Insulin signaling pathway

The insulin receptor comprises two extracellular α subunits and two transmembrane β subunits linked together by disulfide bonds. The binding of insulin to the α subunit induces a conformational change resulting in the autophosphorylation of several tyrosine residues in the β subunit1. These residues are recognized by phosphotyrosine-binding (PTB) domains of adaptor proteins, such as members of the insulin receptor substrate family (IRS)^{2, 3}.

Insulin receptor activation leads to the phosphorylation of key tyrosine residues on IRS proteins, some of which are recognized by the Src homology 2 (SH2) domain of the p85 regulatory subunit of PI3-kinase (a lipid kinase).

The catalytic subunit of PI3-kinase, p110, then phosphorylates phosphatidylinositol (4,5) bisphosphate [PtdIns(4,5)P2] leading to the formation of Ptd(3,4,5)P3. A key downstream effector of Ptd(3,4,5)P3 is AKT, which is recruited to the plasma membrane. Activation of AKT also requires the protein kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1), which, combined with an as-yet unidentified kinase, leads to the phosphorylation of AKT (see Figure 1).

Once active, AKT enters the cytoplasm, where it leads to the phosphorylation and inactivation of glycogen synthase kinase 3 (GSK3) (see Figure 2). A major substrate of GSK3 is glycogen synthase, an enzyme that catalyzes the final step in glycogen synthesis. Phosphorylation of glycogen synthase by GSK3 inhibits glycogen synthesis; therefore, the inactivation of GSK3 by AKT promotes glucose storage as glycogen.

In addition to promoting glucose storage, insulin inhibits the production and release of glucose by the liver by blocking gluconeogenesis and glycogenolysis2. Insulin directly controls the activities of a set of metabolic enzymes by phosphorylation and dephosphorylation events and also regulates the expression of genes encoding hepatic enzymes involved in gluconeogenesis.

Recent evidence suggests that forkhead transcription factors, which are excluded from the nucleus following phosphorylation by AKT, play a role in hepatic enzyme regulation by insulin ^{4, 5}. 

A key action of insulin is to stimulate glucose uptake into cells by inducing translocation of the glucose transporter, GLUT4, from intracellular storage to the plasma membrane. PI3-kinase and AKT are known to play a role in GLUT4 translocation3. In addition, a PI3-kinase-independent pathway provides a second cue for GLUT4 recruitment to the plasma membrane^2. 

In this pathway, insulin receptor activation leads to the phosphorylation of Cbl, which is associated with the adaptor protein CAP. Following phosphorylation, the Cbl-CAP complex translocates to lipid rafts in the plasma membrane. Cbl then interacts with the adaptor protein Crk, which is constitutively associated with the Rho-family guanine nucleotide exchange factor, C3G. C3G, in turn, activates members of the GTP-binding protein family, TC10, which promote GLUT4 translocation to the plasma membrane through the activation of as yet unknown adaptor molecules.

Insulin stimulates amino acid uptake into cells, inhibits protein degradation (through an unknown mechanism) and promotes protein synthesis². 

Under basal conditions, the constitutive activity of GSK3 leads to the phosphorylation and inhibition of a guanine nucleotide exchange factor eIF2B, which regulates the initiation of protein translation. Therefore, upon receipt of an insulin signal, the inactivation of GSK3 by AKT leads to the dephosphorylation of eIF2B, thereby promoting protein synthesis and the storage of amino acids³. 

AKT also activates the mammalian target of rapamycin (mTOR), which promotes protein synthesis through p70 ribosomal S6 kinase (p70s6k) and inhibition of eIF-4E binding protein (4E-BP1)⁶. 

Insulin promotes the uptake of fatty acids and the synthesis of lipids while inhibiting lipolysis.

Recent studies indicate that lipid synthesis requires increased transcription factor steroid regulatory element-binding protein (SREBP)-1c^7. 

However, the pathway leading to changes in SREBP expression is unknown. Insulin inhibits lipid metabolism by decreasing cellular concentrations of cAMP by activating a cAMP-specific phosphodiesterase in adipocytes⁸.

Other signal transduction proteins interact with IRS, including GRB2, an adaptor protein that contains SH3 domains, which in turn associates with the guanine nucleotide exchange factor son-of-sevenless (SOS) and elicits activation of the MAPK cascade leading to mitogenic responses⁹.

SHC is another substrate for the insulin receptor. Upon phosphorylation, SHC associates with GRB2 and can therefore activate the MAPK pathway independently of IRS.

Important enzymes in the attenuation of PtdIns(3,4,5)P3 signaling are phosphatase and tensin homolog on chromosome 10 (PTEN, a 3’ phosphatase) and the family of SRC homology 2 containing inositol 5’-phosphatase (SHIP, a 5’ phosphatase) proteins, which include two gene products SHIP1 and SHIP2¹⁰. These phosphatases degrade PtdIns(3,4,5)P3 to PtdIns(4,5)P2 or PtdIns(3,4)P2, respectively.

Insulin signaling can also be terminated by the internalization of the insulin-insulin receptor complex into endosomes and the degradation of insulin by the insulin-degrading enzyme (IDE)¹¹.