Figure 1

Insulin potentiates cellular mitogenic responsiveness to growth factors (GFs). GFs (including insulin) interact with their cognate growth factor receptors (GFR) and activate the Sos-Ras-Raf-Map kinase branch of cellular signalling, thus promoting mitogenesis. Initially, GFs stimulate guanine nucleotide exchange factor (Sos) that activates Ras proteins by GTP loading. Sos promotes exchange of GTP for GDP only if Ras is anchored at the plasma membrane. Translocation of Ras protein to the plasma membrane is facilitated by farnesylation of Ras, an attachment of a farnesyl moiety to cysteine residue of Ras under the influence of farnesyltransferase (FTase). Insulin via interaction with its specific cell surface receptor (IR) phosphorylates and activates FTase that increases farnesylation of Ras. Hyperinsulinemia, particularly in the presence of insulin resistance, stimulates FTase and augments the amount of farnesylated Ras available for GTP loading in response to other growth factors. Greater activation of Ras leads to increased mitogenic responsiveness of cells and tissues and enhanced mitogenesis and subsequent pathophysiologic events. Reprinted with permission from Diabetologia 53:229-233, 2010.