Insulin is the chief hormone controlling intermediary metabolism. It affects virtually every tissue in the body, but principally liver, muscle, and adipose tissue. Its short-term effects are to reduce blood glucose and to conserve body fuel supplies. There are also a number of effects of insulin on the regulation of gene transcription and cell replication. The number of insulin receptors in insulin target cells ranges from less than 100 to more than 200,000 per cell. The highest concentrations of the insulin receptor are found in hepatocytes and adipocytes.

The upper A panel of Figure 1 presents a schematic of the general structure of a single insulin receptor comprised of two α and two β subunits that are interlinked by three disulfide bonds, thus creating two ligand binding domains for insulin on one copy of the receptor. The second half of the schematic of Figure 1B provides a sample of the signal transduction path ways that can be initiated and fully activated in a cell by the binding of insulin to its receptor. In this model, four kinds of biological responses are diagrammed; they are (i) vascular constriction, (ii) vascular relaxation, (iii) stimulation of glucose uptake followed by glycogen synthesis in the liver, muscle, and adipose tissues, and (iv) translocation of glucose transporters (GLUT4) to the cell’s plasma membrane. Collectively this provides an introductory overview of the complexity of the signal transduction events that are available in various cell types with the insulin receptor that can lead to generation of a wide variety of various biological responses.

Fig1. Schematic diagram illustrating the consequence of insulin binding to its dimeric insulin receptor that spans the cell’s plasma membrane. Together the receptor with bound insulin generates an initiating “signal” that results (in this example) in the activation of four signal transduction pathways that generate a variety of biological responses in this composite generic cell. (A) Schematic model of the insulin receptor tetramer in the plasma membrane of a target cell. The two smaller extracellular insulin receptor subunits are stabilized by a disulfide bond. The two larger intracellular receptor subunits are each individually stabilized by a disulfide bond with the extracellular smaller insulin receptor subunit. The process of insulin signaling begins through the binding of two insulin molecules, one to each of the two α subunits of the receptor. This results in a conformational change in the α subunits which is detected by the two intracellular insulin receptor β subunits. (B) Summary of the insulin receptor’s stimulation of signal transduction and exocytosis of the GLUT4 glucose transporter. The activated β subunits of the insulin receptor then continue delivery of the signal transduction message so that one or more of the tyrosine kinases on the β subunit becomes activated. Then, in this composite cell, the activated tyrosine kinase will activate one of five signal transduction pathways designated (P1a, P1b, P2, P3, or P4). The ultimate biological outcome of each of the five pathways is described in panel B. It can range from one of the five following processes: (P1a) activation of gene transcription, and protein synthesis that can lead to cell growth and/or cell differentiation via the MAPK pathway; (P1b) vascular constriction of the endothelium via MAPK stimulating blood pressure; (P3) vascular relaxation of the endothelium via PI3-K and Akt stimulating the hormone production of nitric oxide (NO) which causes vascular relaxation; (P2) glucose uptake, activation of gluconeogenesis or glycogen synthesis in liver, skeletal muscle, and adipose tissues by stimulating PKC, FOX1 and GSK3; and (P4) CAP stimulating translocation of GLUT4 to the cell membrane thereby increasing uptake of glucose into the host cell. Abbreviations for signal transduction proteins: (For the pathways, P1a and P1b) SHC, Src homology 2 domain containing transforming protein 1; GRB2, growth factor receptor-bound protein; SOS, son of seven less; RAS, rat sarcoma oncogene; RAF; MEK, mitogen-activated protein kinase kinase; and MAPK, mitogen-activated protein kinase. (For pathway P2 greenish eNOS) endothelial nitrogen oxide synthase which secretes the hormone nitric oxide (NO). (For pathway P3, orangeish color) starting with PI3-K, phosphatidylinositide-dependent protein kinase 1; PDK, a constitutive membrane threonine kinase; Akt, protein kinase B; aPKC, a typical protein kinase; FOXO1, forkhead box-containing protein O; and GSK3, glycogen synthase kinase—3. (For pathway P4) CAP, Cbl-associated protein; Cbl, Cas-Br-M (murine) ecotropic retroviral transforming sequence; Crk, CT-10 factor; C3G, guanine nucleotide exchange factor C3G; and TCIO, small GTP binding protein TCIO.

The insulin receptor is encoded by a single gene. When it is subjected to alternate splicing during transcription it generates two long amino acid chains (each ~450 amino acids), IR-A or IR-B. The IR-A and IR-B are then each proteolytically cleaved to generate pairs of α and β insulin receptor subunits. Thus the intact insulin receptor is a heterotetrameric (α/β/α/β) trans-membrane glycoprotein of ~460 kDa with 906 amino acids. Also, a variety of amino acid substitution mutations have been identified in both the α and β subunits of the insulin receptor present in patients with severe insulin resistance.

Figure 1A presents a schematic of the insulin receptor. The intact insulin receptor is composed of two α subunits (~135 kDa) and two β subunits (95 kDa) that are joined together by three disulfide bonds. The two α subunits are located completely outside of the cell and they are linked to each other by a single disulfide bond. The two β subunits are 10% extracellular and 90% located on the interior surface of the plasma membrane. Each β subunit is linked to an α subunit by a disulfide linkage. As shown in Figure 1A, each α subunit appears to contain an insulin-binding domain; however, when the first site is occupied by its insulin ligand, it can induce negative cooperativity, which can reduce the affinity of the insulin ligand for the second insulin-binding site. Occupancy of the insulin receptor initiates a complex series of response cascades that can involve over 50 proteins-enzymes.

The two β subunits that span the plasma membrane both have 28 extracellular amino acids, 23 transmembrane amino acids, and an intracellular domain of 402 amino acids. The extracellular portion of each β sub unit is attached via a disulfide bond to the bottom of a partner α receptor subunit. The consequence of insulin binding to its α receptor (blue ovals) outside the cell results in the activation of the catalytic activity of the β subunit’s tyrosine kinase activity on the inside of the cell; note the presence of seven tyrosines on the left β subunit. Then one of the insulin receptor’s β subunits selectively phosphorylates one of its partner β subunit’s seven tyrosines, thereby initiating selective activation of a variety of signal transduction pathways.

In the composite diagram described in Figure 1B, physiological concentrations of insulin in the range of 100–500 pM bind to the insulin receptor and selectively activate one of a family of five insulin-dependent signal transduction pathways. Each of these signal transduction pathways mediates unique biological responses appropriate for the host cell type. The insulin modulated biological responses are as follows: the P1a pathway activates gene transcription that can con tribute to growth, mitogenesis, and/or differentiation; in the P1b pathway present in vascular endothelium cells the secretion of the hormone endothelin-1 (ET-1) is stimulated which causes vascular constriction; the P2 pathway stimulates the secretion of the hormone nitric oxide (NO) which mediates vascular relaxation; the P3 pathway is operative in skeletal muscle, adipose tissue, and liver cells where glucose uptake, gluconeogenesis, and glycogen synthesis are stimulated; and the P4 path way regulates the uptake of glucose into skeletal muscle, adipose, and cardiac muscle cells.

General features of the insulin signal transduction pathways are described in this hypothetical generic cell (see Figure 1B). On the bottom of both of the insulin receptors’ β subunit, note the presence of a single phosphorylated tyrosine. In some insulin receptor- containing cells there can be as many as five phosphorylated tyrosines on a single β subunit. They function as a switch that can selectively stimulate (in this model) a menu of five different available signal transduction pathways. (P1a) This MAPK pathway starts at the bot tom left of the phosphorylated β subunit of insulin, which is also covalently linked to the signaling molecule SHC, followed by six additional signaling molecules ending with MAPK. The MAPK can mediate in many cell types the activation and control of general gene transcription, followed by protein synthesis and modulation of cell growth. (P1b) When the MAPK signaling pathway is present in the vascular endothelium its activation can stimulate the secretion of the peptide hormone endothelin-1 (ET-1). (P2/P3) These two signaling pathways start at the bottom of the right-hand β subunit of insulin where the IRS (insulin receptor substrate) is linked via phosphorylation to the insulin receptor and by an additional phosphorylation to the P13-K signaling molecule which leads eventually to the separate activation, depending on the cell type, of either the P2 or P3 pathways. The P2 pathway activates eNOS which stimulates the secretion of the only hormone that is a gas, namely nitric oxide (NO), which then causes vasodilation of the vascular endothelium. The P3 pathway leads to the stimulation of aPKC, FOX01, or GSK3 in skeletal muscle, adipose tissue, and liver, respectively. The result is stimulation of glucose uptake and an increase in gluconeogenesis and glycogen synthesis.

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