Molecular mechanisms of insulin resistance in type 2 diabetes mellitus

Figure 1 Insulin signaling pathway showing binding of insulin with the insulin receptor leading to the activation of glucose transporter 4 which imports glucose into the cell. Binding of insulin to the IR activates PI3-k which produces PI4, 5P2 and PI3, 4, 5P3. These serve as docking sites for PDK1 which then mediates activation of PKB. Activated PKB can regulate transcription of target genes-PEPCK and G6Pase via Foxo-1. Increased free fatty acids may cause serine phosphorylation of IRS proteins, which in turn decreases IRS-tyrosine phosphorylation, impairing downstream effectors. pY: phosphorylated tyrosine; IR: insulin receptor; IRS: insulin receptor protein; PI3-k: phosphatidylinositol 3-kinase; PDK1: phosphoinositidedependent kinase 1; PKB: protein kinase B; Foxo-1: forkhead box protein O; PEPCK: phosphoenolpyruvate carboxykinase; G6Pase: glucose-6-phosphatase; FFA: free fatty acids; PIP2: phosphatidyl-inositol-3,4-bisphosphate; PIP3: phosphatidyl-inositol-3,4,5-tris-phosp-hate; GLUT4: glucose transporter 4.