Insulin is among the principal hormones that regulate metabolism, and we will examine the effects of this hormone on metabolic pathways many times in the course of our study of biochemistry. This section presents an overview of its signal-transduction pathway. Insulin is the hormone released by the β cells of the pancreas after a meal has been eaten and is the biochemical signal designating the fed state. In all of its detail this multibranched pathway is quite complex, and so we will focus solely on the major branch. This branch leads to the mobilization of glucose transporters to the cell surface. These transporters allow the cell to take up the glucose that is plentiful in the bloodstream after a meal.

Insulin is a peptide hormone that consists of two chains, linked by two disulfide bonds (Figure 13.16). The insulin receptor is a member of the receptor tyrosine kinase class of membrane proteins. Unlike the other members of the receptor tyrosine kinase class, however, the insulin receptor exists as a dimer even in the absence of insulin. Each subunit consists of one α chain and one β chain linked to one another by a single disulfide bond. Each α subunit lies completely outside the cell, whereas each β subunit starts in the extracellular domain and spans the membrane with an α helix to the cytoplasmic side, where the kinase domain resides. The two α subunits are linked to one another with disulfide bonds (Figure 13.17).

Insulin binding causes a change in quaternary structure that results in cross-phosphorylation by the two kinase domains, activating the kinase. The activated kinase phosphorylates additional sites within the receptor. These phosphorylated sites act as docking sites for other substrates, including a class of molecules referred to as insulin-receptor substrates (IRS). The IRS proteins are subsequently phosphorylated by the tyrosine kinase activity of the insulin receptor.

In their phosphorylated form, the IRS molecules act as adaptor proteins (Figure 13.18). The phosphotyrosine residues in the IRS proteins are recognized by other proteins, including a lipid kinase that phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP₂) to form phosphatidylinositol 3,4,5-trisphosphate (PIP₃), as depicted in Figure 13.19. This lipid product, in turn, activates PIP₃-dependent protein kinase (PDK1). This activated protein kinase phosphorylates and activates Akt (also called protein kinase B, PKB), another serine or threonine protein kinase (Figure 13.18). Akt is not membrane anchored and moves through the cell to phosphorylate enzymes that stimulate glycogen synthesis as well as components that control the trafficking of the glucose transporter GLUT4 to the cell surface. At the cell surface, GLUT4, one of a family of five glucose transporters, allows the entry of glucose down its concentration gradient into the cell, efficiently removing glucose from the blood. Thus, the signal is conveyed to the cell interior by the IRS protein through a series of membrane-anchored molecules to a protein kinase that finally leaves the membrane and elicits the cellular response to insulin.

The cascade initiated by the binding of insulin to the insulin receptor is summarized in Figure 13.20. The signal is amplified at several stages along this pathway. Because the activated insulin receptor itself is a protein kinase, each activated receptor can phosphorylate multiple IRS molecules. Activated enzymes further amplify the signal in at least two of the subsequent steps. Thus, a small increase in the concentration of circulating insulin can produce a robust intracellular response. Note that, as complicated as the pathway described here is, it is substantially less elaborate than the full network of pathways initiated by insulin.

We have seen that the activated G protein promotes its own inactivation by the release of a phosphoryl group from GTP. In contrast, proteins phosphorylated on serine, threonine, or tyrosine residues, such as insulin-receptor substrates, do not hydrolyze spontaneously; they are extremely stable kinetically. Specific enzymes, called protein phosphatases, are required to hydrolyze these phosphorylated proteins and convert them back into the states that they were in before the initiation of signaling. Similarly, lipid phosphatases are required to remove phosphoryl groups from inositol lipids that had been phosphorylated as part of a signaling cascade. In insulin signaling, three classes of enzymes are of particular note: protein tyrosine phosphatases that remove phosphoryl groups from tyrosine residues on the insulin receptor, lipid phosphatases that hydrolyze PIP₃ to PIP₂, and protein serine phosphatases that remove phosphoryl groups from activated protein kinases such as Akt. Many of these phosphatases are activated or recruited as part of the response to insulin. Thus, the binding of the initial signal sets the stage for the eventual termination of the response.