Review of Medical Physiology - William F. Ganong 2002

Endocrine System, Metabolism, and Reproduction
Endocrine Functions of the Pancreas and Regulation of Carbohydrate Metabolism
Mechanism of Action

Insulin receptors

Insulin receptors are found in many Cells throughout the body, even in those where insulin does not increase glucose uptake. Notably, the Insulin Receptor has a Molecular Weight of approximately 340,000 daltons and is a tetramer composed of two alpha and two beta glycoprotein subunits (Fig. 19-6). They are all synthesized from a single mRNA molecule, after which they are proteolytically cleaved and linked together by Disulfide Bonds. The insulin receptor Gene contains 22 exons and is located on chromosome 19. The alpha subunits bind insulin and are extracellular, whereas the beta subunits span the membrane. The intracellular domains of the beta subunits exhibit Tyrosine kinase activity. Both the alpha and beta subunits are glycosylated with sugar residues that project into the interstitial fluid.

The binding of insulin triggers the tyrosine kinase activity of the beta subunits, leading to their autophosphorylation at tyrosine residues. This autophosphorylation, which is required for the manifestation of insulin's biological effects, results in the phosphorylation of certain cytoplasmic Proteins and the dephosphorylation of others, predominantly at Serine and Threonine residues (Fig. 19-7). Four closely related insulin receptor substrates have been described in cells: IRS-1, IRS-2, IRS-3, and IRS-4. Presumably, each of them mediates a specific aspect of insulin action. For example, a mouse with an insulin receptor gene knockout exhibits marked intrauterine growth retardation, CNS and Skin abnormalities, and dies at birth due to respiratory failure. In contrast, an IRS-1 knockout mouse shows only moderate intrauterine growth retardation, survives, and is insulin-resistant while remaining otherwise virtually normal. Consequently, intracellular pathways independent of IRS-1 must also participate in insulin signaling. The relationship between IRS-2 and beta-Cell accumulation is discussed below.

It is interesting to compare the insulin receptor with other closely related receptors. It is very similar to the IGF-I receptor, yet distinct from the IGF-II receptor (see Fig. 19-6). Other growth factor receptors and various oncogene-encoded receptors also function as tyrosine Kinases. Despite this functional similarity, the Amino Acid Composition of these receptors is entirely different.

Upon insulin binding to its receptors, they undergo aggregation and are internalized into The Cell via receptor-mediated endocytosis (see Chapter 1).

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Fig. 19-6. Insulin, IGF-I, and IGF-II. Each hormone binds primarily to its own receptor, though insulin also binds to the IGF-I receptor, and IGF-I binds to all three. Dark rectangles represent intracellular tyrosine kinase domains. Note the structural similarity between the insulin receptor and the IGF-I receptor, as well as the 15 repeat sequences in the extracellular region of the IGF-II receptor.

Insulin-receptor complexes are delivered to Lysosomes, where the receptors are predominantly degraded or recycled. The half-life of the insulin receptor is approximately 7 hours.

Insulin and Other Hormones, Physical Exercise, diet, and various other factors influence the number or affinity of insulin receptors, or both. Exposure to high concentrations of insulin decreases receptor concentration (down-regulation), whereas reduced insulin levels increase receptor affinity. The number of receptors per cell increases during fasting and decreases in obesity and acromegaly. Receptor affinity increases in adrenal insufficiency and decreases in the presence of excess glucocorticoids (see below).