Advertisement

Cellular Mechanisms of Insulin Action

  • Theodore P. Ciaraldi

Abstract

Insulin is a highly plieotrophic hormone, with predominantly anabolic actions in a variety of tissues. Selectivity of final responses to insulin arises both from cell specific expression of final effector proteins and by activation of different signaling pathways. We will consider first an overview of mechanisms of insulin action in normal human physiology, introducing the pathways, players and principles involved, before returning to consider how these elements are modulated in type 2 diabetes. While the critical initial studies in this area were performed in animal and cell systems and later confirmed in humans, for the consideration of pathophysiology we will concentrate on the literature concerning insulin action in humans.

Keywords

Insulin Receptor Insulin Action Protein Tyrosine Phosphatase Insulin Receptor Substrate Pleckstrin Homology Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ottensmeyer FP, Beniac DR, Luo RZ, Yip CC. Mechanism of transmembrane signaling: insulin binding and the insulin receptor. Biochemistry 39: 12103–12112, 2000.PubMedCrossRefGoogle Scholar
  2. 2.
    Ellis L, Tavare JM, Levine BA. Insulin receptor tyrosine kinase structure and function. Biochem Soc Trans 43–426–432, 1991.Google Scholar
  3. 3.
    Myers MG, White MF. Insulin signal transduction and the IRS proteins. Annu Rev Pharmacol Toxicol 36: 615–658, 1996.PubMedCrossRefGoogle Scholar
  4. 4.
    Hotamisligil GS, Perald, P, Budavar, A, Ellis R, Whit, MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha-and obesity-induced insulin resistance. Science 271: 665–668, 1996.PubMedCrossRefGoogle Scholar
  5. 5.
    Ravichandran LV, Esposito DL, Chen J, Quon MJ. 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 276: 3543–3549, 2001.PubMedCrossRefGoogle Scholar
  6. 6.
    Virkamaki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 103: 931–943, 1999.PubMedCrossRefGoogle Scholar
  7. 7.
    Shepherd PR, Withers DJ, Siddle K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 333: 471–490, 1998.Google Scholar
  8. 8.
    Alessi DR, Deak M, Casamayor A, et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drospohila DSTPK61 kinase. Current Biol 7: 776–789, 1997.CrossRefGoogle Scholar
  9. 9.
    Farese RV. Insulin-sensitive phospholipid signaling systems and glucose transport. Update II. Exp Biol Med 226: 283–295, 2001.Google Scholar
  10. 10.
    Valverde AM, Lorenzo M, Navarro P, Mur C, Benito M. Okadiac acid inhibits insulin-induced glucose transport in fetal brown adipocytes in an Akt-independent and protein kinase C zeta-dependent manner. Febs Letts 472: 153–158, 2000.CrossRefGoogle Scholar
  11. 11.
    Sajan MP, Standaert ML, Bandyopadhyay G, Quon MJ, Burke TR, Farese RV. Protein kinase C-zeta and phosphoinositide-dependent protein kinase-1 are required for insulin induced activation of ERK in rat adipocytes. J Biol Chem 274: 30495–30500, 1999.PubMedCrossRefGoogle Scholar
  12. 12.
    Kellerer M, Mushack J, Seffe, E, Mischsak H, Ullrich A, Haring HU. Protein kinase C isoforms alpha, delta and theta require insulin receptor substrate-1 to inhibit the tyrosine kinase asctivty of the insulin receptor in human kidney embbyronic cells (HEK 293 cells). Diabetologia 41: 833–838, 1998.PubMedCrossRefGoogle Scholar
  13. 13.
    Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Op Cell Biol 262–267, 1998.Google Scholar
  14. 14.
    Kitamura T, Ogawa W, Sakaue H, et al. Requirement for activation of the serine-threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but not of glucose transport. Mol Cell Biol 18: 37083717, 1997.Google Scholar
  15. 15.
    Cross, BAE, Alessi DR, Cohen P, Andjelkovic, M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378: 785–789, 1995.PubMedCrossRefGoogle Scholar
  16. 16.
    Halse R, Rochford JJ, McCormack JG, Vandendeede JR, Hemmings BA, Yeaman SJ. Control of glycogen synthesis in cultured human muscle cells. J Biol Chem 274: 776–780, 1999.PubMedCrossRefGoogle Scholar
  17. 17.
    Elchebly M, Cheng A, Tremblay ML. Modulation of insulin signaling by protein tyrosine phosphatases. J Mol Med 78: 473–482, 2000.PubMedCrossRefGoogle Scholar
  18. 18.
    Hashimoto, N, Feener, EP, Zhang, W-R, Goldstein, BJ: Insulin receptor protein-tyrosine phosphatases. J Biol Chem 267: 13811–13814, 1992.PubMedGoogle Scholar
  19. 19.
    Elchebly M, Payette P, Michaliszyn E, et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase1B gene. Science 282: 1544–1548, 1999.CrossRefGoogle Scholar
  20. 20.
    Rocchi S, Tartare-Decker, S, Sawka-Verhelle D, GamhaA, Van Obberghen E. Interaction of SH2-containing protein tyrosine phosphatase 2 with the insulin receptor and the insulin-like growth factor-I receptor: studies of the domains involved using the yeast two-hybrid system. Endocrinology 137: 4944–4952, 1996.Google Scholar
  21. 21.
    Sugimoto S, Wandless TJ, Sholeson SE, Neel BG, Walsh CT. Activation of the SH2-containing protein tyrosine phosphatase, SH-PTP2, by phosphotyrosine-containing peptides derived from insulin receptor substrate-1. J Biol Chem 269: 13614–13622, 1994.PubMedGoogle Scholar
  22. 22.
    Avruch J, Khokhlatchev A, Kyriakis JM, et al. Ras activation of the Raf kinaseL tyrosine kinase recruitment of the MAP kinase cascade. Rec Prog Horm Res 56: 127–155, 2001.PubMedCrossRefGoogle Scholar
  23. 23.
    Coffer PJ, van Puijenbroek A, Burgering BM, et al. Insulin activates Stat3 independently of p2lras-ERK and PI-3K signal transduction. Oncogene 15: 2529–2539, 1997.PubMedCrossRefGoogle Scholar
  24. 24.
    Mueckler M. Facilitative glucose transporters. Eur J Biochem 219: 713725, 1994.Google Scholar
  25. 25.
    Quon MJ. Advances in kinetic analysis of insulin-stimulated GLUT-4 translocation in adipose cells. Am J Physiol 266: E144 - E150, 1994.PubMedGoogle Scholar
  26. 26.
    Goodyear LG, Kahn BB. Exercise, glucose transport and insulin sensitivity. Ann Rev Med 49: 235–261, 1998.PubMedCrossRefGoogle Scholar
  27. 27.
    Lawrence JC, Roach PJ. New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes 46: 541–547, 1997.PubMedCrossRefGoogle Scholar
  28. 28.
    Brady MJ, Saltiel AR. The role of protein phosphatase-1 in insulin action. Rec Prog Hormone Res 56: 157–173, 2001.CrossRefGoogle Scholar
  29. 29.
    Bak J, Jacobsen U, Jorgensen,F, Pedersen O. Insulin receptor function and glycogen sythase activity in skeletal muscle biopsies from the patients with insulin-dependent diabetes mellitus: Effects of physical training. J Clin Endocrinol Metab 69: 158–164, 1989.PubMedCrossRefGoogle Scholar
  30. 30.
    Handberg A, Vaag A, Vinte, J, Beck-Nielsen H. Decxreased tyrosine kinase activity in partially purified insulin receptors from muscle of young non-obese first degree relatives of patients with Type 2 (noninsulin-dependent) diabetes mellitus. Diabetologia 36: 668–674, 1993.PubMedCrossRefGoogle Scholar
  31. 31.
    Hunter SJ, Garvey WT. Insulin action and insulin resistance: diseases involving defects in insulin receptorss, signal transduction and the glucose transport effector system. Am J Med 105: 331–345, 1998.PubMedCrossRefGoogle Scholar
  32. 32.
    Obermaier-Kusser B, White MF, Pongrantz DE, et al. A defective intramolecular autoactivation cascade may cause the reduced kinase activity of skeletal muscle insulin receptor from patients with noninsulin-dependent diabetes mellitus. J Biol Chem 264: 9497–9504, 1989.PubMedGoogle Scholar
  33. 33.
    Freidenberg GR, Henry RR, Klein HH, Reichart DR, Olefsky JM. Decreased kinase activity of insulin receptors from adipocytes of Noninsulin-dependent diabetic subjects. J Clin Invest 79: 240–250, 1987.PubMedCrossRefGoogle Scholar
  34. 34.
    Kellerer M, Coghlan M, Capp E, et al. Mechanism of insulin receptor kinase inhibition in non-insulin-dependent diabetes mellitus patients. J Clin Invest 96: 6–11, 1995.PubMedCrossRefGoogle Scholar
  35. 35.
    Freidenberg GR, Reichart D, Olefsky JM, Henry RR. Reversibility of defective adipocyte insulin receptor kinase activity in non-insulindependent diabetes mellitus. J Clin Invest 82: 1398–1406, 1988.PubMedCrossRefGoogle Scholar
  36. 36.
    Hajduch E, Hainault I, Meunier C, et al. Regulation of glucose transporters in cultured rat adipocytes: synergistic effect of insulin and dexamethasone on GLUT4 gene expression through promoter activation. Endocrinology 136: 4782–4789, 1995.PubMedCrossRefGoogle Scholar
  37. 37.
    Lei H-H, Coresh J, Shuldiner AR, Boerwinkle E, Brancati FL. Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African Americans. Diabetes 48: 1868–1872, 1999.PubMedCrossRefGoogle Scholar
  38. 38.
    Yoshimura R, Araki E, Ura S, et al. Impact of IRS-1 mutations on insulin signals. Diabetes 46: 929–936, 1997.PubMedCrossRefGoogle Scholar
  39. 39.
    Ura S, Araki E, Kishikawa H, et al. Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese patients with NIDDM: identification of five novel polymorphisms. Diabetologia 39: 600–608, 1996.PubMedCrossRefGoogle Scholar
  40. 40.
    Bernal D, Almind K, Yenush L, et al. Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among caucasians. Diabetes 47: 976–979, 1998.PubMedCrossRefGoogle Scholar
  41. 41.
    Bektas A, Warram JH, White MF, Krolewski AS, Doria A. Exclusion of insulin receptor substrate 2 (IRS-2) as a major locus for early-onset autosomal dominant type 2 diabetes. Diabetes 48: 640–642, 1999.PubMedCrossRefGoogle Scholar
  42. 42.
    Rondinone CM, Wang L-M, Lonnroth P, Wesslau C, Pierc, JH, Smith U. Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phospahtidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 94: 4171–4175, 1997.PubMedCrossRefGoogle Scholar
  43. 43.
    Andreelli F, Laville M, Ducluzeau et al. Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients. Diabetologia 42: 358–364, 1999.PubMedCrossRefGoogle Scholar
  44. 44.
    Bjornholm M, Kawano Y, Lehtihet M, Zierath, JR. Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 46: 524–527, 1997.PubMedCrossRefGoogle Scholar
  45. 45.
    Smith U, Axelsen M, Carvalho E, Eliasson B, Jansson P. Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes. Ann NY Acad Sci 892: 119–126, 1999.PubMedCrossRefGoogle Scholar
  46. 46.
    Krook A, Roth RA, Jiang XJ, Zierat, JR, Wallberg-Henriksson H: Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. Diabetes 47: 1281–1286, 1998.PubMedCrossRefGoogle Scholar
  47. 47.
    Kim Y-B, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB. Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Invest 104: 733–741, 1999.PubMedCrossRefGoogle Scholar
  48. 48.
    Kossila M, Sinkovic M, Karkkaiinen P, et al. Gene coding for the catalytic subunit p110ß of human phosphatidylinositol 3-kinase. Cloniong, genomic structure, and screening for variant in patients with type 2 diabetes. Diabetes 49: 1740–1743, 2000.PubMedCrossRefGoogle Scholar
  49. 49.
    Baier,LJ, Wiedrich C, Hanson RL, Bogardus C: Variant in the regulatory subunit of phosphatidylinositol 3-kinase (p85alpha). Diabetes 47: 973975, 1998.Google Scholar
  50. 50.
    Hansen T, Andersen CB, Echwald SM, et al. Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. Diabetes 46: 494–501, 1997.PubMedCrossRefGoogle Scholar
  51. 51.
    Cusi K, Maezono K, Osman A, et al. Insulin resistance differentially affects the PI 3-kinase-and MAP kinase-mediated signaling in human muscle. J Clin Invest 105: 311–320, 2000.PubMedCrossRefGoogle Scholar
  52. 52.
    Marsh BJ, Alm RA, McIntosh SR, James DE: Molecular regulation of GLUT-4 targeting in 3T3–L1 adipocytes. J Cell Biol 130: 1081–1091, 1995.PubMedCrossRefGoogle Scholar
  53. 53.
    Itani, SI, Pories WJ, Macdonald KG, Dohm GL. Increased protein kinase C theta in skeletal muscle of diabetic patients. Metabolism 50: 553–557, 2001.PubMedCrossRefGoogle Scholar
  54. 54.
    Cheung A, Kusari J, Jansen D, Bandyopadhyay D, Kusari A, Bryer-Ash M. Marked impairment of protein tyrosine phosphatase 1B activity in adipose tissue of obese subjects with and without type 2 diabetes mellitus. J Lab Clin Med 134: 115–123, 1999.PubMedCrossRefGoogle Scholar
  55. 55.
    Kusari J, Kenner KA, Suh K-L, Hill DE, Henry RR. Skeletal muscle protein tyrosine phosphatase activity and tyrosine phosphataselB protein content are associated with insulin action and resistance. J Clin Invest 93: 1156–1162, 1994.PubMedCrossRefGoogle Scholar
  56. 56.
    Worm D, Vinten J, Staehr P, Henriksen JE, Handberg A, Beck-Nielsen H. Altered basal and insulin-stimulated phosphotyrosine phosphatase (PTPase) activity in skeletal muscle from NIDDM paitents compared with control subjects. Diabetologia 39: 1208–1214, 1996.PubMedCrossRefGoogle Scholar
  57. 57.
    Ahmad F, Azevedo JL, Cortright R, Dohm GL, Goldstein,BJ. Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes. J Clin Invest 100: 449458, 1997.Google Scholar
  58. 58.
    McGuire M, Fields R, Nyomba B, et al. Abnormal Regulation of Protein Tyrosine Phosphatase Activities in Skeletal Muscle of Insulin-Resistant Humans. Diabetes 40: 939–942, 1991.PubMedCrossRefGoogle Scholar
  59. 59.
    Lesage S, Zouali H, Vionnet N, et al. Genetic analyses of glucose transporter genes in French non-insulin-dependent diabetic families. Diabetes and Metabolism 23: 137–142, 1997.PubMedGoogle Scholar
  60. 60.
    Pontiroli AE, Capra F, Vegila F, et al. Genetic contribution of polymorphism of the GLUT1 and GLUT4 genes to the susceptibility to type 2 (non-insulin-dependent) diabetes mellitus in different populations. Acta Diabetologia 33: 193–197, 1996.CrossRefGoogle Scholar
  61. 61.
    Garvey WT, Maianu L, Huecksteadt TP, Birnbaum MJ, Molina JM, Ciaraldi TP. Pretranslational suppression of GLUT4 glucose transporters causes insulin resistance in type II diabetes. J Clin Invest 87: 1072–1081, 1991.PubMedCrossRefGoogle Scholar
  62. 62.
    Garvey WT. Glucose transport and NIDDM. Diabetes Care 15: 396–417, 1992.PubMedCrossRefGoogle Scholar
  63. 63.
    Ryder JW, Yang, J, Galuska D, et al. Use of a novel impermeable biotinylated photolabeling reagent to assess insulin-and hypoxiastimulated cell surface GLUT4 content in skeletal muscle from type 3 diabetic patients. Diabetes 49: 647–654, 2000.PubMedCrossRefGoogle Scholar
  64. 64.
    Garvey WT, Maianu L, Zhu J-H, Brechtel-Hook G, Wallace P, Baron AD. Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance. J Clin Invest 101: 2377–2386, 1998.PubMedCrossRefGoogle Scholar
  65. 65.
    Kennedy JW, Hirshman MF, Gervino EV, et al. Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes. Diabetes 48: 1192–1197, 1999.PubMedCrossRefGoogle Scholar
  66. 66.
    Thornburn AW, Gumbiner B, Bulacan F, Wallace P, Henry RR. Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin dependent (Type II) diabetes independent of impaired glucose uptake. J Clin Invest 85: 522–529, 1990.CrossRefGoogle Scholar
  67. 67.
    Bjorbaek C, Echwald SM, Hubrich, P, et al. Genetic varients in promoters and coding regions of the muscle glycogen synthase and the insulin responsive GLUT4 genes in NIDDM. Diabetes 43: 976–983, 1994.PubMedCrossRefGoogle Scholar
  68. 68.
    Vestergaard H, Lund S, Larsen FS, Bjerrum OJ, Pedersen O. Glycogen synthase and phosphofructokinase protein ans mRNA levels in skeletal msucle from insulin-resistant patients with non-insulin-dependent diabetes mellitus. J Clin Invest 91: 2342–2350, 1993.PubMedCrossRefGoogle Scholar
  69. 69.
    Bjorbaek C, Vik TA, Echwald SM, et al. Cloning of a human insulin-stimulated protein kinase (ISPK-1) gene and analysis of coding regions and mRNA levels of the ISPK-1 and protein phosphatase-1 genes in muscle from NIDDM patients. Diabetes 44: 90–97, 1995.PubMedCrossRefGoogle Scholar
  70. 70.
    Freymond D, Bogardus C, Okubo M, Stone K, Mott D. Impaired insulin-stimulated muscle glycogen synthase activation in vivo in man is related to low fasting glycogen synthase phosphatase activity. J Clin Invest 82: 1503–1509, 1988.PubMedCrossRefGoogle Scholar
  71. 71.
    Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L, Henry RR. Role of glycogen synthase kinase 3 in skeletal muscle insulin resistance of Type 2 diabetes. Diabetes 49: 263–271, 2000.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Theodore P. Ciaraldi

There are no affiliations available

Personalised recommendations