**52**(2):568-572

[13] Coco C, Sgarra L, et al. Can epigenetics of endothelial dysfunction

represent the key to precision medicine in type 2 diabetes mellitus? International Journal of Molecular

[14] Hattersley AT, Greeley SAW, Polak M, et al. ISPAD clinical practice consensus guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatric Diabetes.

Sciences. 2019;**20**:2949

2018;**19**(Suppl. 27):47-63

[15] Timsit J, Saint-Martin C, Dubois-Laforgue D, Bellanné-Chantelot C.Searching for maturityonset diabetes of the young (MODY): When and what for? Canadian Journal

of Diabetes. 2016;**40**:455-461

[16] Kim SH. Maturity-onset diabetes of the young: What do clinicians need

*DOI: http://dx.doi.org/10.5772/intechopen.89924*

[1] Durruty P, Pérez-Bravo F. Patogénesis de la diabetes mellitus. García de los Ríos M y Durruty P. Diabetes Mellitus. Santiago, Chile. Ed Mediterráneo 2014:

[2] Salas F, Santos J, Pérez-Bravo F. Genética de la diabetes mellitus tipo 1. Revista Chilena de Endocrinología y

[3] Paschou S, Papadopoulou-Marketou N, Chrousos G et al. On type 1 diabetes mellitus pathogenesis. Endocrine Connections. 2018;**7**:R38-R-46

[4] Thompson M, Mclnnes R, Willard H. Genética en Medicina, Thompson & Thompson. 4th Edición ed. Barcelona, España: Editorial Masson; 1996.

Pérez-Bravo F. Marcadores genéticos (HLA) y perfil de auto-anticuerpos en una familia mapuche con un caso de diabetes tipo 1. Revista Médica de Chile.

[6] Lyssenko V, Jonsson A, Almgren P, et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. The New England Journal of Medicine.

[7] Lyssenko V, Almgren P, Anevski D, et al. Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes. 2005;**54**(1):166-174

White CC, et al. Genetic evidence for a normal-weight metabolically obese phenotype linking insulin resistance, hypertension, coronary artery

disease, and type 2 diabetes. Diabetes.

Etiopatogenia de la diabetes mellitus.

Diabetes. 2013;**6**(1):15-22

25-39

**References**

pp. 345-349

2004;**132**:47-50

[5] Asenjo S, Gleisner A,

2008;**359**(21):2220-2232

[8] Yaghootkar H, Scott RA,

2014;**63**(12):4369-4377

[9] Durruty P, Pérez-Bravo F.

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases DOI: http://dx.doi.org/10.5772/intechopen.89924*

#### **References**

*Cellular Metabolism and Related Disorders*

characteristics with DM2, that is, BMI >30 kg/m<sup>2</sup>

**6.5 Clinical features of DM1, LADA, and DM2**

**Author details**

the chapter.

**Acknowledgements**

treatment.

Karina Elgueta1,7

Chile, Santiago, Chile

Santiago, Chile

Santiago, Chile

Chile

Lilian Sanhueza1,2\*, Pilar Durruty3,4, Cecilia Vargas4

Hospital, University of Chile, Santiago, Chile

1 Diabetes Unit, Internal Medicine Service, San Juan de Dios Hospital, Santiago,

The role of the iDPP4 is not established. Patients with LADA treated with insulin glargine, the effect of adding sitagliptin or placebo was compared, the group with sitagliptin had a minimal decrease in C-peptide at one-year follow-up, compared to placebo. However, more studies support this evidence. We should keep in mind, like DM1 and DM2, patients with LADA require a multidisciplinary approach to proper

This Table summarizes major clinical features of DM1, LADA, and DM2.

Special thanks to Miss Macarena Darby for her contribution in the translation of

2 Department of Medicine, Faculty of Medical Sciences, University of Santiago of

3 Diabetes Unit, Department of Medicine, Faculty of Medicine, San Juan de Dios

4 Endocrinonology and Diabetes Section, Department of Medicine, Faculty of

5 Diabetes Unit, Department of Internal Medicine, Padre Hurtado Hospital,

7 Adult Diabetes Unit, Department of Internal Medicine Las Condes Clinic,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Medicine, Clinical Hospital University of Chile, Santiago, Chile

6 Faculty of Medicine, Development University, Santiago, Chile

\*Address all correspondence to: lilianllay@yahoo.es

provided the original work is properly cited.

, Paulina Vignolo5,6 and

and signs of insulin resistance.

**66**

[1] Durruty P, Pérez-Bravo F. Patogénesis de la diabetes mellitus. García de los Ríos M y Durruty P. Diabetes Mellitus. Santiago, Chile. Ed Mediterráneo 2014: 25-39

[2] Salas F, Santos J, Pérez-Bravo F. Genética de la diabetes mellitus tipo 1. Revista Chilena de Endocrinología y Diabetes. 2013;**6**(1):15-22

[3] Paschou S, Papadopoulou-Marketou N, Chrousos G et al. On type 1 diabetes mellitus pathogenesis. Endocrine Connections. 2018;**7**:R38-R-46

[4] Thompson M, Mclnnes R, Willard H. Genética en Medicina, Thompson & Thompson. 4th Edición ed. Barcelona, España: Editorial Masson; 1996. pp. 345-349

[5] Asenjo S, Gleisner A,

Pérez-Bravo F. Marcadores genéticos (HLA) y perfil de auto-anticuerpos en una familia mapuche con un caso de diabetes tipo 1. Revista Médica de Chile. 2004;**132**:47-50

[6] Lyssenko V, Jonsson A, Almgren P, et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. The New England Journal of Medicine. 2008;**359**(21):2220-2232

[7] Lyssenko V, Almgren P, Anevski D, et al. Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes. 2005;**54**(1):166-174

[8] Yaghootkar H, Scott RA, White CC, et al. Genetic evidence for a normal-weight metabolically obese phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes. Diabetes. 2014;**63**(12):4369-4377

[9] Durruty P, Pérez-Bravo F. Etiopatogenia de la diabetes mellitus. In: García de los Ríos M, Durruty P, editors. Diabetes Mellitus. Santiago, Chile: Ed Mediterráneo; 2003. pp. 42-55

[10] Weedon MN, Schwarz PE, Horikawa Y, et al. Meta-analysis and a large association study confirm a role for calpain-10 variation in type 2 diabetes susceptibility. American Journal of Human Genetics. 2003;**73**:1208-1212

[11] Sale MM, Smith SG, Mychaleckyj JC, et al. Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African–American population enriched for nephropathy. Diabetes. 2007;**56**(10):2638-2642

[12] Gloyn AL, Weedon MN, Owen KR, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir62 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23 K variant is associated with type 2 diabetes. Diabetes. 2003;**52**(2):568-572

[13] Coco C, Sgarra L, et al. Can epigenetics of endothelial dysfunction represent the key to precision medicine in type 2 diabetes mellitus? International Journal of Molecular Sciences. 2019;**20**:2949

[14] Hattersley AT, Greeley SAW, Polak M, et al. ISPAD clinical practice consensus guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatric Diabetes. 2018;**19**(Suppl. 27):47-63

[15] Timsit J, Saint-Martin C, Dubois-Laforgue D, Bellanné-Chantelot C.Searching for maturityonset diabetes of the young (MODY): When and what for? Canadian Journal of Diabetes. 2016;**40**:455-461

[16] Kim SH. Maturity-onset diabetes of the young: What do clinicians need to know? Diabetes and Metabolism Journal. 2015;**39**(6):468-477

[17] Shields BM, Shepherd M, Hudson M, et al. Population-based assessment of a biomarker-based screening pathway to aid diagnosis of monogenic diabetes in youngonset patients. Diabetes Care. 2017;**40**(8):1017-1025

[18] Thomas CC, Philipson LH. Update on diabetes classification. The Medical Clinics of North America. 2015;**99**(1):1-16

[19] Urakami T. Maturity-onset diabetes of the young (MODY): Current perspectives on diagnosis and treatment. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2019;**12**:1047-1056

[20] McDonald TJ, Ellard S. Maturity onset diabetes of the young: Identification and diagnosis. Annals of Clinical Biochemistry. 2013;**50**:403-415

[21] Estica M, Selenfreund D, Durruty P, Briones G. Hallazgo de una nueva mutación en una familia chilena con diabetes monogénica. Caso Clínico. Revista Médica de Chile. 2018;**146**:929-932

[22] Classification and diagnosis of diabetes. Standards of medical care in diabetes 2019. Diabetes Care. 2019;**42**(suppl 1):S13-S28

[23] Hernandez M, Mollo A, Marsal JP, et al. Insulin secretion in patients with latent autoimmune diabetes (LADA): Half way between type 1 and type 2 diabetes: Action LADA 9. BMC Endocrine Disorders. 2015;**15**:1-6

[24] Tuomi T, Groop LC, Zimmet P, et al. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a noninsulin dependent onset of disease. Diabetes. 1993;**42**:359-362

[25] Fourlanos S, Dotta F, Greenbaum CJ, et al. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia. 2005;**48**:2206-2212

[26] Mølbak AG, Christau B, Marner B, Borch-Johnsen K, Nerup J. Incidence of insulin- dependent diabetes mellitus in age groups over 30 years in Denmark. Diabetic Medicine. 1994;**11**:650-655

[27] Landin-Olsson M, Nilsson KO, Lernmark A, Sundkvist G. Islet cell antibodies and fasting C-peptide predict insulin requirement at diagnosis of diabetes mellitus. Diabetologia. 1990;**33**(9):561-568

[28] Hawa MI, Kolb H, Schloot N, et al. Adult onset autoinmune diabetes in Europe is prevalent with broad clinical phenotype: Action LADA 7. Diabetes Care. 2013;**36**:908-913

[29] Zhou Z, Xiang Y, Ji L, et al. Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): A nationwide, multicenter, clinic-based cross-sectional study. Diabetes. 2013;**62**:543-550

[30] Cervin C, Lyssenko V, Bakhtadze E, Lindholm E, Nilsson P, Tuomi T, et al. Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes. 2008;**57**:1433-1437

[31] Leslie RD, Delli Castelli M. Agedependent influences on the origins of autoimmune diabetes: Evidence and implications. Diabetes. 2004;**53**:3033-3040

[32] Brooks-Worrell BM, Juneja R, Minokadeh A, Greenbaum CJ, Palmer JP. Cellular immune responses to human islet proteins in antibobypositive type 2 diabetic patients. Diabetes. 1999;**48**:983-988

**69**

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases*

*DOI: http://dx.doi.org/10.5772/intechopen.89924*

[33] Lampasona V, Petrone A, Tiberti C, Capizzi M, Spoletini M, Di PS, et al. Zinc transporter 8 antibodies complement GAD and IA–2 antibodies in the identification and characterization of adultonset autoimmune diabetes: Non insulin requiring autoimmune diabetes (NIRAD). Diabetes Care.

[34] Zhou Z, Li X, Huang G, et al. Rosiglitazone combines with insulin preserves islet beta cell function in adult- onset latent autoimmune diabetes. (LADA). Diabetes/Metabolism Research and Reviews. 2005;**21**:203-208

[35] de Buzzeti R et al. Nature Reviews.

2010;**33**:104-108

2017;**13**:674-686

*Diabetes Mellitus: A Group of Genetic-Based Metabolic Diseases DOI: http://dx.doi.org/10.5772/intechopen.89924*

[33] Lampasona V, Petrone A, Tiberti C, Capizzi M, Spoletini M, Di PS, et al. Zinc transporter 8 antibodies complement GAD and IA–2 antibodies in the identification and characterization of adultonset autoimmune diabetes: Non insulin requiring autoimmune diabetes (NIRAD). Diabetes Care. 2010;**33**:104-108

*Cellular Metabolism and Related Disorders*

to know? Diabetes and Metabolism Journal. 2015;**39**(6):468-477

[25] Fourlanos S, Dotta F, Greenbaum CJ, et al. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia. 2005;**48**:2206-2212

[26] Mølbak AG, Christau B, Marner B, Borch-Johnsen K, Nerup J. Incidence of insulin- dependent diabetes mellitus in age groups over 30 years in Denmark. Diabetic Medicine. 1994;**11**:650-655

[27] Landin-Olsson M, Nilsson KO, Lernmark A, Sundkvist G. Islet cell antibodies and fasting C-peptide predict insulin requirement at diagnosis of diabetes mellitus. Diabetologia.

[28] Hawa MI, Kolb H, Schloot N, et al. Adult onset autoinmune diabetes in Europe is prevalent with broad clinical phenotype: Action LADA 7. Diabetes

1990;**33**(9):561-568

Care. 2013;**36**:908-913

2013;**62**:543-550

2008;**57**:1433-1437

2004;**53**:3033-3040

[29] Zhou Z, Xiang Y, Ji L, et al. Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): A nationwide, multicenter, clinic-based cross-sectional study. Diabetes.

[30] Cervin C, Lyssenko V, Bakhtadze E, Lindholm E, Nilsson P, Tuomi T, et al. Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes.

[31] Leslie RD, Delli Castelli M. Agedependent influences on the origins of autoimmune diabetes: Evidence and implications. Diabetes.

[32] Brooks-Worrell BM, Juneja R, Minokadeh A, Greenbaum CJ,

Palmer JP. Cellular immune responses to human islet proteins in antibobypositive type 2 diabetic patients. Diabetes. 1999;**48**:983-988

[18] Thomas CC, Philipson LH. Update

on diabetes classification. The Medical Clinics of North America.

[19] Urakami T. Maturity-onset diabetes of the young (MODY): Current perspectives on diagnosis and treatment. Diabetes, Metabolic Syndrome and Obesity: Targets and

Therapy. 2019;**12**:1047-1056

onset diabetes of the young:

[21] Estica M, Selenfreund D, Durruty P, Briones G. Hallazgo de una nueva mutación en una familia chilena con diabetes monogénica. Caso Clínico. Revista Médica de Chile.

[22] Classification and diagnosis of diabetes. Standards of medical care in diabetes 2019. Diabetes Care. 2019;**42**(suppl 1):S13-S28

[23] Hernandez M, Mollo A, Marsal JP, et al. Insulin secretion in patients with latent autoimmune diabetes (LADA): Half way between type 1 and type 2 diabetes: Action LADA 9. BMC Endocrine Disorders. 2015;**15**:1-6

[24] Tuomi T, Groop LC, Zimmet P, et al. Antibodies to glutamic acid

Diabetes. 1993;**42**:359-362

decarboxylase reveal latent autoimmune diabetes mellitus in adults with a noninsulin dependent onset of disease.

2018;**146**:929-932

[20] McDonald TJ, Ellard S. Maturity

Identification and diagnosis. Annals of Clinical Biochemistry. 2013;**50**:403-415

[17] Shields BM, Shepherd M, Hudson M, et al. Population-based assessment of a biomarker-based screening pathway to aid diagnosis of monogenic diabetes in youngonset patients. Diabetes Care.

2017;**40**(8):1017-1025

2015;**99**(1):1-16

**68**

[34] Zhou Z, Li X, Huang G, et al. Rosiglitazone combines with insulin preserves islet beta cell function in adult- onset latent autoimmune diabetes. (LADA). Diabetes/Metabolism Research and Reviews. 2005;**21**:203-208

[35] de Buzzeti R et al. Nature Reviews. 2017;**13**:674-686

**Chapter 5**

**Abstract**

*Gaffar S. Zaman*

Pathogenesis of Insulin Resistance

*Insulin resistance*is interpreted as being a normal or raised insulin level giving rise to a biological reaction which is attenuated in effect; classically this cites to the weakened sensitivity to the disposal of insulin arbitrate glucose. *Compensatory hyperinsulinemia* eventuates when the secretion of the β cells of pancreas gets elevated to sustain the level of blood glucose in normal levels. The term *insulin resistance syndrome*is used to refer to a group of abnormalities and interconnected physical consequences that eventuate in long-standing insulin-resistant persons. Under standard situations of insulin reactivity, the response of insulin triggers the intake of glucose into the body cells, for utilization as energy, and impedes the utilization of fat for energy, as a result of which, the concentration of glucose circulating in the blood decreases. There are a number of risk factors for insulin resistance. Four major metabolic abnormalities characterize type 2 diabetes mellitus (T2DM): impaired insulin action, obesity, increased endogenous glucose output, and insulin secretory dysfunction. The evolution (and subsequent progression) of type 2 diabetes mellitus is delineated by a gradual deterioration of glucose tolerance over several years. Glucose tolerance testing, hyperinsulinemic euglycemic clamp, modified insulin suppression test, homeostatic model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI) method for insulin assessment are some of the methods by which insulin resistance can be measured. Moreover, longer-term effective researches as well are essential to preferably ascertain the significance of the glycemic index in the blood glucose regulation and to prevent the complications of diabetes, particularly in relations to insulin resistance risk factors. The possible role of insulin resistance in the glycemic index in depleting oxidative stress postprandially and related

pro-inflammatory situations also merits further appraisal.

type 2 diabetes mellitus, obesity

**1. Introduction**

**71**

**Keywords:** insulin resistance, compensatory hyperinsulinemia,

One of the most renowned hormones of our body is insulin which enables glucose to go inside the cells which additionally decreases blood glucose. The hormone insulin is secreted by the pancreas in response to glucose entering the bloodstream after a meal. Insulin resistance (IR) is contemplated as a pathological situation in which our body cells decline to react normally to insulin hormone [1]. To avert hyperglycemia and apparent damage to our body organs in the future [2], insulin production by the body starts when glucose enters into the bloodstream, predominantly from the dietary carbohydrate digestion and absorption. Under

#### **Chapter 5**

## Pathogenesis of Insulin Resistance

*Gaffar S. Zaman*

#### **Abstract**

*Insulin resistance*is interpreted as being a normal or raised insulin level giving rise to a biological reaction which is attenuated in effect; classically this cites to the weakened sensitivity to the disposal of insulin arbitrate glucose. *Compensatory hyperinsulinemia* eventuates when the secretion of the β cells of pancreas gets elevated to sustain the level of blood glucose in normal levels. The term *insulin resistance syndrome*is used to refer to a group of abnormalities and interconnected physical consequences that eventuate in long-standing insulin-resistant persons. Under standard situations of insulin reactivity, the response of insulin triggers the intake of glucose into the body cells, for utilization as energy, and impedes the utilization of fat for energy, as a result of which, the concentration of glucose circulating in the blood decreases. There are a number of risk factors for insulin resistance. Four major metabolic abnormalities characterize type 2 diabetes mellitus (T2DM): impaired insulin action, obesity, increased endogenous glucose output, and insulin secretory dysfunction. The evolution (and subsequent progression) of type 2 diabetes mellitus is delineated by a gradual deterioration of glucose tolerance over several years. Glucose tolerance testing, hyperinsulinemic euglycemic clamp, modified insulin suppression test, homeostatic model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI) method for insulin assessment are some of the methods by which insulin resistance can be measured. Moreover, longer-term effective researches as well are essential to preferably ascertain the significance of the glycemic index in the blood glucose regulation and to prevent the complications of diabetes, particularly in relations to insulin resistance risk factors. The possible role of insulin resistance in the glycemic index in depleting oxidative stress postprandially and related pro-inflammatory situations also merits further appraisal.

**Keywords:** insulin resistance, compensatory hyperinsulinemia, type 2 diabetes mellitus, obesity

#### **1. Introduction**

One of the most renowned hormones of our body is insulin which enables glucose to go inside the cells which additionally decreases blood glucose. The hormone insulin is secreted by the pancreas in response to glucose entering the bloodstream after a meal. Insulin resistance (IR) is contemplated as a pathological situation in which our body cells decline to react normally to insulin hormone [1]. To avert hyperglycemia and apparent damage to our body organs in the future [2], insulin production by the body starts when glucose enters into the bloodstream, predominantly from the dietary carbohydrate digestion and absorption. Under

standard situations of insulin reactivity, the response of insulin triggers the intake of glucose into the body cells, for utilization as energy, and impedes the utilization of fat for energy, as a result of which, the concentration of glucose circulating in the blood decreases, which results in glucose remaining within the normal range in case of consumption of a substantial amount of carbohydrates. Carbohydrates contains sugars, i.e., from only one glucose containing monosaccharides, such as fructose and glucose; two glucose containing disaccharides, like cane sugar; and many glucose containing polysaccharides (e.g., starches) and glycoprotein, glycolipids, etc. Fructose, ultimately metabolized into triglycerides inside the liver, stimulates the production of insulin and is seen to have a more impressive sequel than other carbohydrates. A customarily increased intake of carbohydrates, and specifically fructose, imparts to insulin resistance and has been connected to gain of weight and obesity [3–5]. If surplus blood glucose is not adequately transported into the cells even in the insulin's presence, the augmented level of blood glucose can elicit in the classic hyperglycemic triad of polydipsia (increased thirst), polyphagia (increased appetite), and polyuria (increased urination). Circumventing carbohydrates, a zero-carbohydrate diet or conditions of fasting can counteract insulin resistance [6, 7]. The first narration of insulin resistance is found historically in the 1960s, soon after the invention of radioimmunoassays helped in making serum insulin quantification possible and subsequently revealed that people having late-onset diabetes mellitus had high levels of insulin [8, 9]. Drs. Yalow and Berson [8, 9] defined insulin resistance as "a state in which a greater than normal amount of insulin is required to elicit a quantitatively normal response." The next milestone discovery in this context was the detection and ascertaining of the insulin receptor and also the discovery that insulin resistance led to hyperinsulinemia and the fact that this was interconnected very much with atypical/unconventional binding of insulin hormone with its receptor in various rodent models [10, 11]. The succeeding milestone discovery in the history of insulin resistance came with the pioneering recognition of the receptor for insulin and the observation that high insulin in blood, secondary to the insulin resistance, was interconnected with atypical binding of insulin hormone to its receptor [10, 11]. It was not before the year 1976 when the evidence came that defects in receptor for insulin could be interlinked with resistance to the insulin hormone in humans, provided genetic translational verification for the significance of insulin resistance [10]. Researchers like Kahn et al. [10] delineated two syndromes that were distinguished by virilization, acanthosis nigricans, hirsutism, anovulation, acne, and flawed binding of insulin on the insulin receptor of lymphocytes circulating in the blood. This initial syndrome was designated as type A insulin resistance when it took place without the existence of antiinsulin antibodies and the corresponding accountability of the insulin receptor was the main factor, and in contrast it was designated as the type B when it occurred with the clinical characteristics of various autoimmune ailments and it always occurred when neutralizing anti-insulin antibodies were present [10]. After this specification of type A and type B syndrome, all rare and extreme levels of insulin resistance like acanthosis nigricans syndrome, hyperandrogenism, the Rabson-Mendenhall syndrome, lipodystrophy, and leprechaunism were discovered [12, 13]. To defend the idea by Himsworth that some cases of diabetes were not secondary to absolute insulin deficiency, it was imperative to prove the truth that insulin circulating in the blood was present in the insensitive form in those patients as classified by Himsworth. This was put to rest with the publication by Yalow and Berson in 1960 of an immunoassay research of endogenous blood insulin in humans. During this novel innovative work, Berson and Yalow delineated an excellent immunological technique for measuring the amount of insulin that integrated the degree of specificity with sensitivity required to take the measurement of even the smallest

concentrations of insulin contained in the body circulation. Utilizing this novel technique to categorize immunoreactive insulin amounts present in plasma in normal people to those particular patients having maturity-onset type diabetes, it was conceived that the amounts of insulin were on the average elevated in the patients with diabetes. Putting stress on the rationale of these particular outcomes, both of them summarized that the tissues of a person with maturity-onset diabetes do not have a good response to the level of insulin; on the contrary, the tissues of a nondiabetic person respond very well to his level of insulin. In the words or terminology of Himsworth, patients with this character in diabetes can be considered as "insulin insensitive." In spite of the fact these results of the novel publication by Yalow and Berson were afterwards authenticated by various research groups, it became evident that the interconnection between insulin concentrations and plasma glucose in patients having type 2 diabetes was not such a simple one. To be precise, in a person with comparatively slight increments of fasting plasma glucose concentration, the responses of plasma insulin to oral glucose were equivalent or prominently higher than the normal but with elevated proportions of glucose intolerance and with the appearance of noteworthy hyperglycemia during fasting [14–17]. It was obligatory to evolve an exploratory perspective that would quantify in an unequivocal way the capability of an individual person to get rid of fixed glucose load under the influence

A number of risk factors are found for insulin resistance, together with being overweight or obese or pursuing a sedentary lifestyle [19]. Numerous genetic constituents can elevate the chances for the same, and there are some particular med-

The National Institute of Diabetes and Digestive and Kidney Diseases has spec-

2.Native Alaskan, Asian American, American Indian, African American, Native

3.Having abnormal health states such as increased systolic/diastolic pressure and

6. In addition, some medications and other health conditions can raise the risk [19].

Individuals who have hereditary factors or lifestyle-related factors are bound to have

in their later life insulin resistance or prediabetes [20]. Hazard factors incorporate:

of identical insulin stimuli during steady-state conditions [18].

ical circumstances correlated with insulin resistance [19].

Hawaiian, or Latino/Hispanic ethnicity.

5.Having a history stroke or heart disease [19].

**2.1 Types of people more likely to develop insulin resistance**

increased levels of cholesterol.

• Overweight or obesity.

• Age 45 or more.

**73**

4.Having gestational diabetes history.

**2. Risk factors for insulin resistance**

ified several hazard factors:

*Pathogenesis of Insulin Resistance*

*DOI: http://dx.doi.org/10.5772/intechopen.92864*

1.Age of 45 or more.

#### *Pathogenesis of Insulin Resistance DOI: http://dx.doi.org/10.5772/intechopen.92864*

standard situations of insulin reactivity, the response of insulin triggers the intake of glucose into the body cells, for utilization as energy, and impedes the utilization of fat for energy, as a result of which, the concentration of glucose circulating in the blood decreases, which results in glucose remaining within the normal range in case of consumption of a substantial amount of carbohydrates. Carbohydrates contains sugars, i.e., from only one glucose containing monosaccharides, such as fructose and glucose; two glucose containing disaccharides, like cane sugar; and many glucose containing polysaccharides (e.g., starches) and glycoprotein, glycolipids, etc. Fructose, ultimately metabolized into triglycerides inside the liver, stimulates the production of insulin and is seen to have a more impressive sequel than other carbohydrates. A customarily increased intake of carbohydrates, and specifically fructose, imparts to insulin resistance and has been connected to gain of weight and obesity [3–5]. If surplus blood glucose is not adequately transported into the cells even in the insulin's presence, the augmented level of blood glucose can elicit in the classic hyperglycemic triad of polydipsia (increased thirst), polyphagia (increased appetite), and polyuria (increased urination). Circumventing carbohydrates, a zero-carbohydrate diet or conditions of fasting can counteract insulin resistance [6, 7]. The first narration of insulin resistance is found historically in the 1960s, soon after the invention of radioimmunoassays helped in making serum insulin quantification possible and subsequently revealed that people having late-onset diabetes mellitus had high levels of insulin [8, 9]. Drs. Yalow and Berson [8, 9] defined insulin resistance as "a state in which a greater than normal amount of insulin is required to elicit a quantitatively normal response." The next milestone discovery in this context was the detection and ascertaining of the insulin receptor and also the discovery that insulin resistance led to hyperinsulinemia and the fact that this was interconnected very much with atypical/unconventional binding of insulin hormone with its receptor in various rodent models [10, 11]. The succeeding milestone discovery in the history of insulin resistance came with the pioneering recognition of the receptor for insulin and the observation that high insulin in blood, secondary to the insulin resistance, was interconnected with atypical binding of insulin hormone to its receptor [10, 11]. It was not before the year 1976 when the evidence came that defects in receptor for insulin could be interlinked with resistance to the insulin hormone in humans, provided genetic translational verification for the significance of insulin resistance [10]. Researchers like Kahn et al. [10] delineated two syndromes that were distinguished by virilization, acanthosis nigricans, hirsutism, anovulation, acne, and flawed binding of insulin on the insulin receptor of lymphocytes circulating in the blood. This initial syndrome was designated as type A insulin resistance when it took place without the existence of antiinsulin antibodies and the corresponding accountability of the insulin receptor was the main factor, and in contrast it was designated as the type B when it occurred with the clinical characteristics of various autoimmune ailments and it always occurred when neutralizing anti-insulin antibodies were present [10]. After this specification of type A and type B syndrome, all rare and extreme levels of insulin resistance like acanthosis nigricans syndrome, hyperandrogenism, the Rabson-Mendenhall syndrome, lipodystrophy, and leprechaunism were discovered [12, 13]. To defend the idea by Himsworth that some cases of diabetes were not secondary to absolute insulin deficiency, it was imperative to prove the truth that insulin circulating in the blood was present in the insensitive form in those patients as classified by Himsworth. This was put to rest with the publication by Yalow and Berson in 1960 of an immunoassay research of endogenous blood insulin in humans. During this novel innovative work, Berson and Yalow delineated an excellent immunological technique for measuring the amount of insulin that integrated the degree of specificity with sensitivity required to take the measurement of even the smallest

*Cellular Metabolism and Related Disorders*

**72**

concentrations of insulin contained in the body circulation. Utilizing this novel technique to categorize immunoreactive insulin amounts present in plasma in normal people to those particular patients having maturity-onset type diabetes, it was conceived that the amounts of insulin were on the average elevated in the patients with diabetes. Putting stress on the rationale of these particular outcomes, both of them summarized that the tissues of a person with maturity-onset diabetes do not have a good response to the level of insulin; on the contrary, the tissues of a nondiabetic person respond very well to his level of insulin. In the words or terminology of Himsworth, patients with this character in diabetes can be considered as "insulin insensitive." In spite of the fact these results of the novel publication by Yalow and Berson were afterwards authenticated by various research groups, it became evident that the interconnection between insulin concentrations and plasma glucose in patients having type 2 diabetes was not such a simple one. To be precise, in a person with comparatively slight increments of fasting plasma glucose concentration, the responses of plasma insulin to oral glucose were equivalent or prominently higher than the normal but with elevated proportions of glucose intolerance and with the appearance of noteworthy hyperglycemia during fasting [14–17]. It was obligatory to evolve an exploratory perspective that would quantify in an unequivocal way the capability of an individual person to get rid of fixed glucose load under the influence of identical insulin stimuli during steady-state conditions [18].

### **2. Risk factors for insulin resistance**

A number of risk factors are found for insulin resistance, together with being overweight or obese or pursuing a sedentary lifestyle [19]. Numerous genetic constituents can elevate the chances for the same, and there are some particular medical circumstances correlated with insulin resistance [19].

The National Institute of Diabetes and Digestive and Kidney Diseases has specified several hazard factors:


#### **2.1 Types of people more likely to develop insulin resistance**

Individuals who have hereditary factors or lifestyle-related factors are bound to have in their later life insulin resistance or prediabetes [20]. Hazard factors incorporate:


well as taking into consideration where we disperse fat in our body and how

It is a well-known fact that genes help control and regulate every metabolic activity in the body, and mutations, in genes, which have influence in the digestion and absorption process can cause problem with controlling blood glucose level. To date scientists have distinguished more than 60 genes related with type 2 diabetes

Corticosteroids treat mainly inflammatory disorders, as rheumatoid joint inflammation, lupus, and hypersensitivities. Normal steroids incorporate hydrocortisone and prednisone. Be that as it may, steroid creams (for a rash) or inhalers (for

Medications that treat nervousness, attention deficit hyperactivity disorder (ADHD), sorrow, and other emotional well-being issues can incorporate clozapine,

• Medications that treat hypertension, for example, beta-blockers and thiazide

• High doses of asthma medications or medications that you infuse for asthma

• A few meds that treat *human immunodeficiency virus* (HIV) and hepatitis

• Pseudoephedrine, a decongestant in some cold and influenza prescriptions

Alongside these hazard factors, different things that may add to insulin

• Antihypertensive agents such as β-blockers, diuretics, oral contraceptives, corticosteroids, nicotinic acid, and antipsychotic agents are said to increase insulin resistance [22, 23]; in addition, many anti-retroviral protease inhibitors utilized to treat human immunodeficiency virus infection also cause insulin resistance. The mechanisms of actions vary: β-blockers impede the secretion of insulin from the pancreas by blocking the β-adrenoceptors, depletion of the blood levels of potassium is the main action of thiazide diuretics, counterregulatory hormonal activity is the main action of oral contraceptives and corticosteroids, and loss of peripheral subcutaneous fat with partial

efficiently our muscles allow glucose to enter from the blood.

mellitus (T2DM).

*Pathogenesis of Insulin Resistance*

*DOI: http://dx.doi.org/10.5772/intechopen.92864*

**2.4 Medication**

asthma) aren't an issue.

• Contraception pills

diuretics

treatment

olanzapine, risperidone, and quetiapine:

• Statins to bring down cholesterol

• Isotretinoin for skin breakout

• Niacin or vitamin B3

resistance incorporate:

**75**

• Adrenaline for serious hypersensitive responses

• Tacrolimus, which you get after an organ transplant


In spite of the fact that you cannot change hazard factors, for example, family ancestry, age, or ethnicity, you can change lifestyle factors such as eating, physical activity, and weight. These ways of life changes can bring down your odds of creating insulin resistance or prediabetes [21].

There are a number of other hazard factors that are firmly connected to insulin resistance; however, these factors are yet to give clear answers about how much these variables might be a reason for the same.

The variables include:


#### **2.2 Diet**

The food that we take are regularly seen as a conspicuous reason for diabetes and frequently supposed as a reason.

Many studies have shown that our diet can have an effect in type 2 diabetes; however, it is one factor among numerous others, and speculations ought not be drawn without the thought of other contributing variables.

#### **2.3 Contributions of genetics**

Research has revealed various factors, which are related with an elevated danger of diabetes. There are various elements which can impact our plasma glucose, as

#### *Pathogenesis of Insulin Resistance DOI: http://dx.doi.org/10.5772/intechopen.92864*

well as taking into consideration where we disperse fat in our body and how efficiently our muscles allow glucose to enter from the blood.

It is a well-known fact that genes help control and regulate every metabolic activity in the body, and mutations, in genes, which have influence in the digestion and absorption process can cause problem with controlling blood glucose level. To date scientists have distinguished more than 60 genes related with type 2 diabetes mellitus (T2DM).

#### **2.4 Medication**

• Having a parent, sibling, or sister with diabetes.

• Physical idleness.

• A history of gestational diabetes.

*Cellular Metabolism and Related Disorders*

• A history of coronary illness or stroke.

• Sleep issues, particularly rest apnea.

creating insulin resistance or prediabetes [21].

these variables might be a reason for the same.

• Having hypertension or hypercholesterolemia

• Having a nearby relative with type 2 diabetes

• Having potential to develop type 2 diabetes

drawn without the thought of other contributing variables.

• History of gestational diabetes

frequently supposed as a reason.

**2.3 Contributions of genetics**

The variables include:

• Abundance of fat

**2.2 Diet**

**74**

• Polycystic ovary disorder, also known as PCOS.

• African American, Alaskan Native, American Indian, Asian American, Hispanic/Latino, Native Hawaiian, or Pacific Islander American ethnicity.

• Health conditions, for example, hypertension and high cholesterol levels.

• Individuals who have metabolic disorder—hypertension, irregular cholesterol

In spite of the fact that you cannot change hazard factors, for example, family ancestry, age, or ethnicity, you can change lifestyle factors such as eating, physical activity, and weight. These ways of life changes can bring down your odds of

There are a number of other hazard factors that are firmly connected to insulin resistance; however, these factors are yet to give clear answers about how much

The food that we take are regularly seen as a conspicuous reason for diabetes and

Research has revealed various factors, which are related with an elevated danger of diabetes. There are various elements which can impact our plasma glucose, as

Many studies have shown that our diet can have an effect in type 2 diabetes; however, it is one factor among numerous others, and speculations ought not be

levels, and enormous waist size—are bound to have prediabetes.

• Hormonal imbalances, for example, Cushing's disorder and acromegaly.

Corticosteroids treat mainly inflammatory disorders, as rheumatoid joint inflammation, lupus, and hypersensitivities. Normal steroids incorporate hydrocortisone and prednisone. Be that as it may, steroid creams (for a rash) or inhalers (for asthma) aren't an issue.

Medications that treat nervousness, attention deficit hyperactivity disorder (ADHD), sorrow, and other emotional well-being issues can incorporate clozapine, olanzapine, risperidone, and quetiapine:


Alongside these hazard factors, different things that may add to insulin resistance incorporate:

• Antihypertensive agents such as β-blockers, diuretics, oral contraceptives, corticosteroids, nicotinic acid, and antipsychotic agents are said to increase insulin resistance [22, 23]; in addition, many anti-retroviral protease inhibitors utilized to treat human immunodeficiency virus infection also cause insulin resistance. The mechanisms of actions vary: β-blockers impede the secretion of insulin from the pancreas by blocking the β-adrenoceptors, depletion of the blood levels of potassium is the main action of thiazide diuretics, counterregulatory hormonal activity is the main action of oral contraceptives and corticosteroids, and loss of peripheral subcutaneous fat with partial

lipodystrophy (with resultant accumulation of truncal adipose tissue) is the main action of HIV-1 protease inhibitors. All these ultimately lead to insulin resistance [24].

inactive people, triglycerides themselves have been disassociated from insulin resistance, recommending that other lipids (e.g., diacylglycerols, ceramides, and so on) intervene insulin resistance [73]. Various investigations have depicted the interrelationship insulin resistance in muscles and between diacylglycerol (DAG) content. Insulin-animated tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and IRS-1-related phospho-inositide 3-kinase (PI3K) actuation were intensely debilitated in skeletal muscle of lipid-injected people [74] and rodents [75, 76]. In rodents, lipids and high-fat intake bring about transient increments in muscle DAG content [75], bringing about continued appearance of protein kinase C-theta (PKCθ) that constrained phosphorylation of IRS-1 by insulin receptor substrate 1 (IRTK). Lipid mixtures in normal human volunteers correspondingly elevated skeletal muscle DAG [77, 78] and caused muscle insulin resistance. The improvement of muscle insulin resistance can prompt metabolic ailment. This has been seen in hereditary mouse models of particular muscle insulin resistance [79], which are inclined to hepatic steatosis [75] and increased adiposity [77]. In young, lean, and people with skeletal muscle insulin resistance, ingested glucose is not taken up by muscle and gets occupied to the liver, where it becomes substrate for liver once more by lipogenesis, increasing liver triglyceride; furthermore, plasma triglyceride increase results in decreasing plasma high-density lipoprotein (HDL) levels [80]. Nonalcoholic fatty liver disease (NAFLD) is unequivocally connected with hepatic insulin resistance. In patients with lipodystrophy, ectopic lipid accumulation in the liver and skeletal muscle was related with extreme hepatic and muscle insulin resistance [81]. Leptin treatment diminished the consumption of calorie, settled hepatic steatosis, and improved insulin activity [82]. Lipodystrophic mice have a comparable phenotype, and fat transplantation protected these mice by permitting redistribution of lipids from ectopic destinations to transplanted fat tissue and standardization of insulin activity [83]. Mice overexpressing lipoprotein lipase in the liver cause hepatic steatosis and liver-explicit insulin resistance [84]. In rodents and mice, high-fat eating regimens lead to hepatic steatosis and hepatic insulin resistance. In this way, these considerations show that

*Pathogenesis of Insulin Resistance*

*DOI: http://dx.doi.org/10.5772/intechopen.92864*

ectopic lipid in the liver is explicitly related with hepatic insulin resistance.

insulin action.

**77**

Magkos et al. showed that hepatic DAG content (not hepatic ceramide content) was the best indicator of hepatic insulin resistance in obese people [85]. There are a few conditions wherein hepatic steatosis shows up disassociated from hepatic insulin resistance. A typical single-nucleotide polymorphism (rs738409, I48M) in the lipid bead protein-like phospholipase domain-containing protein 3 [patatin-like phospholipase domain-containing A3 gene (PNPLA3), likewise called adiponutrin (ADPN)] has been related with expanded hepatic steatosis, but not insulin resistance [86–88]. Along these lines, occasions of obvious disassociation of hepatic steatosis and hepatic insulin opposition might be clarified by a superior comprehension of the subcellular conveyance of DAG [89]. Ceramides are additionally bioactive lipid particles that are embroiled in the advancement of insulin resistance. Increments in hepatic and muscle ceramide content have been related with insulin resistance in rodents, and inhibitors of ceramide blend can forestall insulin resistance [90, 91]. In any case, a disassociation between ceramide substance and tissue insulin resistance has been revealed in numerous investigations [85, 92, 93], and the fundamental component connecting ceramides to insulin resistance has not been completely finalized. As of late, some investigations analyzed how a particular ceramide species, C16:0, resists mitochondrial oxidation, permitting triglyceride to accumulate and cause insulin resistance [94, 95]. Despite the fact it has not been concluded, it is conceivable that the equal relationship between C16:0 ceramide and mitochondrial oxidation could additionally cause increments DAG and impede

#### **2.5 Lifestyle factors**

Many hormones can instigate insulin resistance, prominent among them being human placental lactogen, growth hormone, and cortisol [25]. Counteraction of insulin is done by cortisol and can cause elevated hepatic gluconeogenesis, decreasing peripheral use of glucose and elevating insulin resistance [26]. Cortisol does this by diminishing the translocation of glucose transporters (especially GLUT4) to the respective cell membrane [27, 28]. This is based on the noteworthy augmentation in the sensitivity of insulin in humans after doing bariatric surgery and surgical removal of the duodenum in rats [29]; it has been speculated that some substance is manufactured in the mucosa of duodenum, which gives a signal to the body cells to become insulin resistant. With removal of the producing tissue, cessation of the signal occurs, and reverting back of the body cells to normal insulin sensitivity is seen. No such particular substance has been discovered as yet, and the certainty of such a substance remains speculative. Leptin is a hormone derived from the adipocytes and ob gene [30] whose role is the regulation of hunger by forewarning the body when it is full [31]. Researches have depicted that dearth of leptin leads to severe obesity and is intensely associated with insulin resistance [32].

#### **3. Pathogenesis**

Four major metabolic abnormalities characterize type 2 diabetes mellitus: impaired insulin action, obesity, increased endogenous glucose output, and insulin secretory dysfunction [33–35]. In spite of the fact that there is considerable authentication that three of these idiosyncrasies exist in most people before the commencement of diabetes, the concatenation with which they evolve and their corresponding contributions to the advancement from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), and ultimately to type 2 diabetes [36–38], cannot be confirmed for sure even though some detailed longitudinal studies have provided some information [39–44]. Contemporaneous comprehension of the pathogenesis of type 2 diabetes is established on a wide-reaching number of cross-sectional [45–57] and prospective [58–72] studies. The evolution (and subsequent progress) of type 2 diabetes mellitus is delineated by a gradual degeneration of glucose tolerance over several years [33–38]. Prospective and cross-sectional data demonstrate that defects in insulin secretion, body weight gain, insulin action, and an elevation in endogenous glucose output are cardinal in this decline [45–56]. The pathogenetic history of diabetes—the corporeal chain of events with which these metabolic aberrations evolve in relation to one another throughout the various stages of the illness—remains unrevealed. Many authors have suggested that a flaw in insulin activity is the principal aberration in the premature stages of the evolution of type 2 diabetes and that secretory dysfunction of insulin takes place only at a later stage.

#### **3.1 Molecular mechanism of insulin resistance in the muscle**

Cellular contents of lipids inside myocytes (of muscles) are referred to as intramyocellular lipid (IMCL) and basically reflect intramyocellular triglyceride content. Although IMCL emphatically relates with muscle insulin resistance in

#### *Pathogenesis of Insulin Resistance DOI: http://dx.doi.org/10.5772/intechopen.92864*

lipodystrophy (with resultant accumulation of truncal adipose tissue) is the main action of HIV-1 protease inhibitors. All these ultimately lead to insulin

Many hormones can instigate insulin resistance, prominent among them being human placental lactogen, growth hormone, and cortisol [25]. Counteraction of insulin is done by cortisol and can cause elevated hepatic gluconeogenesis, decreasing peripheral use of glucose and elevating insulin resistance [26]. Cortisol does this by diminishing the translocation of glucose transporters (especially GLUT4) to the respective cell membrane [27, 28]. This is based on the noteworthy augmentation in the sensitivity of insulin in humans after doing bariatric surgery and surgical removal of the duodenum in rats [29]; it has been speculated that some substance is manufactured in the mucosa of duodenum, which gives a signal to the body cells to become insulin resistant. With removal of the producing tissue, cessation of the signal occurs, and reverting back of the body cells to normal insulin sensitivity is seen. No such particular substance has been discovered as yet, and the certainty of such a substance remains speculative. Leptin is a hormone derived from the adipocytes and ob gene [30] whose role is the regulation of hunger by forewarning the body when it is full [31]. Researches have depicted that dearth of leptin leads to

severe obesity and is intensely associated with insulin resistance [32].

**3.1 Molecular mechanism of insulin resistance in the muscle**

Cellular contents of lipids inside myocytes (of muscles) are referred to as intramyocellular lipid (IMCL) and basically reflect intramyocellular triglyceride content. Although IMCL emphatically relates with muscle insulin resistance in

Four major metabolic abnormalities characterize type 2 diabetes mellitus: impaired insulin action, obesity, increased endogenous glucose output, and insulin secretory dysfunction [33–35]. In spite of the fact that there is considerable authentication that three of these idiosyncrasies exist in most people before the commencement of diabetes, the concatenation with which they evolve and their corresponding contributions to the advancement from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), and ultimately to type 2 diabetes [36–38], cannot be confirmed for sure even though some detailed longitudinal studies have provided some information [39–44]. Contemporaneous comprehension of the pathogenesis of type 2 diabetes is established on a wide-reaching number of cross-sectional [45–57] and prospective [58–72] studies. The evolution (and subsequent progress) of type 2 diabetes mellitus is delineated by a gradual degeneration of glucose tolerance over several years [33–38]. Prospective and cross-sectional data demonstrate that defects in insulin secretion, body weight gain, insulin action, and an elevation in endogenous glucose output are cardinal in this decline [45–56]. The pathogenetic history of diabetes—the corporeal chain of events with which these metabolic aberrations evolve in relation to one another throughout the various stages of the illness—remains unrevealed. Many authors have suggested that a flaw in insulin activity is the principal aberration in the premature stages of the evolution of type 2 diabetes and that secretory dysfunction of insulin takes place

resistance [24].

*Cellular Metabolism and Related Disorders*

**2.5 Lifestyle factors**

**3. Pathogenesis**

only at a later stage.

**76**

inactive people, triglycerides themselves have been disassociated from insulin resistance, recommending that other lipids (e.g., diacylglycerols, ceramides, and so on) intervene insulin resistance [73]. Various investigations have depicted the interrelationship insulin resistance in muscles and between diacylglycerol (DAG) content. Insulin-animated tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and IRS-1-related phospho-inositide 3-kinase (PI3K) actuation were intensely debilitated in skeletal muscle of lipid-injected people [74] and rodents [75, 76]. In rodents, lipids and high-fat intake bring about transient increments in muscle DAG content [75], bringing about continued appearance of protein kinase C-theta (PKCθ) that constrained phosphorylation of IRS-1 by insulin receptor substrate 1 (IRTK). Lipid mixtures in normal human volunteers correspondingly elevated skeletal muscle DAG [77, 78] and caused muscle insulin resistance. The improvement of muscle insulin resistance can prompt metabolic ailment. This has been seen in hereditary mouse models of particular muscle insulin resistance [79], which are inclined to hepatic steatosis [75] and increased adiposity [77]. In young, lean, and people with skeletal muscle insulin resistance, ingested glucose is not taken up by muscle and gets occupied to the liver, where it becomes substrate for liver once more by lipogenesis, increasing liver triglyceride; furthermore, plasma triglyceride increase results in decreasing plasma high-density lipoprotein (HDL) levels [80]. Nonalcoholic fatty liver disease (NAFLD) is unequivocally connected with hepatic insulin resistance. In patients with lipodystrophy, ectopic lipid accumulation in the liver and skeletal muscle was related with extreme hepatic and muscle insulin resistance [81]. Leptin treatment diminished the consumption of calorie, settled hepatic steatosis, and improved insulin activity [82]. Lipodystrophic mice have a comparable phenotype, and fat transplantation protected these mice by permitting redistribution of lipids from ectopic destinations to transplanted fat tissue and standardization of insulin activity [83]. Mice overexpressing lipoprotein lipase in the liver cause hepatic steatosis and liver-explicit insulin resistance [84]. In rodents and mice, high-fat eating regimens lead to hepatic steatosis and hepatic insulin resistance. In this way, these considerations show that ectopic lipid in the liver is explicitly related with hepatic insulin resistance. Magkos et al. showed that hepatic DAG content (not hepatic ceramide content) was the best indicator of hepatic insulin resistance in obese people [85]. There are a few conditions wherein hepatic steatosis shows up disassociated from hepatic insulin resistance. A typical single-nucleotide polymorphism (rs738409, I48M) in the lipid bead protein-like phospholipase domain-containing protein 3 [patatin-like phospholipase domain-containing A3 gene (PNPLA3), likewise called adiponutrin (ADPN)] has been related with expanded hepatic steatosis, but not insulin resistance [86–88]. Along these lines, occasions of obvious disassociation of hepatic steatosis and hepatic insulin opposition might be clarified by a superior comprehension of the subcellular conveyance of DAG [89]. Ceramides are additionally bioactive lipid particles that are embroiled in the advancement of insulin resistance. Increments in hepatic and muscle ceramide content have been related with insulin resistance in rodents, and inhibitors of ceramide blend can forestall insulin resistance [90, 91]. In any case, a disassociation between ceramide substance and tissue insulin resistance has been revealed in numerous investigations [85, 92, 93], and the fundamental component connecting ceramides to insulin resistance has not been completely finalized. As of late, some investigations analyzed how a particular ceramide species, C16:0, resists mitochondrial oxidation, permitting triglyceride to accumulate and cause insulin resistance [94, 95]. Despite the fact it has not been concluded, it is conceivable that the equal relationship between C16:0 ceramide and mitochondrial oxidation could additionally cause increments DAG and impede insulin action.

#### **3.2 Insulin resistance in the adipose tissue**

Some of the actions of insulin on adipose tissue are (1) stimulation of uptake of glucose and biosynthesis of triglyceride and (2) suppression of triglyceride hydrolysis-cum release of free fatty acids (FFA) and glycerol into the blood [96, 97]. It has been seen that adipose tissue insulin resistance (Adipo-IR), which means diminished suppression of lipolysis when high insulin levels are present, is interlinked with glucose intolerance, and increased plasma FFA amounts have also shown to diminish insulin signaling in muscles, endorse gluconeogenesis in the liver, and diminish glucose-activated insulin response [97–103]. In spite of the fact that the natural history and role of β-cell abnormality (or impairment) and insulin resistance in muscle are firmly established in the evolution of T2DM, the influence of Adipo-IR in the progression from normal glucose tolerance (NGT) to type 2 diabetes mellitus (T2DM) is still not clear. It is possible to quantitate palmitate turnover by the utilization of tracers [104–106] which can also provide the release rate of glycerol [107, 108] to furnish a lipolysis index. Tracer turnover (i.e., labeled palmitate or glycerol) or FFA suppression during insulin infusion (euglycemic-hyperinsulinemic clamp) or oral glucose tolerance test (OGTT) has led to the development of a number of indices of Adipo-IR [109]. Gastaldelli et al. [104] *confirmed that* fasting Adipo-IR index can be considered as a reliable index of insulin resistance in the fat cell when considered over the entire spectrum from NGT to T2DM. There has been consistent demonstration of weakened suppression of plasma FFA and also glycerol and 14C-palmitate turnover with the stepped hyperinsulinemic clamp [106, 110, 111] (i.e., adipocyte insulin resistance) in persons having T2DM. Therefore a decline in insulin secretion/insulin resistance (disposition) index has been seen with progression from lean NGT to obese NGT to IGT [112]. A decline in the secretion from β-cell of insulin is also interlinked with an elevation in the fasting Adipo-IR. Therefore, it can be said that the fasting adipocyte insulin resistance index (fasting FFA fasting insulin) increases in a forward-looking, innovative manner over the stretch of glucose tolerance, extending from NGT to T2DM, and furnishes a reliable index of fat cell sensitivity to the actions of insulin [113–115]. In contradiction, there is increment of adipocyte insulin resistance index during OGTT (from NGT to IGT) and decrease with advancement of IGT to T2DM; this is due to gradual deficiency of the secretion of insulin in this group having diabetes. In conclusion, the gradual decrease in β-cell function that progresses from NGT is interlinked with a gradual elevation in fasting Adipo-IR and FFA [104].

**4.2 Glucose tolerance testing**

*DOI: http://dx.doi.org/10.5772/intechopen.92864*

*Pathogenesis of Insulin Resistance*

of infusion is 10–120 mU per m2

**4.4 Modified insulin suppression test**

varying rates of 32 and 267 mg/m2

**4.5 Homeostatic model assessment (HOMA)**

cell function can be possibly elucidated:

**79**

While performing a glucose tolerance test (GTT), a patient who is fasting is given a 75 g of glucose orally. Then plasma glucose levels are continuously moni-

The elucidation of the test is established on the guidelines of the World Health Organization (WHO). After a period of 2 hours, a plasma glucose amount of less than 7.8 mmol/L (140 mg/dL) is regarded as normal, and a plasma glucose amount of between 7.8 and 11.0 mmol/L (140 to 197 mg/dL) is regarded as impaired glucose tolerance (IGT), and a plasma glucose amount of greater than or equal to 11.1 mmol/L (200 mg/dL) is regarded as diabetes mellitus. Extension of the testing (for several more hours) may reveal a hypoglycemic "dip" that is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.

"Hyperinsulinemic euglycemic clamp" is also known as the gold standard for investigating and quantifying insulin resistance. It is so-called because it calculates the level of glucose obligatory to reimburse for an elevated insulin level without giving rise to hypoglycemia [122]. It is a kind of glucose clamping technique. The test is seldom carried out in clinical settings but is utilized in medical research [123]. The process takes around 2 hours. Insulin is infused through a peripheral vein. The rate is

infusion of insulin, 20% glucose is infused to sustain blood glucose levels between 5 and 5.5 mmol/L. The blood sugar levels every 5 to 10 minutes, to determine the rate of infusion of glucose [123]. The determination of insulin sensitivity is made by the rate of glucose infusion in the last 30 minutes of the test. If greater levels (7.5 mg/min or greater) are required, the patient is considered as insulin sensitive. Low levels such as 4.0 mg/min or lower than that designates that the body is resistant to actions of insulin. Levels between 4.0 and 7.5 mg/min are not conclusive and indicate "impaired glucose tolerance," which is a premature gesticulation of insulin resistance [123, 127]. This basic method may be modified significantly by the utilization of glucose tracers.

Gerald Reaven developed the modified insulin suppression test at Stanford University. The test corresponds well with the euglycemic clamp, with minute operator-dependent error. Particularly, this test has been utilized in research correlating to the metabolic syndrome [123]. A 25 μg of octreotide (Sandostatin) is given to the patient in 5 mL of normal saline over a period of 3–5 minutes through intravenous infusion (IV) as a primary bolus. Subsequently, the patient is continu-

internal glucose and insulin secretion. Next, 20% glucose and insulin are infused at

90 minutes, and lastly at 120 minutes and subsequently after each 10 minutes for the final 30 minutes of the study. The averages of these final four values are utilized to ascertain the steady-state plasma glucose level (SSPG). People having an SSPG

By this method it is possible to quantify insulin resistance. Also, pancreatic beta-

greater than 150 mg/dL are contemplated to have insulin resistance [45].

ously infused with an IV infusion of somatostatin (0.27 μg/m<sup>2</sup>

/minute. With the intention to recompense for the

/min. Plasma glucose is monitored at 0, 30, 60,

/min) to repress

tored (along with urine glucose) for a period of 2 hours.

**4.3 Using the hyperinsulinemic euglycemic clamp**

Fat insulin resistance is the failure of insulin to activate fat glucose transport, advance lipid take-up, and diminish lipolysis. While diminished fat glucose take-up is exhibited in both in vivo and in vitro models, metabolic effect of hindered insulin-intervened glucose take-up in fat tissue is not well explained. For instance, the loss of fat GLUT4 in mice does not modify adiposity or, on the other hand, how weight gain prompts insulin resistance in skeletal muscle and liver [116]. Glucose transport into fat cells initiates starch reaction component restricting protein (ChREBP), which may affect fat lipid digestion [117]. Adipocytes discharge explicit unsaturated fats that are related with increased insulin affectability, as palmitoleate [118, 119] or monomethyl chain unsaturated fats [120].

#### **4. Methods for diagnosis**

#### **4.1 Fasting insulin levels**

A fasting serum insulin amount of more than 25 mU/L or in other sense 174 pmol/L designates insulin resistance. The same amounts pertain to 3 hours after taking the last meal [121].

#### **4.2 Glucose tolerance testing**

**3.2 Insulin resistance in the adipose tissue**

*Cellular Metabolism and Related Disorders*

[118, 119] or monomethyl chain unsaturated fats [120].

A fasting serum insulin amount of more than 25 mU/L or in other sense 174 pmol/L designates insulin resistance. The same amounts pertain to 3 hours after

**4. Methods for diagnosis**

**4.1 Fasting insulin levels**

taking the last meal [121].

**78**

Some of the actions of insulin on adipose tissue are (1) stimulation of uptake of

hydrolysis-cum release of free fatty acids (FFA) and glycerol into the blood [96, 97]. It has been seen that adipose tissue insulin resistance (Adipo-IR), which means diminished suppression of lipolysis when high insulin levels are present, is interlinked with glucose intolerance, and increased plasma FFA amounts have also shown to diminish insulin signaling in muscles, endorse gluconeogenesis in the liver, and diminish glucose-activated insulin response [97–103]. In spite of the fact that the natural history and role of β-cell abnormality (or impairment) and insulin resistance in muscle are firmly established in the evolution of T2DM, the influence of Adipo-IR in the progression from normal glucose tolerance (NGT) to type 2 diabetes mellitus (T2DM) is still not clear. It is possible to quantitate palmitate turnover by the utilization of tracers [104–106] which can also provide the release rate of glycerol [107, 108] to furnish a lipolysis index. Tracer turnover (i.e., labeled palmitate or glycerol) or FFA suppression during insulin infusion (euglycemic-hyperinsulinemic clamp) or oral glucose tolerance test (OGTT) has led to the development of a number of indices of Adipo-IR [109]. Gastaldelli et al. [104] *confirmed that* fasting Adipo-IR index can be considered as a reliable index of insulin resistance in the fat cell when considered over the entire spectrum from NGT to T2DM. There has been consistent demonstration of weakened suppression of plasma FFA and also glycerol and 14C-palmitate turnover with the stepped hyperinsulinemic clamp [106, 110, 111] (i.e., adipocyte insulin resistance) in persons having T2DM. Therefore a decline in insulin secretion/insulin resistance (disposition) index has been seen with progression from lean NGT to obese NGT to IGT [112]. A decline in the secretion from β-cell of insulin is also interlinked with an elevation in the fasting Adipo-IR. Therefore, it can be said that the fasting adipocyte insulin resistance index (fasting FFA fasting insulin) increases in a forward-looking, innovative manner over the stretch of glucose tolerance, extending from NGT to T2DM, and furnishes a reliable index of fat cell sensitivity to the actions of insulin [113–115]. In contradiction, there is increment of adipocyte insulin resistance index during OGTT (from NGT to IGT) and decrease with advancement of IGT to T2DM; this is due to gradual deficiency of the secretion of insulin in this group having diabetes. In conclusion, the gradual decrease in β-cell function that progresses from NGT is interlinked with a gradual elevation in fasting Adipo-IR and FFA [104]. Fat insulin resistance is the failure of insulin to activate fat glucose transport, advance lipid take-up, and diminish lipolysis. While diminished fat glucose take-up is exhibited in both in vivo and in vitro models, metabolic effect of hindered insulin-intervened glucose take-up in fat tissue is not well explained. For instance, the loss of fat GLUT4 in mice does not modify adiposity or, on the other hand, how weight gain prompts insulin resistance in skeletal muscle and liver [116]. Glucose transport into fat cells initiates starch reaction component restricting protein (ChREBP), which may affect fat lipid digestion [117]. Adipocytes discharge explicit unsaturated fats that are related with increased insulin affectability, as palmitoleate

glucose and biosynthesis of triglyceride and (2) suppression of triglyceride

While performing a glucose tolerance test (GTT), a patient who is fasting is given a 75 g of glucose orally. Then plasma glucose levels are continuously monitored (along with urine glucose) for a period of 2 hours.

The elucidation of the test is established on the guidelines of the World Health Organization (WHO). After a period of 2 hours, a plasma glucose amount of less than 7.8 mmol/L (140 mg/dL) is regarded as normal, and a plasma glucose amount of between 7.8 and 11.0 mmol/L (140 to 197 mg/dL) is regarded as impaired glucose tolerance (IGT), and a plasma glucose amount of greater than or equal to 11.1 mmol/L (200 mg/dL) is regarded as diabetes mellitus. Extension of the testing (for several more hours) may reveal a hypoglycemic "dip" that is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.

#### **4.3 Using the hyperinsulinemic euglycemic clamp**

"Hyperinsulinemic euglycemic clamp" is also known as the gold standard for investigating and quantifying insulin resistance. It is so-called because it calculates the level of glucose obligatory to reimburse for an elevated insulin level without giving rise to hypoglycemia [122]. It is a kind of glucose clamping technique. The test is seldom carried out in clinical settings but is utilized in medical research [123]. The process takes around 2 hours. Insulin is infused through a peripheral vein. The rate is of infusion is 10–120 mU per m2 /minute. With the intention to recompense for the infusion of insulin, 20% glucose is infused to sustain blood glucose levels between 5 and 5.5 mmol/L. The blood sugar levels every 5 to 10 minutes, to determine the rate of infusion of glucose [123]. The determination of insulin sensitivity is made by the rate of glucose infusion in the last 30 minutes of the test. If greater levels (7.5 mg/min or greater) are required, the patient is considered as insulin sensitive. Low levels such as 4.0 mg/min or lower than that designates that the body is resistant to actions of insulin. Levels between 4.0 and 7.5 mg/min are not conclusive and indicate "impaired glucose tolerance," which is a premature gesticulation of insulin resistance [123, 127]. This basic method may be modified significantly by the utilization of glucose tracers.

#### **4.4 Modified insulin suppression test**

Gerald Reaven developed the modified insulin suppression test at Stanford University. The test corresponds well with the euglycemic clamp, with minute operator-dependent error. Particularly, this test has been utilized in research correlating to the metabolic syndrome [123]. A 25 μg of octreotide (Sandostatin) is given to the patient in 5 mL of normal saline over a period of 3–5 minutes through intravenous infusion (IV) as a primary bolus. Subsequently, the patient is continuously infused with an IV infusion of somatostatin (0.27 μg/m<sup>2</sup> /min) to repress internal glucose and insulin secretion. Next, 20% glucose and insulin are infused at varying rates of 32 and 267 mg/m2 /min. Plasma glucose is monitored at 0, 30, 60, 90 minutes, and lastly at 120 minutes and subsequently after each 10 minutes for the final 30 minutes of the study. The averages of these final four values are utilized to ascertain the steady-state plasma glucose level (SSPG). People having an SSPG greater than 150 mg/dL are contemplated to have insulin resistance [45].

#### **4.5 Homeostatic model assessment (HOMA)**

By this method it is possible to quantify insulin resistance. Also, pancreatic betacell function can be possibly elucidated:

$$\text{HOMA-IR} = \frac{\text{Glucose} \times \text{Insulin}}{22.5} \tag{1}$$

and

$$\text{HOMA-}\beta = \frac{20 \times \text{Insulin}}{\text{Glucose} - 3.5\%} \tag{2}$$

where glucose is in mmol/L. Also,

$$\text{HOMA-IR} = \frac{\text{Glucose} \times \text{Insulin } \%}{405} \tag{3}$$

and

$$\text{HOMA-}\beta = \frac{\text{360} \times \text{Insulin} \,\%}{\text{Glucose} - \text{63}} \tag{4}$$

**Author details**

*Pathogenesis of Insulin Resistance*

*DOI: http://dx.doi.org/10.5772/intechopen.92864*

Gaffar S. Zaman

**81**

Department of Clinical Laboratory Sciences, College of Applied Medical Science,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

King Khalid University, Abha, Kingdom of Saudi Arabia

\*Address all correspondence to: drgszaman@gmail.com

provided the original work is properly cited.

where glucose is in mg/dL.

Note: insulin is taken in μU/mL; both glucose and insulin are taken during fasting; IR means insulin resistance; HOMA-β is the percentage of beta cell function [124–128].

#### **4.6 Quantitative insulin sensitivity check index (QUICKI) method for insulin assessment**

QUICKI is obtained utilizing the inverse of the addition of the logarithms of the fasting insulin and fasting glucose:

$$\mathbf{1}/[\log\left(\text{fastig }\text{insulin}\,\mu\text{U/mL}\right) + \log\left(\text{fastig }\text{glucose }\text{mg/dL}\right)] \tag{5}$$

The QUICKI method corresponds well with glucose clamp researches (r = 0.78) and is very good for the measurement of insulin sensitivity (IS), which is derived by utilizing the reciprocal quantity of insulin resistance (IR).

#### **5. Conclusions**

From the time insulin resistance was discovered, the cellular and molecular mechanisms were the considerations for which drugs were tried for diabetes mellitus. Considering the cellular mechanisms of insulin resistance which are mostly concerned with plasma cell membrane glycoprotein-1 (PC-1), also termed as ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), the mechanism is really complex. The full understanding of the cellular mechanisms will permit the development of novel targets for various treatment modalities. From the therapeutic point of view, we need to have a clear knowledge about the cellular mechanism of insulin resistance in order to treat and also to prevent the occurrence of diabetes from prediabetic stage. From recent studies, it is evident that insulin resistance can be stopped or reversed if the pathophysiology is clear. It is the necessity to implement a huge global strategic plan for identifying and preventing/treatment of insulin resistance in the prediabetic stage.

*Pathogenesis of Insulin Resistance DOI: http://dx.doi.org/10.5772/intechopen.92864*

HOMA‐IR <sup>¼</sup> Glucose � Insulin

HOMA‐<sup>β</sup> <sup>¼</sup> <sup>20</sup> � Insulin

HOMA‐IR <sup>¼</sup> Glucose � Insulin %

HOMA‐<sup>β</sup> <sup>¼</sup> <sup>360</sup> � Insulin %

Note: insulin is taken in μU/mL; both glucose and insulin are taken during fasting; IR means insulin resistance; HOMA-β is the percentage of beta cell function

**4.6 Quantitative insulin sensitivity check index (QUICKI) method for insulin**

QUICKI is obtained utilizing the inverse of the addition of the logarithms of the

The QUICKI method corresponds well with glucose clamp researches (r = 0.78) and is very good for the measurement of insulin sensitivity (IS), which is derived by

From the time insulin resistance was discovered, the cellular and molecular mechanisms were the considerations for which drugs were tried for diabetes mellitus. Considering the cellular mechanisms of insulin resistance which are mostly concerned with plasma cell membrane glycoprotein-1 (PC-1), also termed as ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), the mechanism is really complex. The full understanding of the cellular mechanisms will permit the development of novel targets for various treatment modalities. From the therapeutic point of view, we need to have a clear knowledge about the cellular mechanism of insulin resistance in order to treat and also to prevent the occurrence of diabetes from prediabetic stage. From recent studies, it is evident that insulin resistance can be stopped or reversed if the pathophysiology is clear. It is the necessity to implement a huge global strategic plan for identifying and preventing/treatment of

1*=*½ � *log fasting insulin* ð *μU=mL*Þ þ *log fasting glucose mg* ð Þ *=dL* (5)

and

Also,

and

[124–128].

**assessment**

**5. Conclusions**

**80**

where glucose is in mmol/L.

*Cellular Metabolism and Related Disorders*

where glucose is in mg/dL.

fasting insulin and fasting glucose:

insulin resistance in the prediabetic stage.

utilizing the reciprocal quantity of insulin resistance (IR).

<sup>22</sup>*:*<sup>5</sup> (1)

<sup>405</sup> (3)

Glucose � <sup>63</sup> (4)

Glucose � <sup>3</sup>*:*5% (2)

### **Author details**

Gaffar S. Zaman

Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Kingdom of Saudi Arabia

\*Address all correspondence to: drgszaman@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 4

Metabolic Syndrome

Section 4
