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Insulin Pathway

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Signaling Pathways in Liver Diseases

Abstract

Insulin is the principal hormone controlling blood glucose levels. Insulin stimulates the uptake of glucose, and amino and fatty acids into cells, and increases the expression and/or activity of enzymes that enhance glycogen, lipid and protein synthesis, while inhibiting the activity or expression of those enzymes that catalyze the degradation of glycogen [1]. The increase in circulating insulin levels stimulates glucose transport into peripheral tissues and inhibits hepatic gluconeogenesis. Decreased secretion of insulin coupled with tissue resistance results in type 2 diabetes and is also associated with central obesity, hypertension, polycystic ovarian syndrome, dyslipidemia, and atherosclerosis. In addition, insulin has a role as a hepatotrophic factor and promotes hepatocyte proliferation, although the mechanisms by which it stimulates liver growth are not completely understood. At the cellular level, insulin action is characterized by diverse effects, including changes in vesicle trafficking, stimulation of protein kinases and phosphatases, promotion of cellular growth and differentiation, as well as activation or repression of gene transcription [2, 3]. The stimulation of the insulin/insulin receptor substrate-1 (IRS-1) system activates a number of intracellular signaling cascades that ultimately lead to important downstream biologic effects critical for cell function (Fig. 15.1). This complexity of cellular actions implies that insulin stimulation must involve multiple signaling pathways that diverge at or near the activation of receptor tyrosine kinase. Indeed, it is likely that even individual effects of the hormone require the activities of multiple signaling cascades. Although understanding of the signal transduction pathways that underlie insulin’s major physiologic effects is still incomplete, remarkable advances have occurred in the last decade. It is now clear that activation of insulin receptor tyrosine kinase, acting through the insulin receptor substrate (IRS) proteins as multisite docking molecules, creates binding sites that enable the IRSs to recruit and activate multiple, independent intracellular signal generators [4]. In this chapter, we discuss some of the known structural and functional features of the insulin receptor and IRS proteins and focus on recent advances in the understanding of the role of IRS proteins in insulin signaling effects. We will summarize the evidence regarding the potential role of IRS-1 in the pathogenesis of hepatocellular carcinoma (HCC) and explore insulin action on hepatocyte proliferation and liver development in the setting of chronic ethanol abuse.

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Acknowledgment

This work was supported in part by NIH grants CA-35711 AA-02666 (JRW) and COBRE RR-­P20RR017695 (MK).

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Authors and Affiliations

  1. The Liver Research Center, Alpert Medical School of Brown University, 55 Claverick Street, 4th Floor, Providence, RI, 02903, USA

    Miran Kim & Jack R. Wands

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  1. Miran Kim
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  2. Jack R. Wands
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Correspondence to Jack R. Wands .

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Editors and Affiliations

  1. Inselspital, Universität Bern, Murtenstr. 35, Bern, 3010, Switzerland

    Jean-Francois Dufour

  2. Klinik für Viszeral- und, Universitätsspital Zürich, Rämistr. 100, Zürich, 8091, Switzerland

    Pierre-Alain Clavien

Selected Reading

Selected Reading

1.Nandi A, Kitamura Y, Kahn CR et al. (2004) Mouse models of insulin resistance. Physiol Rev 84:623–647 (this review paper describes animal models including IRSs and IR knockout/transgenic mice in detail)

2.Mounier C, Poster BI (2006) Transcriptional regulation by insulin: from the receptor to the gene. Can J Physiol Pharmacol 84:713–724 (this review addresses the regulation by insulin of gene transcription in the liver)

3.Kubota N, Kubota T, Itoh S et al (2008) Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab 8:49–64 (this article shows hepatic IRS-1 and IRS-2 function in a distinct manner in the regulation of glucose homeostasis using KO and Tg mice)

4.Longato L, de al Monte S, Califano S et al. (2008) Synergistic permalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liver. Hepatol Res 38:940–953 (this recent paper shows the effects of ethanol in IRS-1 transgenic mice)

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Kim, M., Wands, J.R. (2010). Insulin Pathway. In: Dufour, JF., Clavien, PA. (eds) Signaling Pathways in Liver Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00150-5_15

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  • DOI: https://doi.org/10.1007/978-3-642-00150-5_15

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