Insulin Receptor Signaling in Normal and Insulin-resistant States

Overview

Journal Cold Spring Harb Perspect Biol

Specialties Biology
Molecular Biology

Date 2014 Jan 4

PMID 24384568

Citations 640

Authors

Jeremie Boucher

Andre Kleinridders

C Ronald Kahn

Affiliations

Soon will be listed here.

Abstract

In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms. Understanding these pathways is essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications.

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References

Boucher J, Tseng Y, Kahn C . Insulin and insulin-like growth factor-1 receptors act as ligand-specific amplitude modulators of a common pathway regulating gene transcription. J Biol Chem. 2010; 285(22):17235-45. PMC: 2878077. DOI: 10.1074/jbc.M110.118620. View

Ni Y, Wang N, Cao D, Sachan N, Morris D, Gerard R . FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases. Proc Natl Acad Sci U S A. 2007; 104(51):20517-22. PMC: 2154463. DOI: 10.1073/pnas.0610290104. View

Sachithanandan N, Fam B, Fynch S, Dzamko N, Watt M, Wormald S . Liver-specific suppressor of cytokine signaling-3 deletion in mice enhances hepatic insulin sensitivity and lipogenesis resulting in fatty liver and obesity. Hepatology. 2010; 52(5):1632-42. DOI: 10.1002/hep.23861. View

Ozcan U, Cao Q, Yilmaz E, Lee A, Iwakoshi N, Ozdelen E . Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004; 306(5695):457-61. DOI: 10.1126/science.1103160. View

Evans J, Maddux B, Goldfine I . The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal. 2005; 7(7-8):1040-52. DOI: 10.1089/ars.2005.7.1040. View

Cochran E, Musso C, Gorden P . The use of U-500 in patients with extreme insulin resistance. Diabetes Care. 2005; 28(5):1240-4. DOI: 10.2337/diacare.28.5.1240. View

Matsushima R, Harada N, Webster N, Tsutsumi Y, Nakaya Y . Effect of TRB3 on insulin and nutrient-stimulated hepatic p70 S6 kinase activity. J Biol Chem. 2006; 281(40):29719-29. DOI: 10.1074/jbc.M511636200. View

Fridlyand L, Philipson L . Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes Obes Metab. 2006; 8(2):136-45. DOI: 10.1111/j.1463-1326.2005.00496.x. View

Holt L, Lyons R, Ryan A, Beale S, Ward A, Cooney G . Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis. Mol Endocrinol. 2009; 23(9):1406-14. PMC: 2737556. DOI: 10.1210/me.2008-0386. View

10.

Koh E, Lee W, Kim M, Park J, Lee I, Lee K . Intracellular fatty acid metabolism in skeletal muscle and insulin resistance. Curr Diabetes Rev. 2008; 1(3):331-6. DOI: 10.2174/157339905774574347. View

11.

Sano H, Kane S, Sano E, Miinea C, Asara J, Lane W . Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem. 2003; 278(17):14599-602. DOI: 10.1074/jbc.C300063200. View

12.

Ravichandran L, Esposito D, Chen J, Quon M . Protein kinase C-zeta phosphorylates insulin receptor substrate-1 and impairs its ability to activate phosphatidylinositol 3-kinase in response to insulin. J Biol Chem. 2000; 276(5):3543-9. DOI: 10.1074/jbc.M007231200. View

13.

Stiles B, Wang Y, Stahl A, Bassilian S, Lee W, Kim Y . Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci U S A. 2004; 101(7):2082-7. PMC: 357055. DOI: 10.1073/pnas.0308617100. View

14.

Rotter V, Nagaev I, Smith U . Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem. 2003; 278(46):45777-84. DOI: 10.1074/jbc.M301977200. View

15.

Xia P, Inoguchi T, Kern T, ENGERMAN R, Oates P, King G . Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia. Diabetes. 1994; 43(9):1122-9. DOI: 10.2337/diab.43.9.1122. View

16.

Taniguchi C, Tran T, Kondo T, Luo J, Ueki K, Cantley L . Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN. Proc Natl Acad Sci U S A. 2006; 103(32):12093-7. PMC: 1524929. DOI: 10.1073/pnas.0604628103. View

17.

Li X, Monks B, Ge Q, Birnbaum M . Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature. 2007; 447(7147):1012-6. DOI: 10.1038/nature05861. View

18.

White M . Regulating insulin signaling and beta-cell function through IRS proteins. Can J Physiol Pharmacol. 2006; 84(7):725-37. DOI: 10.1139/y06-008. View

19.

Huang C, Thirone A, Huang X, Klip A . Differential contribution of insulin receptor substrates 1 versus 2 to insulin signaling and glucose uptake in l6 myotubes. J Biol Chem. 2005; 280(19):19426-35. DOI: 10.1074/jbc.M412317200. View

20.

Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher A . Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999; 399(6736):601-5. DOI: 10.1038/21224. View