Insulin exerts all of its biological activities, both as a hormone and as a growth factor, by binding to a cell surface receptor complex. The insulin receptor is a member of the membrane-spanning receptor family that harbors intrinsic tyrosine kinase activity. However, the insulin receptor is unique in that it is a heterotetrameric complex composed of two completely extracellular α-peptides that are disulfide bonded to the two transmembrane-spanning β-peptides. Both the α- and β- subunits of the receptor complex are derived from a single gene (symbol: INSR). This processing of the receptor is reminiscent of the processing of the preproinsulin protein leading to two peptides (A and B) disulfide bonded together to form bioactive insulin.
The INSR gene is located on chromosome 19p13.3-p13.2 and is composed of 22 exons. Two alternative splicing variants of the insulin receptor preproprotein are generated from the INSR precursor mRNA. One form contains exon 11 sequences (termed the IR-B form or the Long preproprotein isoform) while the IR-A form (Short preproprotein isoform) does not. The result of the alternative splicing is that the α-subunit from the IR-B form has a 12-amino acid extension at its C-terminus. This form of the α-subunit is referred to as αCT. The insulin receptor can also bind the related growth factors mentioned above, IGF-1 and IGF-2. When insulin binds to the receptor it activates the intrinsic tyrosine kinase activity of the β-subunits resulting in autophosphorylation of the receptor. These autophosphorylations occur on between 6 and 13 tryosine residues with the most frequently observed being tyrosines at amino acid position 1316, 1322, 1146, 1150, and 1151 in the intracellular portions of the β-subunits.
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All of the post-receptor responses initiated by insulin binding to its receptor are mediated as a consequence of the activation of several divergent and/or intersecting signal transduction pathways (see Figure below). These include association of insulin receptor substrates (of which there are three: IRS1, IRS2, and IRS4) with the receptor resulting in the activation of phosphatidylinositol-3-kinase (PI3K) and growth factor receptor binding protein 2 (GRB2). Activated PI3K phosphorylates membrane phospholipids, the major product being phosphatidylinositol-3,4,5-trisphosphate, (PIP3). PIP3 in turn activates the enzyme, PIP3-dependent kinase 1, (PDK1). PDK1 activates another kinase called protein kinase B, PKB (also called AKT). There are three members of the PKB/AKT family of serine/threonine kinases identified as AKT1 (PKB, also PKBα), AKT2 (PKBβ), and AKT3 (PKBγ). It is AKT2 that is important in insulin-mediated glucose homeostasis. Insulin-mediated activation of PKB/AKT also results in inhibition of lipolysis and gluconeogenesis and activation of protein synthesis and glycogen synthesis. Another important metabolism regulating enzyme activated by insulin receptor signaling is small ribosomal subunit protein 6 (p70) kinase, (p70S6K). Acting as a growth factor, insulin signaling activates the MAP kinase (MAPK) pathway either through insulin receptor phosphorylation of SRC homology 2 containing protein (Shc) which then interacts with growth factor receptor binding protein-2 (GRB2) or via IRS1 activation.
Insulin-mediated glucose uptake involves activated PDK1 which phosphorylates some isoforms of protein kinase C, PKC. The PKC isoform, PKCλ/ζ, phosphorylates intracellular vesicles containing the glucose transporter, GLUT4, resulting in their migration to and fusion with, the plasma membrane. This results in increased glucose uptake and metabolism. The activation of GRB2 results in signal transduction via the monomeric G-protein, RAS. Activation of RAS ultimately leads to changes in the expression of numerous genes via activation of members of the extracellular signal-regulated kinases, ERK. In addition to its effects on enzyme activity, insulin exerts effects on the transcription of numerous genes, effects that are primarily mediated by regulated activity of sterol-regulated element binding protein, SREBP. These transcriptional effects include (but are not limited to) increases in glucokinase, liver pyruvate kinase (L-PK), lipoprotein lipase (LPL), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) gene expression, and decreases in glucose 6-phosphatase, fructose 1,6-bisphosphatase and phosphoenolpyruvate carboxykinase (PEPCK) gene expression.
Multiple roles of insulin. When insulin binds to its receptor it triggers receptor autophosphorylation that generates docking sites for insulin receptor substrate proteins (IRS-1–IRS4). IRS proteins in turn trigger the activation of a wide array of signal transducing proteins (highly simplified in this Figure). The end results of insulin receptor activation are varied and in many cases cell-type specific but includes alterations in metabolism, ion fluxes, protein translocation, transcription rates, and growth properties of responsive cells. Arrows represent positive, activating functions. T-lines represent inhibitory functions. Most abbreviations are described within the text below. PDE3B: phosphodiesterase 3B (also called adipocyte cAMP phosphodiesterase), GS: glycogen synthase, HSL: hormone sensitive lipase, ACC: acetyl-CoA carboxylase, ACL: ATP-citrate lyase.