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Cellular Mechanisms of Insulin Action

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Principles of Diabetes Mellitus

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Abstract

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 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. This is intended to be an overview of the field; readers will be directed to reviews on specific topics.

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References

  1. Ottensmeyer FP, Beniac DR, Luo RZ, et al. Mechanism of transmembrane signaling: insulin binding and the insulin receptor. Biochemistry. 2000;39:12103–12112.

    Article  PubMed  CAS  Google Scholar 

  2. Ellis L, Tavare JM, Levine BA. Insulin receptor tyrosine kinase structure and function. Biochem Soc Trans. 1991;43:426–432.

    Google Scholar 

  3. Lee YH, White MF. Insulin receptor substrate proteins and diabetes. Arch Pharm Res. 2004;27:361–370.

    Article  PubMed  CAS  Google Scholar 

  4. Gual P, Le Marchand-Brustel Y, Tanti J-F. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie. 2005;87:99–109.

    Article  PubMed  CAS  Google Scholar 

  5. Tanti J-F, Gremeaux T, Van Obberghen E, et al. Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling. J Biol Chem. 1994;269:6051–6057.

    PubMed  CAS  Google Scholar 

  6. Bouzarki K, Roques M, Gual 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;52:1319–1325.

    Article  Google Scholar 

  7. Haruta T, Uno T, Kawahara J, et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endo. 2000;14:783–794.

    Article  CAS  Google Scholar 

  8. Danielsson A, Ost A, Nystron FH, et al. Attenuation of insulin-stimulated insulin receptor substrate-1 serine 307 phosphorylation in insulin resistance of type 2 diabetes. J Biol Chem. 2005;280:34389–34392.

    Article  PubMed  CAS  Google Scholar 

  9. Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J. Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem. 2003;278:24944–24950.

    Article  PubMed  CAS  Google Scholar 

  10. Gao Z, Hwang D, Bataille F, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kB kinase complex. J Biol Chem. 2002;277:48115–48121.

    Article  PubMed  CAS  Google Scholar 

  11. Jiang G, Dallas-Yang Q, Liu F, et al. Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor α (TNFα)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. J Biol Chem. 2003;278:180–186.

    Article  PubMed  CAS  Google Scholar 

  12. 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;280:4422–4428.

    Article  PubMed  CAS  Google Scholar 

  13. Gual P, Gremeaux T, Gonzalez T, et al. MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612, and 632. Diabetologia. 2003;46:1532–1542.

    Article  PubMed  CAS  Google Scholar 

  14. 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;271:11222–11227.

    Article  PubMed  CAS  Google Scholar 

  15. Li Y, Soos TJ, Li X, et al. Protein kinase C theta inhibits insulin signaling by phosphorylating IRS1 at Ser1001. J Biol Chem. 2004;279:45304–45307.

    Article  PubMed  CAS  Google Scholar 

  16. Tremblay F, Brule S, Um SH, et al. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc Natl Acad Sci USA. 2007;104:14056–14061.

    Article  PubMed  CAS  Google Scholar 

  17. Virkamaki A, Ueki K, Kahn CR. Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest. 1999;103:931–943.

    Article  PubMed  CAS  Google Scholar 

  18. Shepherd PR. Mechanisms regulating phosphainositide 3-kinase signalling in insulin-sensitive tissues. Acta Physiol Scand. 2005;183:3–12.

    Article  PubMed  CAS  Google Scholar 

  19. Myers MG, White MF. Insulin signal transduction and the IRS proteins. Annu Rev Pharmacol Toxicol. 1996;36:615–658.

    Article  PubMed  CAS  Google Scholar 

  20. Alessi DR, Deak M, Casamayor A, et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol. 1997;7:776–789.

    Article  PubMed  CAS  Google Scholar 

  21. Farese RV. Insulin-sensitive phospholipid signaling systems and glucose transport. Update II. Exp Biol Med. 2001;226:283–295.

    CAS  Google Scholar 

  22. Valverde AM, Lorenzo M, Navarro P, et al. 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;472:153–158.

    Article  PubMed  CAS  Google Scholar 

  23. Sajan MP, Standaert ML, Bandyopadhyay G, et al. 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;274:30495–30500.

    Article  PubMed  CAS  Google Scholar 

  24. Ravichandran LV, Esposito DL, Chen J, et al. 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;276:3543–3549.

    Article  PubMed  CAS  Google Scholar 

  25. Kellerer M, Mushack J, Seffer E, et al. Protein kinase C isoforms alpha, delta and theta require insulin receptor substrate-1 to inhibit the tyrosine kinase activity of the insulin receptor in human kidney embryonic cells (HEK 293 cells). Diabetologia. 1998;41:833–838.

    Article  PubMed  CAS  Google Scholar 

  26. Farese RV, Sajan MP, Standaert ML. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt: actions and defects in obesity and type II diabetes. Exp Biol Med (Maywood). 2005;230:593–605.

    CAS  Google Scholar 

  27. 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. 1997;18:3708–3717.

    Google Scholar 

  28. Cross BAE, Alessi DR, Cohen P, et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785–789.

    Article  PubMed  CAS  Google Scholar 

  29. Ishikura S, Koshkina A, Klip A. Small G proteins in insulin action: Rab and Rho families at the crossroads of signal transduction and GLUT4 vesicle traffic. Acta Physiol (Oxf). 2008;192:61–74.

    Article  CAS  Google Scholar 

  30. Musi N, Goodyear LJ. AMP-activated protein kinase and muscle glucose uptake. Acta Physiol Scand. 2003;178:337–345.

    Article  PubMed  CAS  Google Scholar 

  31. 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;56:414–423.

    Article  PubMed  CAS  Google Scholar 

  32. Halse R, Rochford JJ, McCormack JG, et al. Control of glycogen synthesis in cultured human muscle cells. J Biol Chem. 1999;274:776–780.

    Article  PubMed  CAS  Google Scholar 

  33. Barthel A, Schmoll D, Unterman TG. FoxO proteins in insulin action and metabolism. Trends Endocrinol Metab. 2005;16:183–189.

    Article  PubMed  CAS  Google Scholar 

  34. Elchebly M, Cheng A, Tremblay ML. Modulation of insulin signaling by protein tyrosine phosphatases. J Mol Med. 2000;78:473–482.

    Article  PubMed  CAS  Google Scholar 

  35. Hashimoto N, Feener EP, Zhang W-R, et al. Insulin receptor protein-tyrosine phosphatases. J Biol Chem. 1992;267:13811–13814.

    PubMed  CAS  Google Scholar 

  36. Elchebly M, Payette P, Michaliszyn E, et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science. 1999;282:1544–1548.

    Article  Google Scholar 

  37. Rocchi S, Tartare-Deckert S, Sawka-Verhelle D, et al. 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;137:4944–4952.

    Article  PubMed  CAS  Google Scholar 

  38. Sugimoto S, Wandless TJ, Sholeson SE, et al. Activation of the SH2-containing protein tyrosine phosphatase, SH-PTP2, by phosphotyrosine-containing peptides derived from insulin receptor substrate-1. J Biol Chem. 1994;269:13614–13622.

    PubMed  CAS  Google Scholar 

  39. Lazar DF, Saltiel AR. Lipid phosphatases as drug discovery targets for type 2 diabetes. Nat Rev Drug Disc. 2006;5:333–342.

    Article  CAS  Google Scholar 

  40. Brognard J, Sierecki E, Gao T, et al. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell. 2007;25:917–931.

    Article  PubMed  CAS  Google Scholar 

  41. Avruch J, Khokhlatchev A, Kyriakis JM, et al. Ras activation of the Raf kinase tyrosine kinase recruitment of the MAP kinase cascade. Rec Prog Horm Res. 2001;56:127–155.

    Article  PubMed  CAS  Google Scholar 

  42. Coffer PJ, van Puijenbroek A, Burgering BM, et al. Insulin activates Stat3 independently of p21ras-ERK and PI-3 K signal transduction. Oncogene. 1997;15:2529–2539.

    Article  PubMed  CAS  Google Scholar 

  43. Saltiel AR, Pessin JE. Insulin signaling in microdomains of the plasma membrane. Traffic. 2003;4:711–716.

    Article  PubMed  CAS  Google Scholar 

  44. Michelle Furtado L, Poon V, Klip A. GLUT4 activation: thoughts on possible mechanisms. Acta Physiol Scand. 2006;178:287–296.

    Article  Google Scholar 

  45. Scheepers A, Joost HG, Schurmann A. The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function. J Parenter Enteral Nutr. 2004;28:364–371.

    Article  CAS  Google Scholar 

  46. Hou JC, Pessin JE. Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking. Curr Opin Cell Biol. 2007;19:466–473.

    Article  PubMed  CAS  Google Scholar 

  47. Goodyear LG, Kahn BB. Exercise, glucose transport and insulin sensitivity. Ann Rev Med. 1998;49:235–261.

    Article  PubMed  CAS  Google Scholar 

  48. Lawrence JC, Roach PJ. New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes. 1997;46:541–547.

    Article  PubMed  CAS  Google Scholar 

  49. Brady MJ, Saltiel AR. The role of protein phosphatase-1 in insulin action. Rec Prog Hormone Res. 2001;56:157–173.

    Article  CAS  Google Scholar 

  50. Bak J, Jacobsen U, Jorgensen F, et al. Insulin receptor function and glycogen synthase activity in skeletal muscle biopsies from the patients with insulin-dependent diabetes mellitus: Effects of physical training. J Clin Endocrinol Metab. 1989;69:158–164.

    Article  PubMed  CAS  Google Scholar 

  51. Handberg A, Vaag A, Vinten J, et al. 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;36:668–674.

    Article  PubMed  CAS  Google Scholar 

  52. 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;105:331–345.

    Article  PubMed  CAS  Google Scholar 

  53. 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 non-insulin-dependent diabetes mellitus. J Biol Chem. 1989;264:9497–9504.

    PubMed  CAS  Google Scholar 

  54. Freidenberg GR, Henry RR, Klein HH, et al. Decreased kinase activity of insulin receptors from adipocytes of Non-insulin-dependent diabetic subjects. J Clin Invest. 1987;79:240–250.

    Article  PubMed  CAS  Google Scholar 

  55. Kellerer M, Coghlan M, Capp E, et al. Mechanism of insulin receptor kinase inhibition in non-insulin-dependent diabetes mellitus patients. J Clin Invest. 1995;96:6–11.

    Article  PubMed  CAS  Google Scholar 

  56. Freidenberg GR, Reichart D, Olefsky JM, et al. Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. J Clin Invest. 1988;82:1398–1406.

    Article  PubMed  CAS  Google Scholar 

  57. Lei H-H, Coresh J, Shuldiner AR, et al. 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;48:1868–1872.

    Article  PubMed  CAS  Google Scholar 

  58. Yoshimura R, Araki E, Ura S, et al. Impact of IRS-1 mutations on insulin signals. Diabetes. 1997;46:929–936.

    Article  PubMed  CAS  Google Scholar 

  59. 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. 1996;39:600–608.

    Article  PubMed  CAS  Google Scholar 

  60. 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. 1998;47:976–979.

    Article  PubMed  CAS  Google Scholar 

  61. Bektas A, Warram JH, White MF, et al. Exclusion of insulin receptor substrate 2 (IRS-2) as a major locus for early-onset autosomal dominant type 2 diabetes. Diabetes. 1999;48:640–642.

    Article  PubMed  CAS  Google Scholar 

  62. Rondinone CM, Wang L-M, Lonnroth P, et al. Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA. 1997;94:4171–4175.

    Article  PubMed  CAS  Google Scholar 

  63. Andreelli F, Laville M, Ducluzeau P-H, 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;42:358–364.

    Article  PubMed  CAS  Google Scholar 

  64. Bjornholm M, Kawano Y, Lehtihet M, et al. Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes. 1997;46:524–527.

    Article  PubMed  CAS  Google Scholar 

  65. Smith U, Axelsen M, Carvalho E, et al. Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes. Ann NY Acad Sci. 1999;892:119–126.

    Article  PubMed  CAS  Google Scholar 

  66. Krook A, Roth RA, Jiang XJ, et al. Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. Diabetes. 1998;47:1281–1286.

    Article  PubMed  CAS  Google Scholar 

  67. Kim Y-B, Nikoulina SE, Ciaraldi TP, et al. In vivo activation of Akt/Protein Kinase B (PKB) by insulin is normal in spite of decreased activation of phosphoinositide 3-kinase in skeletal muscle of humans with type 2 diabetes. J Clin Invest. 1999;104:733–741.

    Article  PubMed  CAS  Google Scholar 

  68. Griffin ME, Marcucci MJ, Cline GW, 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;48:1270–1274.

    Article  PubMed  CAS  Google Scholar 

  69. Hundal RS, Petersen KF, Mayerson AB, et al. Mechanisms by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest. 2002;109:1321–1326.

    PubMed  CAS  Google Scholar 

  70. Kossila M, Sinkovic M, Karkkaiinen P, et al. Gene coding for the catalytic subunit p110ß of human phosphatidylinositol 3-kinase. Cloning, genomic structure, and screening for variant in patients with type 2 diabetes. Diabetes. 2000;49:1740–1743.

    Article  PubMed  CAS  Google Scholar 

  71. Hansen T, Andersen CB, Echwald SM, et al. Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of the phosphatidylinositol 3-kinase: effects on glucose disappearance, glucose effectiveness, and the insulin sensitivity index. Diabetes. 1997;46:494–501.

    Article  PubMed  CAS  Google Scholar 

  72. Baier LJ, Wiedrich C, Hanson RL, et al. Variant in the regulatory subunit of phosphatidylinositol 3-kinase (p85alpha). Diabetes. 1998;47:973–975.

    Article  PubMed  CAS  Google Scholar 

  73. 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. 2000;105:311–320.

    Article  PubMed  CAS  Google Scholar 

  74. Itani SI, Pories WJ, Macdonald KG, Dohm GL. Increased protein kinase C theta in skeletal muscle of diabetic patients. Metabolism. 2001;50:553–557.

    Article  PubMed  CAS  Google Scholar 

  75. Ahmad F, Considine RV, Bauer TL, et al. Improved sensitivity to insulin in obese subjects following weight loss is accompanied by reduced protein-tyrosine phosphatases in adipose tissue. Metabolism. 1997;46:1140–1145.

    Article  PubMed  CAS  Google Scholar 

  76. Cheung A, Kusari J, Jansen D, et al. Marked impairment ofm protein tyrosine phosphatase 1B activity in adipose tissue of obese subjects with and without type 2 diabetes mellitus. J Lab Clin Med. 1999;134:115–123.

    Article  PubMed  CAS  Google Scholar 

  77. Kusari J, Kenner KA, Suh K-L, et al. Skeletal muscle protein tyrosine phosphatase activity and tyrosine phosphatase 1B protein content are associated with insulin action and resistance. J Clin Invest. 1994;93:1156–1162.

    Article  PubMed  CAS  Google Scholar 

  78. Worm D, Vinten J, Staehr P, et al. Altered basal and insulin-stimulated phosphotyrosine phosphatase (PTPase) activity in skeletal muscle from NIDDM patients compared with control subjects. Diabetologia. 1996;39:1208–1214.

    Article  PubMed  CAS  Google Scholar 

  79. Ahmad F, Azevedo JL, Cortright R, et al. Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes. J Clin Invest. 1997;100:449–458.

    Article  PubMed  CAS  Google Scholar 

  80. Palmer ND, Bento JC, Mychaleckyi CD, et al. Associations of protein tyrosine phosphatase 1B gene polymorphisms with measures of glucose homeostasis in Hispanic Americans: the insulin resistance atherosclerosis study (IRAS) family study. Diabetes. 2004;53:3013–3019.

    Article  PubMed  CAS  Google Scholar 

  81. Florez JC, Agapakis CM, Burtt NP, et al. Association testing of the protein tyrosine phosphatase 1B gene (PTPN1) with type 2 diabetes in 7,883 people. Diabetes. 2005;54:1881–1891.

    Article  Google Scholar 

  82. Meshkani R, Taghikhani M, Al-Kateb H, et al. Polymorphisms 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;53:1585–1592.

    Article  PubMed  CAS  Google Scholar 

  83. Ishihara H, Sasaoka T, Kagawa S, 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;20:450–454.

    Article  Google Scholar 

  84. Hansen L, Jansen JN, Ekstrom CT, et al. Studies of variability in the PTEN gene among Danish caucasian patients with Type II diabetes mellitus. Diabetologia. 2001;44:237–240.

    Article  PubMed  CAS  Google Scholar 

  85. Cozzone D, Frojdo S, Disse E, 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;51:512–521.

    Article  PubMed  CAS  Google Scholar 

  86. 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. 1996;33:193–197.

    Article  CAS  Google Scholar 

  87. Lesage S, Zouali H, Vionnet N, et al. Genetic analyses of glucose transporter genes in French non-insulin-dependent diabetic families. Diabetes Metab. 1997;23:137–142.

    PubMed  CAS  Google Scholar 

  88. Laybutt DR, Chisholm DJ, Kraegen EW. Specific adaptations in muscle and adipose tissue in response to chronic systemic glucose oversupply in rats. Am J Physiol. 1997;273:E1–E9.

    PubMed  CAS  Google Scholar 

  89. Garvey WT, Maianu L, Huecksteadt TP, et al. Pretranslational suppression of GLUT4 glucose transporters causes insulin resistance in type II diabetes. J Clin Invest. 1991;87:1072–1081.

    Article  PubMed  CAS  Google Scholar 

  90. Garvey WT. Glucose transport and NIDDM. Diabetes Care. 1992;15:396–417.

    Article  PubMed  CAS  Google Scholar 

  91. Ryder JW, Yang J, GAluska D, 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;49:647–654.

    Article  PubMed  CAS  Google Scholar 

  92. Garvey WT, Maianu L, Zhu J-H, et al. 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;101:2377–2386.

    Article  PubMed  CAS  Google Scholar 

  93. Karlsson HKR, Zierath JR, Kane S, et al. Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. Diabetes. 2005;54:1692–1697.

    Article  PubMed  CAS  Google Scholar 

  94. Thornburn AW, Gumbiner B, Bulacan F, et al. 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;85:522–529.

    Article  Google Scholar 

  95. Bjorbaek C, Echwald SM, Hubricht P, et al. Genetic variants in promoters and coding regions of the muscle glycogen synthase and the insulin responsive GLUT4 genes in NIDDM. Diabetes. 1994;43:976–983.

    Article  PubMed  CAS  Google Scholar 

  96. Vestergaard H, Lund S, Larsen FS, et al. 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;91:2342–2350.

    Article  PubMed  CAS  Google Scholar 

  97. 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. 1995;44:90–97.

    Article  PubMed  CAS  Google Scholar 

  98. Freymond D, Bogardus C, Okubo M, et al. Impaired insulin-stimulated muscle glycogen synthase activation in vivo in man is related to low fasting glycogen synthase phosphatase activity. J Clin Invest. 1988;82:1503–1509.

    Article  PubMed  CAS  Google Scholar 

  99. Nikoulina SE, Ciaraldi TP, Mudaliar S, et al. Role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes. 2000;49:263–271.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Medicine, VA San Diego Healthcare System, University of California, San Diego, CA, USA

    Theodore P. Ciaraldi

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  1. Div. Endocrinology & Metabolism, Beth Israel Medical Center, East 17th Street 317, New York, 10003, U.S.A.

    Leonid Poretsky

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Ciaraldi, T.P. (2010). Cellular Mechanisms of Insulin Action. In: Poretsky, L. (eds) Principles of Diabetes Mellitus. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-09841-8_5

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