A Twenty-First Century Cancer Epidemic Caused by Obesity: The Involvement of Insulin, Diabetes, and Insulin-Like Growth Factors
Figure 8
Graphic representation of the classic modes of insulin, IGF-1, and IGF-2 signal transduction. Insulin binds to the ectodomain of the insulin receptor and activates both the PI3-kinase and Akt pathway (blue) and the Ras and MAP kinase pathway (salmon pink). Activation of the Akt pathway results in translocation of GLUT4-positive intracellular vesicles to the plasma membrane and increased uptake of glucose, activation of glycogen synthase kinase 3 and the conversion of glucose to glycogen, and activation of pyruvate dehydrogenase and acetyl-CoA carboxylase and the conversion of glucose into the substrate for fatty acid synthesis. Activation of the MAP kinase pathway leads to increased expression of enzymes in the glycolytic pathway and preferential metabolism of glucose for energy. IGF-1 or IGF-2 (IGFs) bind to the ectodomain of type I IGF receptor and activate both the PI3-kinase and Akt pathway (blue) and the Ras and MAP kinase pathway (salmon pink). Activation of the Akt pathway results in inhibition of the Bcl-2 family of stress detection proteins and activation of GSK3β, both of which increase cell survival. Activation of the MAP kinase pathway leads to increased expression of genes that encode proteins important in regulation of cell cycle progression and hence to increased proliferation.
