Cellular Mechanisms of Insulin Action

  • Theodore P. CiaraldiEmail author
Reference work entry


Insulin is a highly pleiotropic 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 insulin-resistant conditions such as obesity and 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. The organizing principles of insulin signaling include the following: (1) presence of phosphorylation/dephosphorylation cascades, (2) phosphorylation of specific sites creates recognition domains that permit the formation of multimolecular complexes, (3) complex formation involves scaffolding or adaptor proteins, (4) these multimolecular complexes often target enzymes to specific intracellular locales where critical substrates reside, and (5) posttranslational modifications other than phosphorylation can effect the behavior of steps 2–4.


Type 2 diabetes Insulin resistance Phosphorylation Post-translational modification IRS – insulin receptor substrate PI 3-K – phosphatidylinositol 3-kinase Akt GLUT4 – insulin-dependent glucose transporter AS160 – Akt substrate of 160 kDa GSK3 – glycogen synthase kinase 3 PKC – protein kinase C mTOR – mammalian Target of Rapamycin 


  1. 1.
    Ottensmeyer FP, Beniac DR, Luo RZ, Yip CC. Mechanism of transmembrane signaling: insulin binding and the insulin receptor. Biochemistry. 2000;39(40):12103–12.PubMedCrossRefGoogle Scholar
  2. 2.
    Hubbard SR. The insulin receptor: both a prototypical and atypical receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013;5:a008946.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Sidle K. Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances. Front Endocrinol. 2012;3:34.Google Scholar
  4. 4.
    Copps KD, White MF. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia. 2012;55:2565–82.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Bouzarki K, Roques M, Gual P, Espinosa S, Guebre-Egziabher F, Riou J-P, et al. Reduced activation of phosphotidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes. 2003;52:1319–25.CrossRefGoogle Scholar
  6. 6.
    Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol. 2000;14(6):783–94.PubMedCrossRefGoogle Scholar
  7. 7.
    Danielsson A, Ost A, Nystron FH, Stralfors P. Attenuation of insulin-stimulated insulin receptor substrate-1 serine 307 phosphorylation in insulin resistance of type 2 diabetes. J Biol Chem. 2005;280(41):34389–92.PubMedCrossRefGoogle Scholar
  8. 8.
    Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J. Asprin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem. 2003;278(27):24944–50.PubMedCrossRefGoogle Scholar
  9. 9.
    Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. JBiol Chem. 2002;277(50):48115–21.CrossRefGoogle Scholar
  10. 10.
    Jiang G, Dallas-Yang Q, Liu F, Moller DE, Zhang BB. Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor a (TNFa)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. J Biol Chem. 2003;278(1):180–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Liberman Z, Eldar-Finkelman H. Serine 332 phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 attenuates insulin signaling. J Biol Chem. 2005;280(6):4422–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Gual P, Gremeaux T, Gonzalez T, Le Marchand-Brustel Y, Tanti J-F. MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612, and 632. Diabetologia. 2003;46:1532–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Mothe I, Van Obberghen E. Phosphorylation of insulin receptor substrate-1 on multiple serine residues 612, 632, 662 and 731, modulates insulin action. J Biol Chem. 1996;271:11222–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Li Y, Soos TJ, Li X, Wu J, DeGennaro M, Sun XJ, et al. Protein kinase C theta inhibits insulin signaling by phosphorylating IRS1 at Ser1001. J Biol Chem. 2004;279:45304–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Tremblay F, Brule S, Um SH, Masuda K, Roden M, Sun XJ, et al. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and onbesity-induced insulin resistance. Proc Natl Acad Sci U S A. 2007;104:14056–61.Google Scholar
  16. 16.
    Kriplani N, Hermida MA, Brown ER, Leslie NR. Class 1 PI 3-kinases: function and evolution. Adv Biol Reg. 2015;59:53–64.Google Scholar
  17. 17.
    Virkamaki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest. 1999;103(7):931–43.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Shepherd PR. Mechanisms regulating phosphainositide 3-kinase signalling in insulin-sentsitive tissues. Acta Physiol Scand. 2005;183:3–12.PubMedCrossRefGoogle Scholar
  19. 19.
    Faes S, Dormond O. PI3K and AKT: unfaithful partners in cancer. Int J Mol Sci. 2015;16:21138–52.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, Norman DG, et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drospohila DSTPK61 kinase. Curr Biol. 1997;7(10):776–89.PubMedCrossRefGoogle Scholar
  21. 21.
    Farese RV. Insulin-sensitive phospholipid signaling systems and glucose transport. Update II. Exp Biol Med. 2001;226(4):283–95.CrossRefGoogle Scholar
  22. 22.
    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 Lett. 2000;472(1):153–8.PubMedCrossRefGoogle Scholar
  23. 23.
    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. 1999;274(43):30495–500.PubMedCrossRefGoogle Scholar
  24. 24.
    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. 2001;276(5):3543–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Kellerer M, Mushack J, Seffer 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. 1998;41(7):833–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Farese RV, Sajan MP, Standaert ML. Atypical protein kinase C in insulin action and insulin resistance. Biochem Soc Trans. 2005;33:350–3.PubMedCrossRefGoogle Scholar
  27. 27.
    Kitamura T, Ogawa W, Sakaue H, Hino Y, Kuroda S, Takata M, 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. 1997;18:3708–17.CrossRefGoogle Scholar
  28. 28.
    Cross BAE, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Amar S, Belmaker RH, Agam G. The possible involvement of glycogen synthase kinase-3 (GSK-3) in diabetes, cancer and central nervous system diseases. Curr Diabetes Des. 2011;17:2264–77.Google Scholar
  30. 30.
    Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS. Glycogen and its metabolism: some new developments and old themes. Biochem J. 2012;441:763–87.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Cartee GD. Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle. Diabetologia. 2015;58:19–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Musi N, Goodyear LJ. Insulin resistance and improvements in signal transduction. Endocrine. 2006;29:73–80.PubMedCrossRefGoogle Scholar
  33. 33.
    Thong FSL, Bilan PJ, Klip A. The Rab GTPase-activating protein AS160 integrates Akt, protein kinase C, and AMP-activated protein kinase signals regulating GLUT4 traffic. Diabetes. 2007;56:414–23.PubMedCrossRefGoogle Scholar
  34. 34.
    Chakrabarti P, Kandror KV. The role of mTOR in lipid homeostasis and diabetes progression. Curr Opin Endocrinol Diabetes Obes. 2015;22:340–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Halse R, Rochford JJ, McCormack JG, Vandendeede JR, Hemmings BA, Yeaman SJ. Control of glycogen synthesis in cultured human muscle cells. J Biol Chem. 1999;274(2):776–80.PubMedCrossRefGoogle Scholar
  36. 36.
    Sanchez AMJ, Candau RB, Bernaedi H. FoxO transcription factors: their roles in the maintenance of skeletal muscle homeostasis. Cell Mol Life Sci. 2014;71:1657–71.PubMedCrossRefGoogle Scholar
  37. 37.
    Klip A, Sun Y, Chiu TT, Foley KP. Signal transduction meets vesicle traffic: the software and hardware of GLUT4 translocation. Am J Physiol Cell Physiol. 2014;306:C879–86.PubMedCrossRefGoogle Scholar
  38. 38.
    Chiu TT, Jensen TE, Sylow L, Richter EA, Klip A. Rac1 signaling towards GLUT4/glucose uptake in skeletal muscle. Cell Signal. 2011;23:1546–54.PubMedCrossRefGoogle Scholar
  39. 39.
    Sylow L, Jensen TE, Kleinert M, Hojlund K, Kiens B, Wojtaszewski J, et al. Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle. Diabetes. 2013;62:1865–75.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Xu E, Schwab M, Marette A. Role of protein tyrosine phosphatases in the modulation of insulin signaling and their implication in the pathogenesis of obesity-linked insulin resistance. Rev Endocr Metab Disord. 2014;15:79–97.PubMedCrossRefGoogle Scholar
  41. 41.
    Elchebly M, Cheng A, Tremblay ML. Modulation of insulin signaling by protein tyrosine phosphatases. J Mol Med. 2000;78(9):473–82.Google Scholar
  42. 42.
    Gurzov EN, Stanley WJ, Brodnicki TC, Thomas HE. Protein tyrosine phosphatases: molecular switches in metabolism and diabetes. Trends Endocrinol Metab. 2015;26:30–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science. 1999;283:1544–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Rocchi S, Tartare-Deckert S, Sawka-Verhelle D, Gamha A, 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. 1996;137:4944–52.PubMedCrossRefGoogle Scholar
  45. 45.
    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. 1994;269:13614–22.PubMedGoogle Scholar
  46. 46.
    Lazar DF, Saltiel AR. Lipid phosphatases as drug discovery targets for type 2 diabetes. Nat Rev Drug Discov. 2006;5:333–42.PubMedCrossRefGoogle Scholar
  47. 47.
    Brognard J, Sierecki E, Gao T, Newton AC. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell. 2007;25:917–31.PubMedCrossRefGoogle Scholar
  48. 48.
    Avruch J, Khokhlatchev A, Kyriakis JM, Luo Z, Tzivion G, Vavvas D, et al. Ras activation of the Raf kinaseL tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog Horm Res. 2001;56:127–55.PubMedCrossRefGoogle Scholar
  49. 49.
    Coffer PJ, van Puijenbroek A, Burgering BM, Klop-de Jonge M, Koenderman L, Bos JL, et al. Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction. Oncogene. 1997;15(21):2529–39.PubMedCrossRefGoogle Scholar
  50. 50.
    Saltiel AR, Pessin JE. Insulin signaling in microdomains of the plasma membrane. Traffic. 2003;4:711–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Scheepers A, Joost HG, Schurmann A. The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function. J Parenter Enter Nutr. 2004;28:364–71.CrossRefGoogle Scholar
  52. 52.
    Hou JC, Pessin JE. Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking. Curr Opin Cell Biol. 2007;19:466–73.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Richter EA, Hargreaves M. Exercise, GLUT4 and skeletal muscle glucose uptake. Physiol Rev. 2013;93:993–1017.PubMedCrossRefGoogle Scholar
  54. 54.
    Brady MJ, Saltiel AR. The role of protein phosphatase-1 in insulin action. Recent Prog Horm Res. 2001;56:157–73.PubMedCrossRefGoogle Scholar
  55. 55.
    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. 1989;69:158–64.PubMedCrossRefGoogle Scholar
  56. 56.
    Handberg A, Vaag A, Vinten J, Beck-Nielsen H. Decreased tyrosine kinase activity in partially purified insulin receptors from muscle of young non-obese first degree relatives of patients with Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1993;36:668–74.PubMedCrossRefGoogle Scholar
  57. 57.
    Kolterman OG, Reaven GM, Olefsky JM. Relationship between in vivo insulin resistance and decreased insulin receptors in obese man. J Clin Endocrinol Metab. 1979;48:487–94.PubMedCrossRefGoogle Scholar
  58. 58.
    Hunter SJ, Garvey WT. Insulin action and insulin resistance: diseases involving defects in insulin receptors, signal transduction and the glucose transport effector system. Am J Med. 1998;105(4):331–45.PubMedCrossRefGoogle Scholar
  59. 59.
    Obermaier-Kusser B, White MF, Pongrantz DE, Su Z, Ermel B, Muhlbacher C, et al. A defective intramolecular autoactivation cascade may cause the reduced kinase activity of skeletal muscle insulin receptor from patients with non-insulin-dependent diabetes mellitus. J Biol Chem. 1989;264:9497–504.PubMedGoogle Scholar
  60. 60.
    Freidenberg GR, Henry RR, Klein HH, Reichart DR, Olefsky JM. Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects. J Clin Invest. 1987;79:240–50.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Kellerer M, Coghlan M, Capp E, Muhlhofer A, Kroder G, Mosthaf L, et al. Mechanism of insulin receptor kinase inhibition in non-insulin-dependent diabetes mellitus patients. J Clin Invest. 1995;96:6–11.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Freidenberg GR, Reichart D, Olefsky JM, Henry RR. Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. J Clin Invest. 1988;82:1398–406.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    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. 1999;48(9):1868–72.PubMedCrossRefGoogle Scholar
  64. 64.
    McGettrick AJ, Feener EP, Kahn CR. Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1 to associate with the insulin receptor and inhibit insulin receptor phosphorylation. J Biol Chem. 2005;280:6441–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Ura S, Araki E, Kishikawa H, Shirotani T, Todaka M, Isami S, et al. Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese patients with NIDDM: identification of five novel polymorphisms. Diabetologia. 1996;39:600–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Florez JC, Sjogren M, Burtt N, Ortho-Melander M, Schayer S, Sun M, et al. Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes. Diabetes. 2004;53:3313–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Bernal D, Almind K, Yenush L, Ayoub M, Zhang Y, Rosshani L, et al. Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among caucasians. Diabetes. 1998;47:976–9.PubMedCrossRefGoogle Scholar
  68. 68.
    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. 1999;48:640–2.PubMedCrossRefGoogle Scholar
  69. 69.
    Le Fur S, Le Stunff C, Bougneres P. Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms. Diabetes. 2002;51 Suppl 3:S304–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Rondinone CM, Wang L-M, Lonnroth P, Wesslau C, Pierce 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 U S A. 1997;94(4):4171–5.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Andreelli F, Laville M, Ducluzeau P-H, Vega N, Vallier P, Khalfallah Y, et al. Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients. Diabetologia. 1999;42:358–64.PubMedCrossRefGoogle Scholar
  72. 72.
    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. 1997;46:524–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Carvalho E, Eliasson B, Wesslau C, Smith U. Impaired phosphorylation and insulin stimulated translocation to the plasma membrane of protein kinaseB/Akt in adipocytes from Type II diabetic subjects. Diabetologia. 2000;43:1107–15.PubMedCrossRefGoogle Scholar
  74. 74.
    Krook A, Roth RA, Jiang XJ, Zierath JR, Wallberg-Henriksson H. Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. Diabetes. 1998;47:1281–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Meyers MG, et al. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes. 2000;49(2):284–92.PubMedCrossRefGoogle Scholar
  76. 76.
    Gregor MF, Hotamisligil GS. Inflammatiory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–45.PubMedCrossRefGoogle Scholar
  77. 77.
    Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 1999;48(6):1270–4.PubMedCrossRefGoogle Scholar
  78. 78.
    Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, et al. Mechanisms by which high-dose asprin improves glucose metabolism in type 2 diabetes. J Clin Invest. 2002;109:1321–6.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Kossila M, Sinkovic M, Karkkaiinen P, Laukkanen MO, Miettinen R, Rissanen J, 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. 2000;49(10):1740–3.Google Scholar
  80. 80.
    Hansen T, Andersen CB, Echwald SM, Urhammer SA, Clausen JO, Vestergaard H, et al. Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. Diabetes. 1997;46:494–501.PubMedCrossRefGoogle Scholar
  81. 81.
    Baier LJ, Wiedrich C, Hanson RL, Bogardus C. Variant in the regulatory subunit of phosphatidylinositol 3-kinase (p85alpha). Diabetes. 1998;47:973–5.Google Scholar
  82. 82.
    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. 1999;104(9):733–41.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000;105(3):311–20.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Karlsson HKR, Zierath JR, Kane S, Krook A, Lienhard GE, Wallberg-Henriksson H. Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. Diabetes. 2005;54:1692–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Itani SI, Pories WJ, Macdonald KG, Dohm GL. Increased protein kinase C theta in skeletal muscle of diabetic patients. Metabolism. 2001;50(5):553–7.PubMedCrossRefGoogle Scholar
  86. 86.
    Farese RV, Lee MC, Sajan MP. Atypical PKC: a target for treating insulin-resistant disorders of obesity, the metabolic syndrome and type 2 diabetes mellitus. Expert Opin Ther Targets. 2014;18:1163–75.PubMedCrossRefGoogle Scholar
  87. 87.
    Ahmad F, Considine RV, Bauer TL, Ohannesian JP, Marco CC, Goldstein BJ. Improved sensitivity to insulin in obese subjects following weight loss is accompanied by reduced protein-tyrosine phosphatases in adipose tissue. Metabolism. 1997;46:1140–5.PubMedCrossRefGoogle Scholar
  88. 88.
    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. 1999;134(2):115–23.PubMedCrossRefGoogle Scholar
  89. 89.
    Kusari J, Kenner KA, Suh K-L, Hill DE, Henry RR. Skeletal muscle protein tyrosine phosphatase activity and tyrosine phosphatase1B protein content are associated with insulin action and resistance. J Clin Invest. 1994;93:1156–62.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    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. 1996;39:1208–14.PubMedCrossRefGoogle Scholar
  91. 91.
    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. 1997;100(2):449–58.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Palmer ND, Bento JC, Mychaleckyi CD, LAngefield JK, Campbell JM. Norris sM, et al. Associations of protein tyrosine phosphatase 1B gene polymorphsims with measures of glucose homeostasis in Hispanic Americans: the insulin resistance atherosclerosis study (IRAS) family study. Diabetes. 2004;53:3013–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Florez JC, Agapakis CM, Burtt NP, Sun M, Almgren P, Rastam L, et al. Association testiing of the protein tyrosine phosphatase 1B gene (PTPN1) with type 2 diabetes in 7,883 people. Diabetes. 2005;54:1881–91.CrossRefGoogle Scholar
  94. 94.
    Meshkani R, Taghikhani M, Al-Kateb H, Larijani B, Khatami S, Sidiropoulos GK, et al. Polymorphmisms with the protein tyrosine phosphatase 1B (PTPN1) gene and promoter: functional characterization and association with type 2 diabetes and related metabolic traits. Clin Chem. 2007;53:1585–92.PubMedCrossRefGoogle Scholar
  95. 95.
    Li YY, Xiao R, Li CP, Huangfu J, Mao JF. Increased plasma levels of FABP4 and PTEN is associated with more severe insulin resistance in women with gestational diabetes mellitus. Med Sci Monit. 2015;21:426–31.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Pak A, Barber TM, Van de Bunt M, Rudge SA, Zhang Q, Lachlan KL, et al. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N Engl J Med. 2012;367:1002–11.CrossRefGoogle Scholar
  97. 97.
    Ishihara H, Sasaoka T, Kagawa S, Murakami S, Fukui K, Kawagishi Y, et al. Association of the polymorphisms in the 5′-untranslated region of PTEN gene with type 2 diabetes in a Japanese population. FEBS Lett. 2003;20:450–4.CrossRefGoogle Scholar
  98. 98.
    Hansen L, Jensen LL, Ekstrom CT, Vestergaard H, Hansen T, Pedersen O. Studies of variability in the PTEN gene among Danish caucasian patients with type II diabetes mellitus. Diabetologia. 2001;44(2):237–40.PubMedCrossRefGoogle Scholar
  99. 99.
    Suwa A, Kurama T, Shimokawa T. SHIP2 and its involvement in various diseases. Expert Opin Ther Targets. 2010;14:727–37.PubMedCrossRefGoogle Scholar
  100. 100.
    Cozzone D, Frojdo S, Disse E, Debard C, Laville M, Pirola L, et al. Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients. Diabetologia. 2008;51:512–21.PubMedCrossRefGoogle Scholar
  101. 101.
    Pontiroli AE, Capra F, Vegila F, Ferrari M, Xiang KS, Bell GI, 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 Diabetol. 1996;33(3):193–7.PubMedCrossRefGoogle Scholar
  102. 102.
    Lesage S, Zouali H, Vionnet N, Philippi A, Velho G, Serradas P, et al. Genetic analyses of glucose transporter genes in French non-insulin-dependent diabetic families. Diabetes Metab. 1997;23(2):137–42.PubMedGoogle Scholar
  103. 103.
    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. 1991;87:1072–81.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Pedersen O, Bak JF, Andersen PH, Lund S, Moller DE, Flier JS, et al. Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM. Diabetes. 1990;39:865–70.PubMedCrossRefGoogle Scholar
  105. 105.
    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. 1998;101:2377–86.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Ryder JW, Yang J, GAluska D, Rincon J, Bjornholm M, Krook A, et al. Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 3 diabetic patients. Diabetes. 2000;49(4):647–54.PubMedCrossRefGoogle Scholar
  107. 107.
    Thorburn 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. 1990;85:522–9.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Bjorbaek C, Echwald SM, Hubricht P, Vestergaard H, Hansen T, Zierath J, et al. Genetic varients in promoters and coding regions of the muscle glycogen synthase and the insulin responsive GLUT4 genes in NIDDM. Diabetes. 1994;43:976–83.PubMedCrossRefGoogle Scholar
  109. 109.
    Vestergaard H, Lund S, Larsen FS, Bjerrum OJ, Pedersen O. Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin-dependent diabetes mellitus. J Clin Invest. 1993;91:2342–50.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Bjorbaek C, Vik TA, Echwald SM, Yang P-Y, Vestergaard H, Wang JP, 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. 1995;44:90–7.PubMedCrossRefGoogle Scholar
  111. 111.
    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. 1988;82:1503–9.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L, Henry RR. Potential role of glycogen synthase kinase 3 in skeletal muscle insulin resistance of Type 2 diabetes. Diabetes. 2000;49:263–71.PubMedCrossRefGoogle Scholar
  113. 113.
    Myslicki JP, Belke DD, Shearer J. Role of O-GlcNAcylation in nutritional sensing, insulin resistance and in mediating the benefits of exercise. Appl Physiol Nutr Metab. 2014;39:1205–13.PubMedCrossRefGoogle Scholar
  114. 114.
    LaBarge S, Migdal C, Schenk S. Is acetylation a metabolic rheostat that regulates skeletal muscle insulin action? Mol Cells. 2015;38:297–303.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Risso G, Blaustein M, Pozzi B, Mammi P, Srebrow A. Akt/PKB: one kinase, many modifications. Biochem J. 2015;468:203–14.PubMedCrossRefGoogle Scholar
  116. 116.
    Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med. 2014;20:1242–53.PubMedCrossRefGoogle Scholar
  117. 117.
    Sireesh D, Bhakkiyalakshmi E, Ramkumar KM, Rathinakumar S, Jennifer PS, Rajaguru P, et al. Targeting SUMOylation cascade for diabetes management. Curr Drug Targets. 2014;15:1094–106.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Medicine-Division of Endocrinology and MetabolismUniversity of California, San DiegoSan DiegoUSA
  2. 2.VA San Diego Healthcare SystemSan DiegoUSA

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