After the glucose intake, the increase in plasma glucose stimulates insulin secretion via pancreatic beta cells. Increased insulin resulting from increased plasma glucose suppresses lipolysis decreasing the rate of lipid oxidation [36]. Simultaneously, insulin stimulates glucose uptake by skeletal muscle, selleck kinase inhibitor increasing the glucose outflow, and by activation of enzymes related to glucose oxidation in this site [37]. The cellular events that initiate the crosstalk between insulin and its receptors are present in the specific surface of skeletal muscle cells. The insulin receptor consists of two subunits (�� and ��) linked by disulfide bonds lying in the extracellular environment sarcoplasmic membrane. The binding of insulin with its receptor leads to phosphorylation of the ��-subunit in several tyrosine residues as the insulin receptor has kinase activity [39].

However, due to the hydrophilic characteristic of the glucose molecule, it does not diffuse through the lipid layer of cell membrane. Therefore, it is necessary a membrane transporter to make possible the uptake of glucose by the cell. In humans, these proteins constitute a family of transporters (GLUT) [39]. GLUT-4 express is the major transporter in skeletal muscle, activated (and translocated) to the surface of the cellular membrane in response to insulin and exercise [40�C42]. The GLUT-4 translocation is stimulated by insulin in skeletal muscle and the reduced speed-determining step in the glycogen synthesis are observed in T2DM patients [43].

While evidence suggests impairment in the GLUT-4 translocation in patients with T2DM, the total GLUT-4 content is not reduced in the skeletal muscle of type 2 diabetic patients [43]. Therefore, the uptake of glucose into skeletal muscle in insulin-resistant individuals can be partially explained by defects in insulin signaling in the GLUT-4 translocation [44]. An overview of the insulin signaling pathways regulating glucose transport can be seen in Figure 4.Figure 4In brief, the insulin binds with its membrane receptor which has intrinsic tyrosine kinase activity, triggers a signaling cascade to downstream substrates resulting in glucose transport. Subsequently, tyrosine phosphorylated IRS (IRS-1/2) recruits signaling …Since PCOS is associated with defects in insulin activation and ��-cell pancreatic dysfunction [45], the interest in the molecular mechanisms underlying the insulin resistance in PCOS has increased.

Insulin resistance in the skeletal muscle is a major risk factor for the development of T2DM in women with PCOS [46]. For instance, Dunaif et al. (1995) studied skeletal muscle tissue of obese and lean PCOS and and reported an excessive serine phosphorylation Brefeldin_A (Ser312) of insulin receptor in cultured human muscle cells and fibroblasts [47]. However, Corbould et al.