Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.
Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.

Organismal Systems; Endocrine system
BRITE hierarchy

PMID:14635525

Ogawa W, Kasuga M.

[Mechanism of insulin action and diabetes mellitus]

Seikagaku 75:1332-44 (2003)

PMID:11282018

Bevan P.

Insulin signalling.

J Cell Sci 114:1429-30 (2001)

PMID:12867054

Kanzaki M, Pessin JE.

Insulin signaling: GLUT4 vesicles exit via the exocyst.

Curr Biol 13:R574-6 (2003)
DOI:10.1016/S0960-9822(03)00478-0

PMID:10196204

Moodie SA, Alleman-Sposeto J, Gustafson TA.

Identification of the APS protein as a novel insulin receptor substrate.

J Biol Chem 274:11186-93 (1999)
DOI:10.1074/jbc.274.16.11186

PMID:15733744

Gual P, Le Marchand-Brustel Y, Tanti JF.

Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.

Biochimie 87:99-109 (2005)
DOI:10.1016/j.biochi.2004.10.019

PMID:9748166

Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ.

Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1.

Science 281:2042-5 (1998)
DOI:10.1126/science.281.5385.2042

PMID:11742412

Saltiel AR, Kahn CR.

Insulin signalling and the regulation of glucose and lipid metabolism.

Nature 414:799-806 (2001)
DOI:10.1038/414799a

PMID:15624019

Inoki K, Corradetti MN, Guan KL.

Dysregulation of the TSC-mTOR pathway in human disease.

Nat Genet 37:19-24 (2005)
DOI:10.1038/ng1494

PMID:16288289

Ruggero D, Sonenberg N.

The Akt of translational control.

Oncogene 24:7426-34 (2005)
DOI:10.1038/sj.onc.1209098

PMID:10567225

Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR.

Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation.

Biochem J 344 Pt 2:427-31 (1999)
DOI:10.1042/bj3440427

PMID:9445476

Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G.

Phosphorylation and activation of p70s6k by PDK1.

Science 279:707-10 (1998)
DOI:10.1126/science.279.5351.707

PMID:9609110

Ogawa W, Matozaki T, Kasuga M.

Role of binding proteins to IRS-1 in insulin signalling.

Mol Cell Biochem 182:13-22 (1998)

PMID:9609111

Ceresa BP, Pessin JE.

Insulin regulation of the Ras activation/inactivation cycle.

Mol Cell Biochem 182:23-9 (1998)

PMID:15229476

Pollak MN, Schernhammer ES, Hankinson SE.

Insulin-like growth factors and neoplasia.

Nat Rev Cancer 4:505-18 (2004)
DOI:10.1038/nrc1387

PMID:9346240

Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME.

Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.

Cell 91:231-41 (1997)
DOI:10.1016/S0092-8674(00)80405-5

PMID:17344645

Ferre P, Foufelle F

SREBP-1c transcription factor and lipid homeostasis: clinical perspective.

Horm Res 68:72-82 (2007)
DOI:10.1159/000100426

PMID:18291668

Raghow R, Yellaturu C, Deng X, Park EA, Elam MB

SREBPs: the crossroads of physiological and pathological lipid homeostasis.

Trends Endocrinol Metab 19:65-73 (2008)
DOI:10.1016/j.tem.2007.10.009

PMID:11343120

Clement S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustel Y, Erneux C, Hue L, Schurmans S

The lipid phosphatase SHIP2 controls insulin sensitivity.

Nature 409:92-7 (2001)
DOI:10.1038/35051094

PMID:12791379

Backers K, Blero D, Paternotte N, Zhang J, Erneux C

The termination of PI3K signalling by SHIP1 and SHIP2 inositol 5-phosphatases.

Adv Enzyme Regul 43:15-28 (2003)
DOI:10.1016/S0065-2571(02)00043-2