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Molecular Medicine

, Volume 10, Issue 7–12, pp 65–71 | Cite as

Insulin Signaling and the Regulation of Glucose Transport

  • Louise Chang
  • Shian-Huey Chiang
  • Alan R Saltiel
In Overview

Abstract

Gaps remain in our understanding of the precise molecular mechanisms by which insulin regulates glucose uptake in fat and muscle cells. Recent evidence suggests that insulin action involves multiple pathways, each compartmentalized in discrete domains. Upon activation, the receptor catalyzes the tyrosine phosphorylation of a number of substrates. One family of these, the insulin receptor substrate (IRS) proteins, initiates activation of the phosphatidylinositol 3-kinase pathway, resulting in stimulation of protein kinases such as Akt and atypical protein kinase C. The receptor also phosphorylates the adapter protein APS, resulting in the activation of the G protein TC10, which resides in lipid rafts. TC10 can influence a number of cellular processes, including changes in the actin cytoskeleton, recruitment of effectors such as the adapter protein CIP4, and assembly of the exocyst complex. These pathways converge to control the recycling of the facilitative glucose transporter Glut4.

References

  1. 1.
    Saltiel AR, Kahn CR. (2001) Insulin signaling and the regulation of glucose and lipid metabolism. Nature 414:799–806.CrossRefGoogle Scholar
  2. 2.
    Furtado LM, Somwar R, Sweeney G, Niu W, Klip A. (2002) Activation of the glucose transporter GLUT4 by insulin. Biochem. Cell. Biol. 80:569–78.CrossRefGoogle Scholar
  3. 3.
    Watson RT, Kanzaki M, Pessin JE. (2004) Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr. Rev. 25:177–204.CrossRefGoogle Scholar
  4. 4.
    Rea S, James DE. (1997) Moving GLUT4: the biogenesis and trafficking of GLUT4 storage vesicles. Diabetes 46:1667–77.CrossRefGoogle Scholar
  5. 5.
    Kandror KV, Pilch PF. (1996) Compartmentalization of protein traffic in insulin-sensitive cells. Am. J. Physiol. 271:E1–14.CrossRefGoogle Scholar
  6. 6.
    Jhun BH, Rampal AL, Liu H, Lachaal M, Jung CY. (1992) Effects of insulin on steady state kinetics of GLUT4 subcellular distribution in rat adipocytes. Evidence of constitutive GLUT4 recycling. J. Biol. Chem. 267:17710–5.PubMedGoogle Scholar
  7. 7.
    Czech MP, Buxton JM. (1993) Insulin action on the internalization of the GLUT4 glucose transporter in isolated rat adipocytes. J. Biol. Chem. 268:9187–90.PubMedGoogle Scholar
  8. 8.
    Martin S et al. (2000) Effects of insulin on intracellular GLUT4 vesicles in adipocytes: evidence for a secretory mode of regulation. J. Cell. Sci. 113 Pt 19: 3427–38.PubMedGoogle Scholar
  9. 9.
    Bogan JS, Hendon N, McKee AE, Tsao TS, Lodish HF. (2003) Functional cloning of TUG as a regulator of GLUT4 glucose transporter trafficking. Nature 425:727–33.CrossRefGoogle Scholar
  10. 10.
    Holman GD, Lo Leggio L, Cushman SW. (1994) Insulin-stimulated GLUT4 glucose transporter recycling: a problem in membrane protein subcellular trafficking through multiple pools. J. Biol. Chem. 269:17516–24.PubMedGoogle Scholar
  11. 11.
    Randhawa VK et al. (2000) VAMP2, but not VAMP3/cellubrevin, mediates insulin-dependent incorporation of GLUT4 into the plasma membrane of L6 myoblasts. Mol. Biol. Cell. 11:2403–17.CrossRefGoogle Scholar
  12. 12.
    Livingstone C, James DE, Rice JE, Hanpeter D, Gould GW. (1996) Compartment ablation analysis of the insulin-responsive glucose transporter (GLUT4) in 3T3-L1 adipocytes. Biochem. J. 315 (Pt 2):487–95.CrossRefGoogle Scholar
  13. 13.
    Brozinick JT Jr, Hawkins ED, Strawbridge AB, Elmendorf JS. (2004) Disruption of cortical actin in skeletal muscle demonstrates an essential role of the cytoskeleton in glucose transporter 4 translocation in insulin-sensitive tissues. J. Biol. Chem. 279:40699–706.CrossRefGoogle Scholar
  14. 14.
    Kanzaki M, Pessin JE. (2001) Insulin-stimulated GLUT4 translocation in adipocytes is dependent upon cortical actin remodeling. J. Biol. Chem. 276:42436–44.CrossRefGoogle Scholar
  15. 15.
    Tong P, Khayat ZA, Huang C, Patel N, Ueyama A, Klip A. (2001) Insulin-induced cortical actin remodeling promotes GLUT4 insertion at muscle cell membrane ruffles. J. Clin. Invest. 108:371–81.CrossRefGoogle Scholar
  16. 16.
    Kanzaki M, Watson RT, Hou JC, Stamnes M, Saltiel AR, Pessin JE. (2002) Small GTP-binding protein TC10 differentially regulates two distinct populations of filamentous actin in 3T3L1 adipocytes. Mol. Biol. Cell 13:2334–46.CrossRefGoogle Scholar
  17. 17.
    Imamura T, Huang J, Usui I, Satoh H, Bever J, Olefsky JM. (2003) Insulin-induced GLUT4 translocation involves protein kinase C-lambda-mediated functional coupling between Rab4 and the motor protein kinesin. Mol. Cell. Biol. 23:4892–900.CrossRefGoogle Scholar
  18. 18.
    Semiz S et al. (2003) Conventional kinesin KIF5B mediates insulin-stimulated GLUT4 movements on microtubules. EMBO J. 22:2387–99.CrossRefGoogle Scholar
  19. 19.
    Thurmond DC, Kanzaki M, Khan AH, Pessin JE. (2000) Munc18c function is required for insulin-stimulated plasma membrane fusion of GLUT4 and insulin-responsive amino peptidase storage vesicles. Mol. Cell. Biol. 20:379–88.CrossRefGoogle Scholar
  20. 20.
    Mastick CC, Falick AL. (1997) Association of N-ethylmaleimide sensitive fusion (NSF) protein and soluble NSF attachment proteins-alpha and -gamma with glucose transporter-4-containing vesicles in primary rat adipocytes. Endocrinology 138:2391–7.CrossRefGoogle Scholar
  21. 21.
    Chen X et al. (2005) Demonstration of differential quantitative requirements for NSF among multiple vesicle fusion pathways of GLUT4 using a dominant-negative ATPase-deficient NSF. Biochem. Biophys. Res. Commun. 333:28–34.CrossRefGoogle Scholar
  22. 22.
    Min J et al. (1999) Synip: a novel insulin-regulated syntaxin 4-binding protein mediating GLUT4 translocation in adipocytes. Mol. Cell 3:751–60.CrossRefGoogle Scholar
  23. 23.
    Oh E, Spurlin BA, Pessin JE, Thurmond DC. (2005) Munc18c heterozygous knockout mice display increased susceptibility for severe glucose intolerance. Diabetes 54:638–47.CrossRefGoogle Scholar
  24. 24.
    Kanda H et al. (2005) Adipocytes from Munc18c-null mice show increased sensitivity to insulin-stimulated GLUT4 externalization. J. Clin. Invest. 115:291–301.CrossRefGoogle Scholar
  25. 25.
    Saltiel AR, Pessin JE. (2003) Insulin signaling in microdomains of the plasma membrane. Traffic 4:711–16.CrossRefGoogle Scholar
  26. 26.
    Tamemoto H et al. (1994) Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372:182–6.CrossRefGoogle Scholar
  27. 27.
    Withers DJ et al. (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–4.CrossRefGoogle Scholar
  28. 28.
    Shepherd PR. (2005) Mechanisms regulating phosphoinositide 3-kinase signaling in insulin-sensitive tissues. Acta Physiol. Scand. 183:3–12.CrossRefGoogle Scholar
  29. 29.
    Maehama T, Dixon JE. (1999) PTEN: a tumor suppressor that functions as a phospholipid phosphatase. Trends Cell Biol. 9:125–8.CrossRefGoogle Scholar
  30. 30.
    Pesesse X, Deleu S, De Smedt F, Drayer L, Erneux C. (1997) Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP. Biochem. Biophys. Res. Commun. 239:697–700.CrossRefGoogle Scholar
  31. 31.
    Habib T, Hejna JA, Moses RE, Decker SJ. (1998) Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein. J. Biol. Chem. 273: 18605–9.CrossRefGoogle Scholar
  32. 32.
    Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M. (1994) Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes: studies with a selective inhibitor wortmannin. J. Biol. Chem. 269:3568–73.PubMedGoogle Scholar
  33. 33.
    Martin SS, Haruta T, Morris AJ, Klippel A, Williams LT, Olefsky JM. (1996) Activated phosphatidylinositol 3-kinase is sufficient to mediate actin rearrangement and GLUT4 translocation in 3T3-L1 adipocytes. J. Biol. Chem. 271:17605–8.CrossRefGoogle Scholar
  34. 34.
    Sharma PM et al. (1998) Inhibition of phosphatidylinositol 3-kinase activity by adenovirus-mediated gene transfer and its effect on insulin action. J. Biol. Chem. 273:18528–37.CrossRefGoogle Scholar
  35. 35.
    Ueki K et al. (2003) Positive and negative roles of p85 alpha and p85 beta regulatory subunits of phosphoinositide 3-kinase in insulin signaling. J. Biol. Chem. 278:48453–66.CrossRefGoogle Scholar
  36. 36.
    Mauvais-Jarvis F et al. (2002) Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J. Clin. Invest. 109:141–9.CrossRefGoogle Scholar
  37. 37.
    Terauchi Y et al. (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat. Genet. 21: 230–5.CrossRefGoogle Scholar
  38. 38.
    Brachmann SM, Ueki K, Engelman JA, Kahn RC, Cantley LC. (2005) Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Mol. Cell. Biol. 25: 1596–607.CrossRefGoogle Scholar
  39. 39.
    Mora A, Komander D, van Aalten DM, Alessi DR. (2004) PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol. 15:161–70.CrossRefGoogle Scholar
  40. 40.
    Corvera S, Czech MP. (1998) Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. Trends Cell Biol. 8: 442–6.CrossRefGoogle Scholar
  41. 41.
    Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–101.CrossRefGoogle Scholar
  42. 42.
    Kohn AD et al. (1998) Construction and characterization of a conditionally active version of the serine/threonine kinase Akt. J. Biol. Chem 273:11937–43.CrossRefGoogle Scholar
  43. 43.
    Kohn AD, Summers SA, Birnbaum MJ, Roth RA. (1996) Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J. Biol. Chem. 271:31372–8.CrossRefGoogle Scholar
  44. 44.
    Wang Q et al. (1999) Protein kinase B/Akt participates in GLUT4 translocation by insulin in L6 myoblasts. Mol. Cell. Biol. 19:4008–18.CrossRefGoogle Scholar
  45. 45.
    Cong LN et al. (1997) Physiological role of Akt in insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. Mol. Endocrinol. 11:1881–90.CrossRefGoogle Scholar
  46. 46.
    Jiang ZY, Zhou QL, Coleman KA, Chouinard M, Boese Q, Czech MP. (2003) Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc. Natl. Acad. Sci. U. S. A. 100:7569–74.CrossRefGoogle Scholar
  47. 47.
    Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ. (2001) Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 276:38349–52.CrossRefGoogle Scholar
  48. 48.
    Cho H et al. (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292:1728–31.CrossRefGoogle Scholar
  49. 49.
    Sano H et al. (2003) Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J. Biol. Chem. 278: 14599–602.CrossRefGoogle Scholar
  50. 50.
    Zeigerer A, McBrayer MK, McGraw TE. (2004) Insulin stimulation of GLUT4 exocytosis, but not its inhibition of endocytosis, is dependent on RabGAP AS160. Mol. Biol. Cell. 15:4406–15.CrossRefGoogle Scholar
  51. 51.
    Karlsson HK, Zierath JR, Kane S, Krook A, Lienhard GE, Wallberg-Henriksson H. (2005) Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. Diabetes 54:1692–7.CrossRefGoogle Scholar
  52. 52.
    Miinea CP et al. (2005) AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem. J. 391 Pt 1:87–93.CrossRefGoogle Scholar
  53. 53.
    Wiese RJ, Mastick CC, Lazar DF, Saltiel AR. (1995) Activation of mitogen-activated protein kinase and phosphatidylinositol 3’-kinase is not sufficient for the hormonal stimulation of glucose uptake, lipogenesis, or glycogen synthesis in 3T3-L1 adipocytes. J. Biol. Chem. 270:3442–6.CrossRefGoogle Scholar
  54. 54.
    Isakoff SJ, Taha C, Rose E, Marcusohn J, Klip A, Skolnik EY. (1995) The inability of phosphatidylinositol 3-kinase activation to stimulate GLUT4 translocation indicates additional signaling pathways are required for insulin-stimulated glucose uptake. Proc. Natl. Acad. Sci. U. S. A. 92:10247–51.CrossRefGoogle Scholar
  55. 55.
    Jiang T, Sweeney G, Rudolf MT, Klip A, Traynor-Kaplan A, Tsien RY. (1998) Membrane-permeant esters of phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273:11017–24.CrossRefGoogle Scholar
  56. 56.
    Smart EJ et al. (1999) Caveolins, liquid-ordered domains, and signal transduction. Mol. Cell. Biol. 19:7289–304.CrossRefGoogle Scholar
  57. 57.
    Parpal S, Karlsson M, Thorn H, Stralfors P. (2001) Cholesterol depletion disrupts caveolae and insulin receptor signaling for metabolic control via insulin receptor substrate-1, but not for mitogen-activated protein kinase control. J. Biol. Chem. 276:9670–8.CrossRefGoogle Scholar
  58. 58.
    Gustavsson J et al. (1999) Localization of the insulin receptor in caveolae of adipocyte plasma membrane. FASEB J. 13:1961–71.CrossRefGoogle Scholar
  59. 59.
    Kimura A, Mora S, Shigematsu S, Pessin JE, Saltiel AR. (2002) The insulin receptor catalyzes the tyrosine phosphorylation of caveolin-1. J. Biol. Chem. 277:30153–8.CrossRefGoogle Scholar
  60. 60.
    Liu J, Kimura A, Baumann CA, Saltiel AR. (2002) APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Mol. Cell. Biol. 22:3599–609.CrossRefGoogle Scholar
  61. 61.
    Baumann CA et al. (2000) CAP defines a second signaling pathway required for insulin-stimulated glucose transport [see comments]. Nature 407:202–7.CrossRefGoogle Scholar
  62. 62.
    Hu J, Liu J, Ghirlando R, Saltiel AR, Hubbard SR. (2003) Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor. Mol. Cell 12:1379–89.CrossRefGoogle Scholar
  63. 63.
    Kimura A, Baumann CA, Chiang SH, Saltiel AR. (2001) The sorbin homology domain: a motif for the targeting of proteins to lipid rafts. Proc. Natl. Acad. Sci. U. S. A. 98: 9098–103.CrossRefGoogle Scholar
  64. 64.
    Ribon V, Printen JA, Hoffman NG, Kay BK, Saltiel AR. (1998) A novel, multifuntional c-Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes. Mol. Cell. Biol. 18:872–9.CrossRefGoogle Scholar
  65. 65.
    Kioka N et al. (1999) Vinexin: a novel vinculin-binding protein with multiple SH3 domains enhances actin cytoskeletal organization. J. Cell. Biol. 144:59–69.CrossRefGoogle Scholar
  66. 66.
    Liu J, Deyoung SM, Zhang M, Dold LH, Saltiel AR. (2005) The stomatin/prohibitin/flotillin/HflK/C domain of flotillin-1 contains distinct sequences that direct plasma membrane localization and protein interactions in 3T3-L1 adipocytes. J. Biol. Chem. 280:16125–34.CrossRefGoogle Scholar
  67. 67.
    Ahn MY, Katsanakis KD, Bheda F, Pillay TS. (2004) Primary and essential role of the adaptor protein APS for recruitment of both c-Cbl and its associated protein CAP in insulin signaling. J. Biol. Chem. 279:21526–32.CrossRefGoogle Scholar
  68. 68.
    Mitra P, Zheng X, Czech MP. (2004) RNAi-based analysis of CAP, Cbl, and CrkII function in the regulation of GLUT4 by insulin. J. Biol. Chem. 279:37431–5.CrossRefGoogle Scholar
  69. 69.
    Zhou QL et al. (2004) Analysis of insulin signaling by RNAi-based gene silencing. Biochem. Soc. Trans. 32:817–21.CrossRefGoogle Scholar
  70. 70.
    Ribon V, Hubbell S, Herrera R, Saltiel AR. (1996) The product of the cbl oncogene forms stable complexes in vivo with endogenous Crk in a tyrosine phosphorylation-dependent manner. Mol. Cell. Biol. 16:45–52.CrossRefGoogle Scholar
  71. 71.
    Knudsen BS, Feller SM, Hanafusa H. (1994) Four proline-rich sequences of the guanine-nucleotide exchange factor C3G bind with unique specificity to the first Src homology 3 domain of Crk. J. Biol. Chem. 269:32781–7.PubMedGoogle Scholar
  72. 72.
    Chiang SH, Hou JC, Hwang J, Pessin JE, Saltiel AR. (2002) Cloning and functional characterization of related TC10 isoforms, a subfamily of Rho proteins involved in insulin-stimulated glucose transport. J. Biol. Chem. 277:13067–73.CrossRefGoogle Scholar
  73. 73.
    Chiang SH et al. (2001) Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 410:944–8.CrossRefGoogle Scholar
  74. 74.
    Novick P, Zerial M. (1997) The diversity of Rab proteins in vesicle transport. Curr. Opin. Cell Biol. 9:496–504.CrossRefGoogle Scholar
  75. 75.
    Chang L, Adams RD, Saltiel AR. (2002) The TC10-interacting protein CIP4/2 is required for insulin-stimulated Glut4 translocation in 3T3L1 adipocytes. Proc. Natl. Acad. Sci. U. S. A. 99:12835–40.CrossRefGoogle Scholar
  76. 76.
    Inoue M, Chang L, Hwang J, Chiang SH, Saltiel AR. (2003) The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin. Nature 422:629–33.CrossRefGoogle Scholar
  77. 77.
    Ewart MA, Clarke M, Kane S, Chamberlain LH, Gould GW. (2005) Evidence for a role of the exocyst in insulin-stimulated Glut4 trafficking in 3T3-L1 adipocytes. J. Biol. Chem. 280:3812–6.CrossRefGoogle Scholar
  78. 78.
    Kanzaki M, Mora S, Hwang JB, Saltiel AR, Pessin JE. (2004) Atypical protein kinase C (PKCzeta/lambda) is a convergent downstream target of the insulin-stimulated phosphatidylinositol 3-kinase and TC10 signaling pathways. J. Cell Biol. 164: 279–90.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2004

Authors and Affiliations

  • Louise Chang
    • 1
  • Shian-Huey Chiang
    • 1
  • Alan R Saltiel
    • 1
  1. 1.Life Sciences Institute, Departments of Internal Medicine and PhysiologyUniversity of MichiganAnn ArborUSA

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