(A) Insulin receptors (INSRs, black) and the related receptor family members, IGF1 receptors (IGF1Rs, blue) and insulin receptor-related receptors (INSRRs, yellow) are expressed at the cell surface as preformed heterotetramers, each comprising two hemi-receptors composed of one α- and one β-subunit. Each α- and β-subunit and the two α-subunits are cross-linked by disulphide bridges. The extracellular α subunits bind insulin or IGFs as indicated or are responsive to alkaline pH_o. The β-subunits have a tyrosine kinase domain (red). Alternative splicing generates two isoforms of INSR, INSR-A and INSR-B, without or with (respectively) exon 11 (pink). Hybrid receptors can form between the family members. IGF2 also binds to the cation-independent mannose 6-phosphate receptor (CI-M6PR) that directs IGF2 and other molecules to the lysosome for degradation. (B) Insulin or IGFs bind to INSRs/IGF1Rs causing receptor phosphorylation and full activation of the tyrosine kinase, with additional phosphorylation of tyrosine residues (pY) on the β-subunit. These recruit adapter proteins including insulin receptor substrates (IRS) that become phosphorylated. IRS proteins recruit phosphoinositide 3′ kinase (PI3K) that stimulates production of phosphatidylinositol 3,4,5 tris phosphate in the membrane (red lipids), recruiting PDK1 and protein kinase B (PKB, also known as Akt). PDK1 phosphorylates PKB/Akt on Thr308. In some cells, INSRs/IGF1Rs also signal via Grb2 and the exchange factor Sos to the small G protein Ras. Activated Ras recruits Raf kinases that phosphorylate and activate mitogen-activated protein kinase kinases 1/2 (MKK1/2) that phosphorylate extracellular signal-regulated kinases 1 and 2 (ERK1/2). However, this pathway is not thought to be activated significantly in the heart and is shaded. (C) (i) PKB/Akt(T308) phosphorylates AS160 (Tbc1d4) to increase translocation of the glucose transporter GLUT4 to the membrane for glucose uptake. Phosphorylation and inhibition of glycogen synthase kinase 3 (GSK3) results in activation of glycogen synthase (GS) to increase glycogen synthesis. Other GSK3 substrates influence apoptosis, metabolism and cardiac hypertrophy. (ii) PKB/Akt(T308) activates mammalian target of rapamycin (mTOR) in mTOR complex 1 (mTORC1). Signalling via p70 ribosomal S6 kinase (p70S6K) increases ribosome biogenesis by increasing translation of RNAs with 5′ terminal oligopyrimidine (TOP) sequences), phosphorylation of Rps6 and regulation of other eukaryotic initiation factors (eIFs). mTORC1-dependent phosphorylation of 4E-BP causes it to dissociate from eIF4E that is then available to bind to the 5′ cap structure of mRNAs to increase translation and enhance protein synthesis. (iii) PKB/Akt(T308) is phosphorylated on Ser473 in mTORC2. Dually phosphorylated PKB/Akt(T308/S473) has greater activity and additional target specificity for forkhead transcription factors of the FoxO family. Phosphorylation of FoxO transcription factors inhibits their effects on gene expression, to influence apoptosis and metabolism.