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Some forms of Type 1 diabetes have no known aetiologies. Some of these patients have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of auto–

immunity. Although, only a minority of patients with Type 1 diabetes fall into this category, of those who do, most are of African or Asian origin. Individuals with this form of diabetes suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes.

This form of diabetes is strongly inherited, lacks immunological evidence for beta–cell auto–immunity, and is not HLA associated (Banerji and Lebovitz, 1989; ADA Expert Committee, 1998; ADA, 2004).

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2.4. Type 2 diabetes

Type 2 diabetes is a major global health problem that affects over 124 million individuals worldwide (Quinn, 2001). It accounts for approximately 90–95% of those with diabetes and previously referred to as non–insulin–dependent diabetes (NIDDM), type II diabetes, or adult–onset diabetes (ADA Expert Committee, 1998; ADA, 2004).

There are two major identifiable pathologic defects in patients with Type 2 diabetes (DeFronzo et al., 1992).

 One is decreased ability of insulin to act on peripheral tissues. This is called insulin resistance and is thought by many to be the primary underlying pathology.

 The other is beta–cell dysfunction, which is, an inability of pancreas to produce sufficient insulin to compensate for insulin resistance. Thus, there is a relative deficiency of insulin early in the disease and absolute insulin deficiency late in the disease (Sacks and McDonald, 1996).

The argument over whether Type 2 diabetes is primarily the result of a defect in beta–cell secretion, peripheral resistance to insulin or both has been raging for decades. However, there are data to support the concept that insulin resistance is the primary defect, preceding derangement in insulin secretion and clinical diabetes by as much as thirty years (Kahn, 1994).

Regardless of whether insulin resistance is the primary or secondary defect, it is clear that Type 2 diabetes is an extremely heterogeneous disease and no single cause is adequate to explain progression from normal glucose tolerance to Type 2 diabetes mellitus.

The fundamental defects in insulin resistance and secretion are caused by a combination of genetic and environmental factors that together contribute to the pathogenesis of Type 2 diabetes (Sacks and McDonald, 1996). Most patients with this form of diabetes are obese, and obesity itself causes some degree of insulin resistance (Kolterman et al., 1981).

Patients who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in abdominal region (ADA, 2004). Ketoacidosis seldom occurs spontaneously in this type of diabetes, when seen; it usually arises in association with stress of another illness such as infection (Banerji et al., 1994; Butkiewicz et al., 1995; Umpiernez et al., 1995). This form of diabetes frequently goes undiagnosed for many years because hyperglycaemia develops gradually and at earlier stages is often not severe enough for patient to notice any of the classic symptoms of diabetes (Harris, 1989; Zimmet, 1992). Nevertheless, such patients are at increased risk of developing

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macro– and micro–vascular complications (Uusitupaa et al., 1993; Kuunisisto et al., 1994;

Anderson and Svaardsudd, 1995). Whereas patients with this form of diabetes may have insulin levels that appear normal or elevated, the higher blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their β–cell function been normal. Thus, insulin secretion is defective in these patients and insufficient to compensate for insulin resistance. Insulin resistance may improve with weight reduction and/or pharmacological treatment of hyperglycaemia but is seldom restored to normal (ADA, 2004). The risk of developing this form of diabetes increases with age, obesity and lack of physical activity (Harris et al., 1995).

Type 2 diabetes occurs more frequently in women with prior gestational diabetes mellitus (GDM) and in individuals with hypertension or dyslipidaemia, and its frequency varies in different racial or ethnic subgroups (Fujimoto et al., 1987). It is often associated with a stronger genetic predisposition, more so than is the auto–immune form of Type 1 diabetes.

However, the genetics of this form of diabetes are complex and unclearly defined (Barnett et al., 1981; Newman et al., 1987).

2.4.1. Environmental factors

Environmental factors, such as diet and physical exercise, are important determinants in pathogenesis of Type 2 diabetes, but the actual underlying mechanisms are unknown.

Both animal and human studies have provided convincing evidence linking obesity to development of Type 2 diabetes. However, the association between these disorders is far from being straightforward. Although, 60% to 80% of Type 2 diabetic subjects are obese, fewer than 25% of obese actually develop diabetes (Sacks and McDonald, 1996).

Virtually all obese subjects even those with normal carbohydrate tolerance, have hyperinsulinaemia and are insulin–resistant. Other factors, such as family history of Type 2 diabetes (genetic predisposition), the duration of obesity and the distribution of fat are also important (Sato, 2000; Boden, 2001; Kelly and Goodpaster, 2001).

Type 2 diabetes is ten times more likely to occur in an obese person with a diabetic family history. Colditz et al. (1995) have provided evidence that women who gained 8 to 10.9 Kg over the expected body mass index or body frame had a relative increased risk for DM of 2.7 fold, whereas loss of more than 5 Kg decreases their risk by at least 50%.

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2.4.2. Genetic factors

It is widely acknowledged that genetic factors contribute to the development of Type 2 diabetes (Elbein et al., 1994; Kahn, 1994). For example, the concordance rate for Type 2 diabetes in identical twins approaches 100% (Barnett et al., 1981). However, despite considerable investigation, the mode of inheritance remains uncertain. There are several reasons for this: some diseases, usually less common (e.g. cystic fibrosis or Duchene‟s muscular dystrophy) appear to be caused by mutations at a single locus. The common diseases such as diabetes mellitus, schizophrenia, atherosclerosis, hypertension, and osteoporosis are not inherited according to Mendalian rules (Barnett et al., 1981). These diseases are genetically more complex and multiple genetic factors interact with exogenous influences such as environmental factors, to produce the phenotype. In contrast to single gene disorders, identification of genes responsible for common polygenic disorders is associated with many problems (Lander and Sahork, 1994; Weissman, 1995). Some of these difficulties are listed in the Table (2.2) below:

Table 2.2. Difficulties in identifying specific gene variations in complex polygene disorders (Adapted from Weissman, 1995)

1. Genetic heterogeneity

2. High incidence of disease–prone genes 3. Small contribution of individual genes

4. Correct patient diagnosis/classification often difficult and ambiguous 5. Excessively large suspect genomic region renders identification difficult 6. Linkage between candidate genes may affect resolution

7. Difficulty in replicating results requires multiple repeat analyses.

8. Discordance between animal models and human disease.

2.5. Other specific types of diabetes A. Genetic defects of the beta–cell

Several types of diabetes are associated with monogenetic defects in beta–cell function.

These types of diabetes are often characterized by onset of hyperglycaemia at an early age, generally before age 25 years. They are referred to as maturity–onset diabetes of the young (MODY) and are characterized by impaired insulin secretion with minimal or no defects in insulin action (Herman et al., 1994; Byrne et al., 1996; Clement et al., 1996; ADA, 2004).

They are inherited in an autosomal dominant pattern. Abnormalities at three genetic loci on different chromosomes have been identified to date. The most common form is associated

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with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)–1α (MODY 3) (Vaxillaire et al., 1995; Yamagata et al., 1996a; ADA, 2004).

A second form is associated with mutations in the glucokinase gene on chromosome 7p and results in a defective glucokinase molecule (MODY 2). Glucokinase converts glucose to glucose–6–phosphate, the metabolism of which, in turn, stimulates insulin secretion by the beta–cell. Thus, glucokinase serves as the „glucose sensor‟ for beta–cell. Increased plasma levels of glucose are necessary to elicit normal levels of insulin secretion because of defects in glucokinase gene (Froguel et al., 1992; Vionnet et al., 1992; ADA, 2004).

The third form is associated with a mutation in the HNF–4α gene on chromosome 20q (MODY 1) (Bell et al., 1991; Yamagata et al., 1996b; ADA, 2004). HNF–4α is a transcription factor involved in regulation of the expression of HNF–1α. The specific genetic defects in a substantial number of other individuals who have a similar clinical presentation are currently unknown (ADA Expert Committee, 1998; ADA, 2004).

Genetic abnormalities that result from the inability of the beta cell to convert pro–insulin to insulin have been identified in a few families, and such traits are inherited in an autosomal dominant pattern. The resultant glucose intolerance is mild (Gruppuso et al., 1984;

Robbins et al., 1984; ADA, 2004).

Similarly, the production of mutant insulin molecules with resultant impaired receptor binding has also been identified in a few families. It is associated with an autosomal inheritance and only mildly impaired or may even have normal glucose metabolism (Given et al., 1980; Haneda et al., 1983; ADA, 2004).