and adipose tissue. The receptors bind insulin with high specificity and affinity in the picomolar range. The full insulin receptor consists of two covalently linked heterodimers, each containing an α subunit, which is entirely extracellular and constitutes the recognition site, and a β subunit that spans the membrane (Figure 41–3). The β subunit contains a tyrosine kinase. The binding of an insulin molecule to the α subunits at the outside surface of the cell activates the receptor and through a conformational change brings the catalytic loops of the opposing cytoplasmic β subunits into closer proximity. This facilitates mutual phosphorylation of tyrosine residues on the β subunits and tyrosine kinase activity directed at cytoplasmic proteins.
The first proteins to be phosphorylated by the activated receptor tyrosine kinases are the docking proteins: insulin receptor substrates (IRS). After tyrosine phosphorylation at several critical sites, the IRS molecules bind to and activate other kinases subserving energy metabolism—most significantly phosphatidylinositol3-kinase—which produce further phosphorylations. Alternatively, they may stimulate a mitogenic pathway and bind to an adaptor protein such as growth factor receptor–binding protein 2, which translates the insulin signal to a guanine nucleotide-releasing factor that ultimately activates the GTP binding protein, Ras, and the mitogen-activated protein kinase (MAPK) system. The particular IRS-phosphorylated tyrosine kinases have binding specificity with downstream molecules based on their surrounding 4–5 amino acid sequences or motifs that recognize specific Src homology 2 (SH2) domains on the other protein. This network of phosphorylations within the cell represents insulin’s second message and results in multiple effects, including translocation of glucose transporters (especially GLUT 4, Table 41–2) to the cell membrane with a resultant increase in glucose uptake; increased glycogen synthase activity and increased glycogen formation; multiple effects on protein synthesis, lipolysis, and lipogenesis; and activation of transcription factors that enhance DNA synthesis and cell growth and division.
Various hormonal agents (eg, glucocorticoids) lower the affinity of insulin receptors for insulin; growth hormone in excess increases this affinity slightly. Aberrant serine and threonine phosphorylation of the insulin receptor β subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation.
Effects of Insulin on Its Targets
Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells (Figure 41–4) and influences cell growth and the metabolic functions of a wide variety of tissues (Table 41–3).
Glucagon is synthesized in the alpha cells of the pancreatic islets of Langerhans (Table 41–1). Glucagon is a peptide— identical in all mammals—consisting of a single chain of
FIGURE 41–3 Schematic diagram of the insulin receptor heterodimer in the activated state. IRS, insulin receptor substrate; MAP, mitogen-activated protein; P, phosphate; Tyr, tyrosine.
29 amino acids, with a molecular weight of 3485. Selective proteolytic cleavage converts a large precursor molecule of approximately 18,000 MW to glucagon. One of the precursor intermediates consists of a 69-amino-acid peptide called glicentin, which contains the glucagon sequence interposed between peptide extensions.
TABLE 41–2 Glucose transporters.