Type 2 diabetes mellitus (T2DM) is a complex metabolic, multifactorial and genetically heterogeneous disease consisting of several sub-groups and various combinations of susceptibility genes (Hansen, 2002). This non-insulin dependent diabetes mellitus (NIDDM) is primarily characterized by insulin resistance, relative insulin deficiency and hyperglycemia. Diabetes develops due to the genetic predisposition and environmental factors, such as improper food-habit, obesity, sedentary lifestyle, urbanization etc. Alterations in glucose metabolism by skeletal muscle and liver, the key insulin-responsive organs that monitors normal glucose homeostasis are seen in Type 2 Diabetes condition (Lowell et al, 2005). Figure 1 depicts the progression in the pathogenesis of Type 2 Diabetes.

        The major pathophysiological basis of Type 2 Diabetes mellitus is characterized by peripheral insulin resistance, insulin deficiency, increased hepatic glucose production, Impaired β-cell function and diminished insulin mediated glucose transport (Mahler et al., 1999). Insulin resistance and declined β-cell function are the core consequences of T2DM (Rhodes et al, 2002).

          Insulin resistance accompanied with impaired glucose uptake from the blood by the cells, disturbs the normal glucose homeostasis of the body leading to the development of T2DM (Kahn et al., 2006). Obesity has also been reported as a major factor in the development of insulin resistance and T2DM (Steinberger et al, 2003). Impaired Glucose Tolerance is defined as the fasting plasma glucose concentration of 7.0 mmol/l and above; and also as 7.8 to 11.1 mmol/l of glucose concentration after 2 hours of 75 g of oral glucose consumption (WHO Report, 1985). This is an intermediate state between normal glucose tolerance and T2DM. In the initial stages, insulin resistance is compensated by the hyper-secretion of insulin by the pancreatic β cells. As insulin resistance increases, the plasma glucose level increases due to the lower insulin sensitivity and the normal functionality of the pancreatic β cells is lost, leading to hyperglycemia (Weir et al, 2004).

         β-cell dysfunction, an inability of the pancreas to provide sufficient insulin to compensate for the insulin resistance is characterized by the impairment of insulin secretion in two phases. In the first phase of insulin secretion, the level of glucose-stimulated insulin release is impaired in Type 2 diabetes condition and decreased in the second phase (Ward et al., 1986). Abnormalities in β-cell function that results in T2DM include reduced non-glucose insulin secretagogues stimulation, asynchronous insulin release, a decreased conversion of proinsulin to insulin and a significant decrease in β-cell mass (Mahler et al., 1999).

         Since oxidative mitochondrial metabolism is required for normal glucose-stimulated insulin secretion from pancreatic β-cells, subtle defects in mitochondrial function result in insulin secretion and β-cell dysfunction (Lowell et al, 2005). The Endoplasmic reticulum stress pathway which is active in adipose tissue and liver has a molecular link between obesity, decreased insulin sensitivity and type 2 diabetes. This endoplasmic reticulum stress in obese individuals leads to suppression of insulin receptor signaling by increased activation of c-Jun N-terminal kinase (JNK) and phosphorylation of insulin receptor substrate–1 (IRS-1) on serine residues (Ozcan et al., 2004). Adiponectin, an insulin sensitizing hormone from adipocytes, is a key factor for predicting T2DM (Hara et al., 2005). The increased levels of non-esterified fatty acid (NEFA), glycerol, Tumor Necrosis Factor-α (TNF-α), and cytokines in the blood plasma lead to the increased level of insulin resistance and reduced insulin sensitivity (Steven et al., 2006). Some common gene variants that are reported to be associated with T2DM are calpain 10 (CAPN10), PPAR-γ coactivator 1 (PGC1), Pro12Ala PPAR-γ (PPARG), Glu23Lys potassium inward rectifying channel (KCNJ11), HNF4α and the glucose transporter (GLUT2) (Shuldiner et al., 2004 and Kahn et al., 2006). Chromosomal regions reported to harbor some T2DM susceptibility genes are 1q21–q24, 2q37, 3q24–q27, 4q32–q33, 11q24, 12q, 20q, 18p11 and 8p21-p23 (Shuldiner et al., 2004 and Das et al., 2006).

Genetic risk factors

         Specific variations in gene and familial history of diabetes are the major genetic factors involved in T2DM (Das et al., 2006). Many candidate genes and the susceptible loci responsible for Type 2 diabetes mellitus have already been reported and this list is being increased as the research on genetic variation in this metabolic disorder progresses all over the world.

Environmental risk factors

         In spite of the genetic factors, environmental factors that increase the risk of developing T2DM are improper food-habit, obesity, lack of physical exercise and sedentary life style (Bener et al., 2005). The various factors contributing to the development of T2DM have been depicted in Figure 2.

         Type 2 diabetes affected individuals have a higher risk of developing some of the following abnormalities (Nazimek et al., 2002):