**4. Insulin resistance**

Patients with T2DM have high whole body glucose production and glucogenesis but low glycogenolysis compared with normal subjects. In patients with IR, there is impairment of glucose transport and insulin signaling in target tissues with release of inflammatory markers from the adipose tissue [23, 24]. The glucose, FFA, autonomic nerves, fat-derived hormones and the gut hormone glucagon-like peptide-1 (GLP-1) are mediators sending signals to the βcells to respond to IR. The maintenance of normal glucose and lipid metabolism is by the reciprocal relation of IR to IS and insulin secretion. Hyperbolic relation is the best description of the curvilinear relation between IS and secretion. This relation is impaired with failure of these signals to act on β-cells to secret insulin ends with subsequent development of dysgly‐ cemia (Impaired Fasting glucose- IFG, impaired Glucose tolerance –IGT and DM) [25].

Obesity is the most common cause of IR and T2DM. Simply being overweight (BMI >25) raises the risk of developing T2DM by a factor of 3 [26].

The main components of IR are dysglycemia, dyslipidemia, obesity, hypertension and hyperinsulinemia. Therefore, it is the key feature of metabolic syndrome (MS) and vascular complications (cardiovascular and stroke). IR components once are acquired, those with genetic predisposition will develop the full picture of the disorder suggesting the final phenotypic expression involves both genetic and acquired influences. The most important environmental factor in IR is central obesity which is mainly caused by intake of high fat, and refined carbohydrate without physical activity. These are exacerbated by genetic predisposi‐ tion but IR could be reduced with minimizing dietary intake and regular exercise [27].

The three potential mechanisms of the controlling glucose metabolism in the skeletal muscles are the glycogen synthase, the hexokinase and the major insulin-stimulated glucose trans‐ porter GLUT4. Therefore, defects in glycogen synthesis in the skeletal muscles playing a major role in the pathogenesis of IR [28]. The decrease in the ability of normal responding skeletal muscles to circulating insulin levels or concentrations is main principle of development of IR which could precede the overt T2DM by 10 to 20years [28].

T2DM is characterized by increased hepatic glucose output, increased peripheral resistance to insulin action (due to receptor and postreceptor defects) and impaired insulin secretion.

Two major variants of insulin receptor abnormalities associated with acanthosis nigricans, hyperinsulinemia and marked hyperandrogenism. The classic type A IR syndrome, which is due to genetic defect in the insulin-signaling system such as mutation in the insulin receptor gene [29] and type B IR syndrome, which results from autoantibodies to the insulin receptor [30].

Many factors could enhance IR include, obesity, inflammation and inflammatory markers, defects in genes and drugs. These will be demonstrated further in this chapter.
