Insulin and the Physiology of Carbohydrate Metabolism

  • Sandra Pereira
  • Adria GiaccaEmail author
Part of the Energy Balance and Cancer book series (EBAC, volume 1)


The discovery of insulin nearly a century ago revolutionized the treatment of diabetes mellitus, particularly type 1 diabetes mellitus (T1DM), and initiated extensive research into the effects of insulin. At approximately the same time, it was shown that patients with cancer were characterized by glucose intolerance and impaired insulin sensitivity of glucose metabolism has been subsequently found in cancer [1, 2]. Insulin, a peptide hormone produced by the β cells in the pancreas, is anabolic, as it stimulates synthesis of glycogen, protein, and triglycerides and it suppresses glucose production by the body, while stimulating glucose uptake from the circulation [3]. Moreover, insulin action is tissue-specific, since it depends on the binding of insulin to its cell-surface receptor. The insulin receptor, which is composed of two transmembrane β chains and two extracellular α chains, has intrinsic tyrosine kinase activity [4, 5] and binding of insulin to its receptor initiates a signaling cascade characterized by phosphorylation events and genomic effects. The insulin receptor is expressed in various tissues, including the most widely studied insulin sensitive tissues, namely liver, skeletal muscle, adipose tissue, and selective regions of the brain. Insulin has mitogenic effects [6], but the ensuing discussion will highlight the metabolic actions of insulin. Furthermore, although insulin regulates the metabolism of all three macronutrients [7], which is interlinked, the focus will be on insulin’s effect on carbohydrate metabolism.



A.G. was supported by research grants from the Canadian Diabetes Asso­ciation (GA-02062131-AG) and the Canadian Institutes of Health Research (CIHR) (MOP-89929) and (MOP-69018).


  1. 1.
    Tayek JA (1992) A review of cancer cachexia and abnormal glucose metabolism in humans with cancer. J Am Coll Nutr 11:445–456PubMedGoogle Scholar
  2. 2.
    Cersosimo E, Pisters PW, Pesola G, Rogatko A, Vydelingum NA, Bajorunas D, Brennan MF (1991) The effect of graded doses of insulin on peripheral glucose uptake and lactate release in cancer cachexia. Surgery 109:459–467PubMedGoogle Scholar
  3. 3.
    Kahn CR (2003) Knockout mice challenge our concepts of glucose homeostasis and the pathogenesis of diabetes. Exp Diabesity Res 4:169–182PubMedPubMedCentralGoogle Scholar
  4. 4.
    Kasuga M, Karlsson FA, Kahn CR (1982) Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science 215:185–187PubMedGoogle Scholar
  5. 5.
    Petruzzelli LM, Ganguly S, Smith CJ, Cobb MH, Rubin CS, Rosen OM (1982) Insulin activates a tyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes and human placenta. Proc Natl Acad Sci USA 79:6792–6796PubMedGoogle Scholar
  6. 6.
    Ish-Shalom D, Christoffersen CT, Vorwerk P, Sacerdoti-Sierra N, Shymko RM, Naor D, De MP (1997) Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia 40(Suppl):S25–31Google Scholar
  7. 7.
    Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96PubMedPubMedCentralGoogle Scholar
  8. 8.
    DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223PubMedGoogle Scholar
  9. 9.
    “euglycemia” (2007) Concise medical dictionary [article online]. Accessed 12 May 2009
  10. 10.
    “clamp” (2009) Oxford English dictionary [article online]. Accessed 12 May 2009
  11. 11.
    “eu” (2007) Concise medical dictionary [article online]. Accessed 12 May 2009
  12. 12.
    “iso” (2007) Concise medical dictionary [article online]. Accessed 12 May 2009
  13. 13.
    Boden G, Chen X, Iqbal N (1998) Acute lowering of plasma fatty acids lowers basal insulin secretion in diabetic and nondiabetic subjects. Diabetes 47:1609–1612PubMedGoogle Scholar
  14. 14.
    Boden G, Chen X (1995) Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Investig 96:1261–1268PubMedGoogle Scholar
  15. 15.
    Park E, Wong V, Guan X, Oprescu AI, Giacca A (2007) Salicylate prevents hepatic insulin resistance caused by short-term elevation of free fatty acids in vivo. J Endocrinol 195:323–331PubMedGoogle Scholar
  16. 16.
    Finegood DT, Bergman RN, Vranic M (1987) Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps. Comparison of unlabeled and labeled exogenous glucose infusates. Diabetes 36:914–924PubMedGoogle Scholar
  17. 17.
    Banerji MA, Lebovitz HE (1989) Insulin-sensitive and insulin-resistant variants in NIDDM. Diabetes 38:784–792PubMedGoogle Scholar
  18. 18.
    Staehr P, Hother-Nielsen O, Levin K, Holst JJ, Beck-Nielsen H (2001) Assessment of hepatic insulin action in obese type 2 diabetic patients. Diabetes 50:1363–1370PubMedGoogle Scholar
  19. 19.
    Stumvoll M, Chintalapudi U, Perriello G, Welle S, Gutierrez O, Gerich J (1995) Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine. J Clin Investig 96:2528–2533PubMedGoogle Scholar
  20. 20.
    Cersosimo E, Garlick P, Ferretti J (2000) Regulation of splanchnic and renal substrate supply by insulin in humans. Metabolism 49:676–683PubMedGoogle Scholar
  21. 21.
    Cersosimo E, Garlick P, Ferretti J (1999) Insulin regulation of renal glucose metabolism in humans. Am J Physiol 276:E78–E84Google Scholar
  22. 22.
    Previs SF, Brunengraber H (1998) Methods for measuring gluconeogenesis in vivo. Curr Opin Clin Nutr Metab Care 1:461–465PubMedGoogle Scholar
  23. 23.
    Devlin TM (2002) Textbook of biochemistry with clinical correlations. Wiley, New YorkGoogle Scholar
  24. 24.
    Baron AD, Brechtel G, Wallace P, Edelman SV (1988) Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans. Am J Physiol 255:E769–E774Google Scholar
  25. 25.
    DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J (1983) Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 32:35–45PubMedGoogle Scholar
  26. 26.
    Wolfe RR, Chinkes DL (2005) Isotope tracers in metabolic research: principles and practice of kinetic analysis. Hoboken, New Jersey, Wiley-LissGoogle Scholar
  27. 27.
    Steele R (1959) Influences of glucose loading and of injected insulin on hepatic glucose output. Ann NY Acad Sci 82:420–430PubMedGoogle Scholar
  28. 28.
    Saad MF, Anderson RL, Laws A, Watanabe RM, Kades WW, Chen YD, Sands RE, Pei D, Savage PJ, Bergman RN (1994) A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Insulin resistance atherosclerosis study. Diabetes 43:1114–1121PubMedGoogle Scholar
  29. 29.
    Brackenridge A, Pearson ER, Shojaee-Moradie F, Hattersley AT, Russell-Jones D, Umpleby AM (2006) Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1beta and -1alpha mutations. Diabetes 55:405–411PubMedGoogle Scholar
  30. 30.
    Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, Buzzigoli E, Sironi AM, Cersosimo E, Ferrannini E, DeFronzo RA (2007) Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 133:496–506PubMedGoogle Scholar
  31. 31.
    Tayek JA, Bergner EA, Lee WP (1991) Correction of glucose carbon recycling for the determination of ‘true’ hepatic glucose production rates by (1-13C1)glucose. Biol Mass Spectrom 20:186–190PubMedGoogle Scholar
  32. 32.
    Lam TK, van de Werve G, Giacca A (2003) Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites. Am J Physiol 284:E281–E290Google Scholar
  33. 33.
    Kolterman OG, Gray RS, Griffin J, Burstein P, Insel J, Scarlett JA, Olefsky JM (1981) Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Investig 68:957–969PubMedGoogle Scholar
  34. 34.
    Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Jarvinen H, Van HT, Renn W, Gerich J (2000) Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 23:295–301PubMedGoogle Scholar
  35. 35.
    Gastaldelli A, Miyazaki Y, Pettiti M, Buzzigoli E, Mahankali S, Ferrannini E, DeFronzo RA (2004) Separate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis. J Clin Endocrinol Metab 89:3914–3921PubMedGoogle Scholar
  36. 36.
    Chevalier S, Burgess SC, Malloy CR, Gougeon R, Marliss EB, Morais JA (2006) The greater contribution of gluconeogenesis to glucose production in obesity is related to increased whole-body protein catabolism. Diabetes 55:675–681PubMedGoogle Scholar
  37. 37.
    Chevalier S, Marliss EB, Morais JA, Lamarche M, Gougeon R (2005) The influence of sex on the protein anabolic response to insulin. Metabolism 54:1529–1535PubMedGoogle Scholar
  38. 38.
    Del PS, Bonadonna RC, Bonora E, Gulli G, Solini A, Shank M, DeFronzo RA (1993) Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus. J Clin Investig 91:484–494Google Scholar
  39. 39.
    Kim JK, Zisman A, Fillmore JJ, Peroni OD, Kotani K, Perret P, Zong H, Dong J, Kahn CR, Kahn BB, Shulman GI (2001) Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4. J Clin Investig 108:153–160PubMedGoogle Scholar
  40. 40.
    Wong V, Stavar L, Szeto L, Uffelman K, Wang CH, Fantus IG, Lewis GF (2006) Atorvastatin induces insulin sensitization in Zucker lean and fatty rats. Atherosclerosis 184:348–355PubMedGoogle Scholar
  41. 41.
    Colwell DR, Higgins JA, Denyer GS (1996) Incorporation of 2-deoxy-d-glucose into glycogen. Implications for measurement of tissue-specific glucose uptake and utilisation. Int J Biochem Cell Biol 28:115–121PubMedGoogle Scholar
  42. 42.
    Youn JH, Kim JK, Buchanan TA (1994) Time courses of changes in hepatic and skeletal muscle insulin action and GLUT4 protein in skeletal muscle after STZ injection. Diabetes 43:564–571PubMedGoogle Scholar
  43. 43.
    Adkins A, Basu R, Persson M, Dicke B, Shah P, Vella A, Schwenk WF, Rizza R (2003) Higher insulin concentrations are required to suppress gluconeogenesis than glycogenolysis in nondiabetic humans. Diabetes 52:2213–2220PubMedGoogle Scholar
  44. 44.
    Rothman DL, Magnusson I, Katz LD, Shulman RG, Shulman GI (1991) Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science 254:573–576PubMedGoogle Scholar
  45. 45.
    Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan SC (1996) Contributions of gluconeogenesis to glucose production in the fasted state. J Clin Investig 98:378–385PubMedGoogle Scholar
  46. 46.
    Hellerstein MK, Neese RA, Linfoot P, Christiansen M, Turner S, Letscher A (1997) Hepatic gluconeogenic fluxes and glycogen turnover during fasting in humans. A stable isotope study. J Clin Investig 100:1305–1319PubMedGoogle Scholar
  47. 47.
    Bock G, Schumann WC, Basu R, Burgess SC, Yan Z, Chandramouli V, Rizza RA, Landau BR (2008) Evidence that processes other than gluconeogenesis may influence the ratio of deuterium on the fifth and third carbons of glucose: implications for the use of 2H2O to measure gluconeogenesis in humans. Diabetes 57:50–55PubMedGoogle Scholar
  48. 48.
    Basu R, Chandramouli V, Dicke B, Landau BR, Rizza RA (2008) Plasma C5 glucose-to-2H2O ratio does not provide an accurate assessment of gluconeogenesis during hyperinsulinemic-euglycemic clamps in either nondiabetic or diabetic humans. Diabetes 57:1800–1804PubMedPubMedCentralGoogle Scholar
  49. 49.
    Ackermans MT, Pereira Arias AM, Bisschop PH, Endert E, Sauerwein HP, Romijn JA (2001) The quantification of gluconeogenesis in healthy men by (2)H2O and [2-(13)C]glycerol yields different results: rates of gluconeogenesis in healthy men measured with (2)H2O are higher than those measured with [2-(13)C]glycerol. J Clin Endocrinol Metab 86:2220–2226PubMedGoogle Scholar
  50. 50.
    Landau BR (1999) Quantifying the contribution of gluconeogenesis to glucose production in fasted human subjects using stable isotopes. Proc Nutr Soc 58:963–972PubMedGoogle Scholar
  51. 51.
    Hetenyi G Jr (1982) Correction for the metabolic exchange of 14C for 12C atoms in the pathway of gluconeogenesis in vivo. Fed Proc 41:104–109PubMedGoogle Scholar
  52. 52.
    Hellerstein MK, Neese RA (1992) Mass isotopomer distribution analysis: a technique for measuring biosynthesis and turnover of polymers. Am J Physiol 263:E998–E1001Google Scholar
  53. 53.
    Chinkes DL, Aarsland A, Rosenblatt J, Wolfe RR (1996) Comparison of mass isotopomer dilution methods used to compute VLDL production in vivo. Am J Physiol 271:E373–E383Google Scholar
  54. 54.
    Landau BR, Fernandez CA, Previs SF, Ekberg K, Chandramouli V, Wahren J, Kalhan SC, Brunengraber H (1995) A limitation in the use of mass isotopomer distributions to measure gluconeogenesis in fasting humans. Am J Physiol 269:E18–E26Google Scholar
  55. 55.
    Previs SF, Fernandez CA, Yang D, Soloviev MV, David F, Brunengraber H (1995) Limitations of the mass isotopomer distribution analysis of glucose to study gluconeogenesis. Substrate cycling between glycerol and triose phosphates in liver. J Biol Chem 270:19806–19815PubMedGoogle Scholar
  56. 56.
    Previs SF, Cline GW, Shulman GI (1999) A critical evaluation of mass isotopomer distribution analysis of gluconeogenesis in vivo. Am J Physiol 277:E154–E160Google Scholar
  57. 57.
    Peroni O, Large V, Beylot M (1995) Measuring gluconeogenesis with [2-13C]glycerol and mass isotopomer distribution analysis of glucose. Am J Physiol 269:E516–E523Google Scholar
  58. 58.
    Tayek JA, Katz J (1996) Glucose production, recycling, and gluconeogenesis in normals and diabetics: a mass isotopomer [U-13C]glucose study. Am J Physiol 270:E709–E717PubMedGoogle Scholar
  59. 59.
    Kelleher JK (1999) Estimating gluconeogenesis with [U-13C]glucose: molecular condensation requires a molecular approach. Am J Physiol 277:E395–E400Google Scholar
  60. 60.
    Tayek JA, Katz J (1997) Glucose production, recycling, Cori cycle, and gluconeogenesis in humans: relationship to serum cortisol. Am J Physiol 272:E476–E484Google Scholar
  61. 61.
    Landau BR, Wahren J, Ekberg K, Previs SF, Yang D, Brunengraber H (1998) Limitations in estimating gluconeogenesis and Cori cycling from mass isotopomer distributions using [U-13C6]glucose. Am J Physiol 274:E954–E961PubMedGoogle Scholar
  62. 62.
    Katz J, Tayek JA (1999) Recycling of glucose and determination of the Cori Cycle and gluconeogenesis. Am J Physiol 277:E401–E407PubMedGoogle Scholar
  63. 63.
    Radziuk J, Lee WP (1999) Measurement of gluconeogenesis and mass isotopomer analysis based on [U-(13)C]glucose. Am J Physiol 277:E199–E207Google Scholar
  64. 64.
    Katz J, Tayek JA (1998) Gluconeogenesis and the Cori cycle in 12-, 20-, and 40-h-fasted humans. Am J Physiol 275:E537–E542Google Scholar
  65. 65.
    Mao CS, Bassilian S, Lim SK, Lee WN (2002) Underestimation of gluconeogenesis by the [U-(13)C(6)]glucose method: effect of lack of isotope equilibrium. Am J Physiol Endocrinol Metab 282:E376–E385PubMedGoogle Scholar
  66. 66.
    Haymond MW, Sunehag AL (2000) The reciprocal pool model for the measurement of gluconeogenesis by use of [U-(13)C]glucose. Am J Physiol Endocrinol Metab 278:E140–E145PubMedGoogle Scholar
  67. 67.
    Allick G, van der Crabben SN, Ackermans MT, Endert E, Sauerwein HP (2006) Measurement of gluconeogenesis by deuterated water: the effect of equilibration time and fasting period. Am J Physiol Endocrinol Metab 290:E1212–E1217PubMedGoogle Scholar
  68. 68.
    Jin ES, Jones JG, Merritt M, Burgess SC, Malloy CR, Sherry AD (2004) Glucose production, gluconeogenesis, and hepatic tricarboxylic acid cycle fluxes measured by nuclear magnetic resonance analysis of a single glucose derivative. Anal Biochem 327:149–155PubMedGoogle Scholar
  69. 69.
    Jones JG, Solomon MA, Cole SM, Sherry AD, Malloy CR (2001) An integrated (2)H and (13)C NMR study of gluconeogenesis and TCA cycle flux in humans. Am J Physiol Endocrinol Metab 281:E848–E856PubMedGoogle Scholar
  70. 70.
    Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan SC (1995) Use of 2H2O for estimating rates of gluconeogenesis. Application to the fasted state. J Clin Investig 95:172–178PubMedGoogle Scholar
  71. 71.
    Jones JG, Carvalho RA, Sherry AD, Malloy CR (2000) Quantitation of gluconeogenesis by (2)H nuclear magnetic resonance analysis of plasma glucose following ingestion of (2)H(2)O. Anal Biochem 277:121–126PubMedGoogle Scholar
  72. 72.
    Basu R, Chandramouli V, Schumann W, Basu A, Landau BR, Rizza RA (2009) Additional evidence that transaldolase exchange, isotope discrimination during the triose-isomerase reaction, or both occur in humans: effects of type 2 diabetes. Diabetes 57:1539–1543Google Scholar
  73. 73.
    Giaccari A, Rossetti L (1989) Isocratic high-performance liquid chromatographic determination of the concentration and specific radioactivity of phosphoenolpyruvate and uridine diphosphate glucose in tissue extracts. J Chromatogr B Biomed Appl 497:69–78Google Scholar
  74. 74.
    Rossetti L, Massillon D, Barzilai N, Vuguin P, Chen W, Hawkins M, Wu J, Wang J (1997) Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. J Biol Chem 272:27758–27763PubMedGoogle Scholar
  75. 75.
    Rossetti L, Giaccari A, Barzilai N, Howard K, Sebel G, Hu M (1993) Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes. J Clin Investig 92:1126–1134PubMedGoogle Scholar
  76. 76.
    Massillon D, Chen W, Hawkins M, Liu R, Barzilai N, Rossetti L (1995) Quantitation of hepatic glucose fluxes and pathways of hepatic glycogen synthesis in conscious mice. Am J Physiol 269:E1037–E1043PubMedGoogle Scholar
  77. 77.
    Goldstein RE, Rossetti L, Palmer BA, Liu R, Massillon D, Scott M, Neal D, Williams P, Peeler B, Cherrington AD (2002) Effects of fasting and glucocorticoids on hepatic gluconeogenesis assessed using two independent methods in vivo. Am J Physiol Endocrinol Metab 283:E946–E957PubMedGoogle Scholar
  78. 78.
    Goldstein RE, Wasserman DH, McGuinness OP, Lacy DB, Cherrington AD, Abumrad NN (1993) Effects of chronic elevation in plasma cortisol on hepatic carbohydrate metabolism. Am J Physiol 264:E119–E127PubMedGoogle Scholar
  79. 79.
    Muniyappa R, Lee S, Chen H, Quon MJ (2008) Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 294:E15–E26PubMedGoogle Scholar
  80. 80.
    Choukem SP, Gautier JF (2008) How to measure hepatic insulin resistance? Diab Metab 34:E664–E673Google Scholar
  81. 81.
    Yokoyama H, Emoto M, Fujiwara S, Motoyama K, Morioka T, Komatsu M, Tahara H, Shoji T, Okuno Y, Nishizawa Y (2003) Quantitative insulin sensitivity check index and the reciprocal index of homeostasis model assessment in normal range weight and moderately obese type 2 diabetic patients. Diabetes Care 26:2426–2432PubMedGoogle Scholar
  82. 82.
    Laakso M (1993) How good a marker is insulin level for insulin resistance? Am J Epidemiol 137:959–965PubMedGoogle Scholar
  83. 83.
    Tran TT, Gupta N, Goh T, Naigamwalla D, Chia MC, Koohestani N, Mehrotra S, Keown-Eyssen G, Giacca A, Bruce WR (2003) Direct measure of insulin sensitivity with the hyperinsulinemic-euglycemic clamp and surrogate measures of insulin sensitivity with the oral glucose tolerance test: correlations with aberrant crypt foci promotion in rats. Cancer Epidemiol Biomark Prev 12:47–56Google Scholar
  84. 84.
    Lee S, Muniyappa R, Yan X, Chen H, Yue LQ, Hong EG, Kim JK, Quon MJ (2008) Comparison between surrogate indexes of insulin sensitivity and resistance and hyperinsulinemic euglycemic clamp estimates in mice. Am J Physiol Endocrinol Metab 294:E261–E270PubMedGoogle Scholar
  85. 85.
    Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes Care 27:1487–1495PubMedGoogle Scholar
  86. 86.
    Turner RC, Holman RR, Matthews D, Hockaday TD, Peto J (1979) Insulin deficiency and insulin resistance interaction in diabetes: estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations. Metabolism 28:1086–1096PubMedGoogle Scholar
  87. 87.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419Google Scholar
  88. 88.
    Hosker JP, Matthews DR, Rudenski AS, Burnett MA, Darling P, Bown EG, Turner RC (1985) Continuous infusion of glucose with model assessment: measurement of insulin resistance and beta-cell function in man. Diabetologia 28:401–411PubMedGoogle Scholar
  89. 89.
    Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, Monauni T, Muggeo M (2000) Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 23:57–63PubMedGoogle Scholar
  90. 90.
    Tripathy D, Almgren P, Tuomi T, Groop L (2004) Contribution of insulin-stimulated glucose uptake and basal hepatic insulin sensitivity to surrogate measures of insulin sensitivity. Diabetes Care 27:2204–2210PubMedGoogle Scholar
  91. 91.
    Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470PubMedGoogle Scholar
  92. 92.
    Abdul-Ghani MA, Matsuda M, DeFronzo RA (2008) Strong association between insulin resistance in liver and skeletal muscle in non-diabetic subjects. Diabet Med 25:1289–1294PubMedGoogle Scholar
  93. 93.
    Abdul-Ghani MA, Matsuda M, Balas B, DeFronzo RA (2007) Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care 30:89–94PubMedGoogle Scholar
  94. 94.
    Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85:2402–2410PubMedGoogle Scholar
  95. 95.
    Rabasa-Lhoret R, Bastard JP, Jan V, Ducluzeau PH, Andreelli F, Guebre F, Bruzeau J, Louche-Pellissier C, MaItrepierre C, Peyrat J, Chagne J, Vidal H, Laville M (2003) Modified quantitative insulin sensitivity check index is better correlated to hyperinsulinemic glucose clamp than other fasting-based index of insulin sensitivity in different insulin-resistant states. J Clin Endocrinol Metab 88:4917–4923PubMedGoogle Scholar
  96. 96.
    Yokoyama H, Emoto M, Fujiwara S, Motoyama K, Morioka T, Komatsu M, Tahara H, Koyama H, Shoji T, Inaba M, Nishizawa Y (2004) Quantitative insulin sensitivity check index and the reciprocal index of homeostasis model assessment are useful indexes of insulin resistance in type 2 diabetic patients with wide range of fasting plasma glucose. J Clin Endocrinol Metab 89:1481–1484PubMedGoogle Scholar
  97. 97.
    Uwaifo GI, Fallon EM, Chin J, Elberg J, Parikh SJ, Yanovski JA (2002) Indices of insulin action, disposal, and secretion derived from fasting samples and clamps in normal glucose-tolerant black and white children. Diabetes Care 25:2081–2087PubMedGoogle Scholar
  98. 98.
    Malita FM, Karelis AD, St-Pierre DH, Garrel D, Bastard JP, Tardif A, Prud’homme D, Rabasa-Lhoret R (2006) Surrogate indexes vs. euglycaemic-hyperinsulinemic clamp as an indicator of insulin resistance and cardiovascular risk factors in overweight and obese postmenopausal women. Diabetes Metab 32:251–255PubMedGoogle Scholar
  99. 99.
    Cacho J, Sevillano J, de Castro J, Herrera E, Ramos MP (2008) Validation of simple indexes to assess insulin sensitivity during pregnancy in Wistar and Sprague-Dawley rats. Am J Physiol Endocrinol Metab 295:E1269–E1276PubMedGoogle Scholar
  100. 100.
    Bonora E, Moghetti P, Zancanaro C, Cigolini M, Querena M, Cacciatori V, Corgnati A, Muggeo M (1989) Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies. J Clin Endocrinol Metab 68:374–378PubMedGoogle Scholar
  101. 101.
    Hirst S, Phillips DI, Vines SK, Clark PM, Hales CN (1993) Reproducibility of the short insulin tolerance test. Diabet Med 10:839–842PubMedGoogle Scholar
  102. 102.
    Chen CC, Wang TY, Hsu SY, Chen RH, Chang CT, Chen SJ (1998) Is the short insulin tolerance test safe and reproducible? Diabet Med 15:924–927PubMedGoogle Scholar
  103. 103.
    Reaven GM (1983) Insulin resistance in noninsulin-dependent diabetes mellitus. Does it exist and can it be measured? Am J Med 74:3–17PubMedGoogle Scholar
  104. 104.
    Gelding SV, Robinson S, Lowe S, Niththyananthan R, Johnston DG (1994) Validation of the low dose short insulin tolerance test for evaluation of insulin sensitivity. Clin Endocrinol 40:611–615Google Scholar
  105. 105.
    Akinmokun A, Selby PL, Ramaiya K, Alberti KG (1992) The short insulin tolerance test for determination of insulin sensitivity: a comparison with the euglycaemic clamp. Diabet Med 9:432–437PubMedGoogle Scholar
  106. 106.
    Young RP, Critchley JA, Anderson PJ, Lau MS, Lee KK, Chan JC (1996) The short insulin tolerance test: feasibility study using venous sampling. Diabet Med 13:429–433PubMedGoogle Scholar
  107. 107.
    Inchiostro S (2005) Measurement of insulin sensitivity in Type 2 diabetes mellitus: comparison between KITT and HOMA-%S indices and evaluation of their relationship with the components of the insulin resistance syndrome. Diabet Med 22:39–44PubMedGoogle Scholar
  108. 108.
    Phillips DI, Clark PM, Hales CN, Osmond C (1994) Understanding oral glucose tolerance: comparison of glucose or insulin measurements during the oral glucose tolerance test with specific measurements of insulin resistance and insulin secretion. Diabet Med 11:286–292PubMedGoogle Scholar
  109. 109.
    Xu E, Dubois MJ, Leung N, Charbonneau A, Turbide C, Avramoglu RK, DeMarte L, Elchebly M, Streichert T, Levy E, Beauchemin N, Marette A (2009) Targeted disruption of carcinoembryonic antigen-related cell adhesion molecule 1 promotes diet-induced hepatic steatosis and insulin resistance. Endocrinology 150:3503–3512PubMedGoogle Scholar
  110. 110.
    Minami A, Iseki M, Kishi K, Wang M, Ogura M, Furukawa N, Hayashi S, Yamada M, Obata T, Takeshita Y, Nakaya Y, Bando Y, Izumi K, Moodie SA, Kajiura F, Matsumoto M, Takatsu K, Takaki S, Ebina Y (2003) Increased insulin sensitivity and hypoinsulinemia in APS knockout mice. Diabetes 52:2657–2665PubMedGoogle Scholar
  111. 111.
    Cariou B, van Harmelen K, Duran-Sandoval D, van Dijk TH, Grefhorst A, Abdelkarim M, Caron S, Torpier G, Fruchart JC, Gonzalez FJ, Kuipers F, Staels B (2006) The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 281:11039–11049PubMedGoogle Scholar
  112. 112.
    Carvalho E, Kotani K, Peroni OD, Kahn BB (2005) Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle. Am J Physiol Endocrinol Metab 289:E551–E561PubMedGoogle Scholar
  113. 113.
    Araujo EP, De Souza CT, Ueno M, Cintra DE, Bertolo MB, Carvalheira JB, Saad MJ, Velloso LA (2007) Infliximab restores glucose homeostasis in an animal model of diet-induced obesity and diabetes. Endocrinology 148:5991–5997PubMedGoogle Scholar
  114. 114.
    Mulder H, Sorhede-Winzell M, Contreras JA, Fex M, Strom K, Ploug T, Galbo H, Arner P, Lundberg C, Sundler F, Ahren B, Holm C (2003) Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact. J Biol Chem 278:36380–36388PubMedGoogle Scholar
  115. 115.
    Ahren B, Pacini G (2006) A novel approach to assess insulin sensitivity reveals no increased insulin sensitivity in mice with a dominant-negative mutant hepatocyte nuclear factor-1alpha. Am J Physiol Regul Integr Comp Physiol 291:R131–R137PubMedGoogle Scholar
  116. 116.
    Kahn SE (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 46:3–19PubMedGoogle Scholar
  117. 117.
    American Diabetes Association (2009) Executive summary: standards of medical care in diabetes – 2009. Diabetes Care 32(Suppl 1):S6–S12Google Scholar
  118. 118.
    Canadian Diabetes Association Clinical Practice Guidelines Expert Committee (2008) Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 32:S1–S201Google Scholar
  119. 119.
    Soonthornpun S, Setasuban W, Thamprasit A, Chayanunnukul W, Rattarasarn C, Geater A (2003) Novel insulin sensitivity index derived from oral glucose tolerance test. J Clin Endocrinol Metab 88:1019–1023PubMedGoogle Scholar
  120. 120.
    Kazama Y, Takamura T, Sakurai M, Shindo H, Ohkubo E, Aida K, Harii N, Taki K, Kaneshige M, Tanaka S, Shimura H, Endo T, Kobayashi T (2008) New insulin sensitivity index from the oral glucose tolerance test. Diab Res Clin Pract 79:24–30Google Scholar
  121. 121.
    Avignon A, Boegner C, Mariano-Goulart D, Colette C, Monnier L (1999) Assessment of insulin sensitivity from plasma insulin and glucose in the fasting or post oral glucose-load state. Int J Obes Relat Metab Disord 23:512–517PubMedGoogle Scholar
  122. 122.
    Tao R, Ye F, He Y, Tian J, Liu G, Ji T, Su Y (2009) Improvement of high-fat-diet-induced metabolic syndrome by a compound from Balanophora polyandra Griff in mice. Eur J Pharmacol 616:328–333PubMedGoogle Scholar
  123. 123.
    Nakaya Y, Minami A, Harada N, Sakamoto S, Niwa Y, Ohnaka M (2000) Taurine improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous type 2 diabetes. Am J Clin Nutr 71:54–58PubMedGoogle Scholar
  124. 124.
    Yao XH, Gregoire Nyomba BL (2007) Abnormal glucose homeostasis in adult female rat offspring after intrauterine ethanol exposure. Am J Physiol Regul Integr Comp Physiol 292:R1926–R1933PubMedGoogle Scholar
  125. 125.
    Parlevliet ET, Heijboer AC, Schroder-van der Elst JP, Havekes LM, Romijn JA, Pijl H, Corssmit EP (2008) Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet. Am J Physiol Endocrinol Metab 294:E142–E147PubMedGoogle Scholar
  126. 126.
    Pacini G, Bergman RN (1986) MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test. Comput Meth Programs Biomed 23:113–122Google Scholar
  127. 127.
    Pacini G, Tonolo G, Sambataro M, Maioli M, Ciccarese M, Brocco E, Avogaro A, Nosadini R (1998) Insulin sensitivity and glucose effectiveness: minimal model analysis of regular and insulin-modified FSIGT. Am J Physiol 274:E592–E599Google Scholar
  128. 128.
    Mehring GH, Coates PA, Brunel PC, Luzio SD, Owens DR (2002) Insulin sensitivity in type 2 diabetes: univariate and multivariate techniques to derive estimates of insulin sensitivity from the insulin modified intravenous glucose tolerance test (FSIGT). Comput Meth Programs Biomed 68:161–176Google Scholar
  129. 129.
    Bergman RN, Ider YZ, Bowden CR, Cobelli C (1979) Quantitative estimation of insulin sensitivity. Am J Physiol 236:E667–E677PubMedGoogle Scholar
  130. 130.
    Bergman RN, Phillips LS, Cobelli C (1981) Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Investig 68:1456–1467PubMedGoogle Scholar
  131. 131.
    Yang YJ, Youn JH, Bergman RN (1987) Modified protocols improve insulin sensitivity estimation using the minimal model. Am J Physiol 253:E595–E602Google Scholar
  132. 132.
    Coates PA, Luzio SD, Brunel P, Owens DR (1995) Comparison of estimates of insulin sensitivity from minimal model analysis of the insulin-modified frequently sampled intravenous glucose tolerance test and the isoglycemic hyperinsulinemic clamp in subjects with NIDDM. Diabetes 44:631–635PubMedGoogle Scholar
  133. 133.
    Brehm A, Thomaseth K, Bernroider E, Nowotny P, Waldhausl W, Pacini G, Roden M (2006) The role of endocrine counterregulation for estimating insulin sensitivity from intravenous glucose tolerance tests. J Clin Endocrinol Metab 91:2272–2278PubMedGoogle Scholar
  134. 134.
    Saad MF, Steil GM, Kades WW, Ayad MF, Elsewafy WA, Boyadjian R, Jinagouda SD, Bergman RN (1997) Differences between the tolbutamide-boosted and the insulin-modified minimal model protocols. Diabetes 46:1167–1171PubMedGoogle Scholar
  135. 135.
    Sumner AE, Luercio MF, Frempong BA, Ricks M, Sen S, Kushner H, Tulloch-Reid MK (2009) Validity of the reduced-sample insulin modified frequently-sampled intravenous glucose tolerance test using the nonlinear regression approach. Metabolism 58:220–225PubMedPubMedCentralGoogle Scholar
  136. 136.
    Caumo A, Vicini P, Zachwieja JJ, Avogaro A, Yarasheski K, Bier DM, Cobelli C (1999) Undermodeling affects minimal model indexes: insights from a two-compartment model. Am J Physiol 276:E1171–E1193PubMedGoogle Scholar
  137. 137.
    Hoffman RP, Vicini P, Cobelli C (2002) Comparison of insulin sensitivity and glucose effectiveness determined by the one- and two-compartment-labeled minimal model in late prepubertal children and early adolescents. Metabolism 51:1582–1586PubMedGoogle Scholar
  138. 138.
    Krudys KM, Dodds MG, Nissen SM, Vicini P (2005) Integrated model of hepatic and peripheral glucose regulation for estimation of endogenous glucose production during the hot IVGTT. Am J Physiol Endocrinol Metab 288:E1038–E1046PubMedGoogle Scholar
  139. 139.
    Tokuyama K, Suzuki M (1998) Intravenous glucose tolerance test-derived glucose effectiveness in endurance-trained rats. Metabolism 47:190–194PubMedGoogle Scholar
  140. 140.
    Pawlak DB, Bryson JM, Denyer GS, Brand-Miller JC (2001) High glycemic index starch promotes hypersecretion of insulin and higher body fat in rats without affecting insulin sensitivity. J Nutr 131:99–104PubMedGoogle Scholar
  141. 141.
    O’Rourke CM, Davis JA, Saltiel AR, Cornicelli JA (1997) Metabolic effects of troglitazone in the Goto-Kakizaki rat, a non-obese and normolipidemic rodent model of non-insulin-dependent diabetes mellitus. Metabolism 46:192–198PubMedGoogle Scholar
  142. 142.
    Pacini G, Thomaseth K, Ahren B (2001) Contribution to glucose tolerance of insulin-independent vs. insulin-dependent mechanisms in mice. Am J Physiol Endocrinol Metab 281:E693–E703PubMedGoogle Scholar
  143. 143.
    Pacini G, Ahren M, Ahren B (2009) Reappraisal of the intravenous glucose tolerance index for a simple assessment of insulin sensitivity in mice. Am J Physiol Regul Integr Comp Physiol 296:R1316–R1324PubMedGoogle Scholar
  144. 144.
    Pei D, Jones CN, Bhargava R, Chen YD, Reaven GM (1994) Evaluation of octreotide to assess insulin-mediated glucose disposal by the insulin suppression test. Diabetologia 37:843–845PubMedGoogle Scholar
  145. 145.
    Kim SH, Reaven GM (2008) Isolated impaired fasting glucose and peripheral insulin sensitivity: not a simple relationship. Diabetes Care 31:347–352PubMedGoogle Scholar
  146. 146.
    Shen SW, Reaven GM, Farquhar JW (1970) Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes. J Clin Investig 49:2151–2160PubMedGoogle Scholar
  147. 147.
    Hwu CM, Kwok CF, Chiang SC, Wang PY, Hsiao LC, Lee SH, Lin SH, Ho LT (2001) A comparison of insulin suppression tests performed with somatostatin and octreotide with particular reference to tolerability. Diab Res Clin Pract 51:187–193Google Scholar
  148. 148.
    Ikebuchi M, Suzuki M, Kageyama A, Hirose J, Yokota C, Ikeda K, Shinozaki K, Todo R, Harano Y (1996) Modified method using a somatostatin analogue, octreotide acetate (Sandostatin) to assess in vivo insulin sensitivity. Endocr J 43:125–130PubMedGoogle Scholar
  149. 149.
    Weir GC, Bonner-Weir S (1990) Islets of Langerhans: the puzzle of intraislet interactions and their relevance to diabetes. J Clin Investig 85:983–987PubMedGoogle Scholar
  150. 150.
    Maheux P, Azhar S, Kern PA, Chen YD, Reuven GM (1997) Relationship between insulin-mediated glucose disposal and regulation of plasma and adipose tissue lipoprotein lipase. Diabetologia 40:850–858PubMedGoogle Scholar
  151. 151.
    Facchini F, Humphreys MH, Jeppesen J, Reaven GM (1999) Measurements of insulin-­mediated glucose disposal are stable over time. J Clin Endocrinol Metab 84:1567–1569PubMedGoogle Scholar
  152. 152.
    Greenfield MS, Doberne L, Kraemer F, Tobey T, Reaven G (1981) Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes 30:387–392PubMedGoogle Scholar
  153. 153.
    Rodnick KJ, Mondon CE, Haskell WL, Azhar S, Reaven GM (1990) Differences in insulin-induced glucose uptake and enzyme activity in running rats. J Appl Physiol 68:513–519PubMedGoogle Scholar
  154. 154.
    Maegawa H, Kobayashi M, Ishibashi O, Takata Y, Shigeta Y (1986) Effect of diet change on insulin action: difference between muscles and adipocytes. Am J Physiol 251:E616–E623Google Scholar
  155. 155.
    Maegawa H, Hasegawa M, Sugai S, Obata T, Ugi S, Morino K, Egawa K, Fujita T, Sakamoto T, Nishio Y, Kojima H, Haneda M, Yasuda H, Kikkawa R, Kashiwagi A (1999) Expression of a dominant negative SHP-2 in transgenic mice induces insulin resistance. J Biol Chem 274:30236–30243PubMedGoogle Scholar
  156. 156.
    Uwaifo GI, Parikh SJ, Keil M, Elberg J, Chin J, Yanovski JA (2002) Comparison of insulin sensitivity, clearance, and secretion estimates using euglycemic and hyperglycemic clamps in children. J Clin Endocrinol Metab 87:2899–2905PubMedGoogle Scholar
  157. 157.
    Carpentier A, Zinman B, Leung N, Giacca A, Hanley AJ, Harris SB, Hegele RA, Lewis GF (2003) Free fatty acid-mediated impairment of glucose-stimulated insulin secretion in nondiabetic Oji-Cree individuals from the Sandy Lake community of Ontario, Canada: a population at very high risk for developing type 2 diabetes. Diabetes 52:1485–1495PubMedGoogle Scholar
  158. 158.
    Mari A, Ahren B, Pacini G (2005) Assessment of insulin secretion in relation to insulin resistance. Curr Opin Clin Nutr Metab Care 8:529–533PubMedGoogle Scholar
  159. 159.
    Goh TT, Mason TM, Gupta N, So A, Lam TK, Lam L, Lewis GF, Mari A, Giacca A (2007) Lipid-induced beta-cell dysfunction in vivo in models of progressive beta-cell failure. Am J Physiol Endocrinol Metab 292:E549–E560PubMedGoogle Scholar
  160. 160.
    Mitrakou A, Vuorinen-Markkola H, Raptis G, Toft I, Mokan M, Strumph P, Pimenta W, Veneman T, Jenssen T, Bolli G (1992) Simultaneous assessment of insulin secretion and insulin sensitivity using a hyperglycemia clamp. J Clin Endocrinol Metab 75:379–382PubMedGoogle Scholar
  161. 161.
    Elahi D, Meneilly GS, Minaker KL, Andersen DK, Rowe JW (1989) Escape of hepatic ­glucose production during hyperglycemic clamp. Am J Physiol 257:E704–E711Google Scholar
  162. 162.
    Ayala JE, Bracy DP, McGuinness OP, Wasserman DH (2006) Considerations in the design of hyperinsulinemic-euglycemic clamps in the conscious mouse. Diabetes 55:390–397PubMedGoogle Scholar
  163. 163.
    Xu B, Bird VG, Miller WT (1995) Substrate specificities of the insulin and insulin-like growth factor 1 receptor tyrosine kinase catalytic domains. J Biol Chem 270:29825–29830PubMedGoogle Scholar
  164. 164.
    Araki E, Lipes MA, Patti ME, Bruning JC, Haag B III, Johnson RS, Kahn CR (1994) Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372:186–190PubMedPubMedCentralGoogle Scholar
  165. 165.
    Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904PubMedPubMedCentralGoogle Scholar
  166. 166.
    Liu SC, Wang Q, Lienhard GE, Keller SR (1999) Insulin receptor substrate 3 is not essential for growth or glucose homeostasis. J Biol Chem 274:18093–18099PubMedGoogle Scholar
  167. 167.
    Fantin VR, Wang Q, Lienhard GE, Keller SR (2000) Mice lacking insulin receptor substrate 4 exhibit mild defects in growth, reproduction, and glucose homeostasis. Am J Physiol Endocrinol Metab 278:E127–E133PubMedGoogle Scholar
  168. 168.
    Cai D, Dhe-Paganon S, Melendez PA, Lee J, Shoelson SE (2003) Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J Biol Chem 278:25323–25330PubMedPubMedCentralGoogle Scholar
  169. 169.
    Sciacchitano S, Taylor SI (1997) Cloning, tissue expression, and chromosomal localization of the mouse IRS-3 gene. Endocrinology 138:4931–4940PubMedGoogle Scholar
  170. 170.
    Fantin VR, Lavan BE, Wang Q, Jenkins NA, Gilbert DJ, Copeland NG, Keller SR, Lienhard GE (1999) Cloning, tissue expression, and chromosomal location of the mouse insulin receptor substrate 4 gene. Endocrinology 140:1329–1337PubMedGoogle Scholar
  171. 171.
    Laustsen PG, Michael MD, Crute BE, Cohen SE, Ueki K, Kulkarni RN, Keller SR, Lienhard GE, Kahn CR (2002) Lipoatrophic diabetes in Irs1(-/-)/Irs3(-/-) double knockout mice. Genes Dev 16:3213–3222PubMedPubMedCentralGoogle Scholar
  172. 172.
    Goren HJ, Kulkarni RN, Kahn CR (2004) Glucose homeostasis and tissue transcript content of insulin signaling intermediates in four inbred strains of mice: C57BL/6, C57BLKS/6, DBA/2, and 129X1. Endocrinology 145:3307–3323PubMedGoogle Scholar
  173. 173.
    Thirone AC, Huang C, Klip A (2006) Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Trends Endocrinol Metab 17:72–78PubMedGoogle Scholar
  174. 174.
    Yamauchi T, Tobe K, Tamemoto H, Ueki K, Kaburagi Y, Yamamoto-Honda R, Takahashi Y, Yoshizawa F, Aizawa S, Akanuma Y, Sonenberg N, Yazaki Y, Kadowaki T (1996) Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol 16:3074–3084PubMedPubMedCentralGoogle Scholar
  175. 175.
    Kubota N, Tobe K, Terauchi Y, Eto K, Yamauchi T, Suzuki R, Tsubamoto Y, Komeda K, Nakano R, Miki H, Satoh S, Sekihara H, Sciacchitano S, Lesniak M, Aizawa S, Nagai R, Kimura S, Akanuma Y, Taylor SI, Kadowaki T (2000) Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. Diabetes 49:1880–1889Google Scholar
  176. 176.
    Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF, Accili D (2000) Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Investig 105:199–205PubMedGoogle Scholar
  177. 177.
    Taniguchi CM, Ueki K, Kahn R (2005) Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J Clin Invest 115:718–727PubMedPubMedCentralGoogle Scholar
  178. 178.
    Simmgen M, Knauf C, Lopez M, Choudhury AI, Charalambous M, Cantley J, Bedford DC, Claret M, Iglesias MA, Heffron H, Cani PD, Vidal-Puig A, Burcelin R, Withers DJ (2006) Liver-specific deletion of insulin receptor substrate 2 does not impair hepatic glucose and lipid metabolism in mice. Diabetologia 49:552–561PubMedGoogle Scholar
  179. 179.
    Dong X, Park S, Lin X, Copps K, Yi X, White MF (2006) Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Investig 116:101–114PubMedGoogle Scholar
  180. 180.
    Razzini G, Ingrosso A, Brancaccio A, Sciacchitano S, Esposito DL, Falasca M (2000) Different subcellular localization and phosphoinositides binding of insulin receptor substrate protein pleckstrin homology domains. Mol Endocrinol 14:823–836PubMedGoogle Scholar
  181. 181.
    Sawka-Verhelle D, Tartare-Deckert S, White MF, Van OE (1996) Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786. J Biol Chem 271:5980–5983PubMedGoogle Scholar
  182. 182.
    He W, Craparo A, Zhu Y, O’Neill TJ, Wang LM, Pierce JH, Gustafson TA (1996) Interaction of insulin receptor substrate-2 (IRS-2) with the insulin and insulin-like growth factor I receptors. Evidence for two distinct phosphotyrosine-dependent interaction domains within IRS-2. J Biol Chem 271:11641–11645PubMedGoogle Scholar
  183. 183.
    Wolf G, Trub T, Ottinger E, Groninga L, Lynch A, White MF, Miyazaki M, Lee J, Shoelson SE (1995) PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities. J Biol Chem 270:27407–27410PubMedGoogle Scholar
  184. 184.
    Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR (1994) Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp 70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol 14:4902–4911PubMedPubMedCentralGoogle Scholar
  185. 185.
    Taniguchi CM, Kondo T, Sajan M, Luo J, Bronson R, Asano T, Farese R, Cantley LC, Kahn CR (2006) Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab 3:343–353PubMedGoogle Scholar
  186. 186.
    Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM (2005) Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54:2351–2359PubMedGoogle Scholar
  187. 187.
    Myers MG Jr, Backer JM, Sun XJ, Shoelson S, Hu P, Schlessinger J, Yoakim M, Schaffhausen B, White MF (1992) IRS-1 activates phosphatidylinositol 3’-kinase by associating with src homology 2 domains of p85. Proc Natl Acad Sci USA 89:10350–10354PubMedGoogle Scholar
  188. 188.
    Geering B, Cutillas PR, Nock G, Gharbi SI, Vanhaesebroeck B (2007) Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proc Natl Acad Sci USA 104:7809–7814PubMedPubMedCentralGoogle Scholar
  189. 189.
    Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD (1997) Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22:267–272PubMedGoogle Scholar
  190. 190.
    Shepherd PR, Withers DJ, Siddle K (1998) Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 333:471–490PubMedPubMedCentralGoogle Scholar
  191. 191.
    Terauchi Y, Tsuji Y, Satoh S, Minoura H, Murakami K, Okuno A, Inukai K, Asano T, Kaburagi Y, Ueki K, Nakajima H, Hanafusa T, Matsuzawa Y, Sekihara H, Yin Y, Barrett JC, Oda H, Ishikawa T, Akanuma Y, Komuro I, Suzuki M, Yamamura K, Kodama T, Suzuki H, Yamamura K, Kodama T, Suzuki H, Koyasu S, Aizawa S, Tobe K, Fukui Y, Yazaki Y, Kadowaki T (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet 21:230–235PubMedGoogle Scholar
  192. 192.
    Chen D, Mauvais-Jarvis F, Bluher M, Fisher SJ, Jozsi A, Goodyear LJ, Ueki K, Kahn CR (2004) p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. Mol Cell Biol 24:320–329PubMedPubMedCentralGoogle Scholar
  193. 193.
    Ueki K, Yballe CM, Brachmann SM, Vicent D, Watt JM, Kahn CR, Cantley LC (2002) Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 99:419–424PubMedPubMedCentralGoogle Scholar
  194. 194.
    Aoki K, Matsui J, Kubota N, Nakajima H, Iwamoto K, Takamoto I, Tsuji Y, Ohno A, Mori S, Tokuyama K, Murakami K, Asano T, Aizawa S, Tobe K, Kadowaki T, Terauchi Y (2009) Role of the liver in glucose homeostasis in PI 3-kinase p85alpha-deficient mice. Am J Physiol 296:E842–E853Google Scholar
  195. 195.
    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 25:1596–1607PubMedPubMedCentralGoogle Scholar
  196. 196.
    Taniguchi CM, Tran TT, Kondo T, Luo J, Ueki K, Cantley LC, Kahn CR (2006) Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN. Proc Natl Acad Sci USA 103:12093–12097PubMedPubMedCentralGoogle Scholar
  197. 197.
    Taniguchi CM, Aleman JO, Ueki K, Luo J, Asano T, Kaneto H, Stephanopoulos G, Cantley LC, Kahn CR (2007) The p85alpha regulatory subunit of phosphoinositide 3-kinase potentiates c-Jun N-terminal kinase-mediated insulin resistance. Mol Cell Biol 27:2830–2840PubMedPubMedCentralGoogle Scholar
  198. 198.
    Logie L, Ruiz-Alcaraz AJ, Keane M, Woods YL, Bain J, Marquez R, Alessi DR, Sutherland C (2007) Characterization of a protein kinase B inhibitor in vitro and in insulin-treated liver cells. Diabetes 56:2218–2227PubMedGoogle Scholar
  199. 199.
    Tanti JF, Grillo S, Gremeaux T, Coffer PJ, Van OE, Le Marchand-Brustel Y (1997) Potential role of protein kinase B in glucose transporter 4 translocation in adipocytes. Endocrinology 138:2005–2010PubMedGoogle Scholar
  200. 200.
    Wang Q, Somwar R, Bilan PJ, Liu Z, Jin J, Woodgett JR, Klip A (1999) Protein kinase B/Akt participates in GLUT4 translocation by insulin in L6 myoblasts. Mol Cell Biol 19:4008–4018PubMedPubMedCentralGoogle Scholar
  201. 201.
    Scheid MP, Marignani PA, Woodgett JR (2002) Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol 22:6247–6260PubMedPubMedCentralGoogle Scholar
  202. 202.
    Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT (1997) Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 277:567–570PubMedGoogle Scholar
  203. 203.
    Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101PubMedPubMedCentralGoogle Scholar
  204. 204.
    Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127:125–137PubMedPubMedCentralGoogle Scholar
  205. 205.
    Liu P, Heng H, Roberts TM, Hao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8:627–644PubMedPubMedCentralGoogle Scholar
  206. 206.
    Bae SS, Cho H, Mu J, Birnbaum MJ (2003) Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J Biol Chem 278:49530–49536PubMedGoogle Scholar
  207. 207.
    Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB III, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292:1728–1731PubMedGoogle Scholar
  208. 208.
    Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR, McNeish JD, Coleman KG (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Investig 112:197–208PubMedGoogle Scholar
  209. 209.
    Tschopp O, Yang ZZ, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T, Michaelis T, Frahm J, Hemmings BA (2005) Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development 132:2943–2954PubMedGoogle Scholar
  210. 210.
    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 276:38349–38352PubMedGoogle Scholar
  211. 211.
    Dummler B, Tschopp O, Hynx D, Yang ZZ, Dirnhofer S, Hemmings BA (2006) Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Mol Cell Biol 26:8042–8051PubMedPubMedCentralGoogle Scholar
  212. 212.
    Brozinick JT Jr, Roberts BR, Dohm GL (2003) Defective signaling through Akt-2 and -3 but not Akt-1 in insulin-resistant human skeletal muscle: potential role in insulin resistance. Diabetes 52:935–941PubMedGoogle Scholar
  213. 213.
    Kim YB, Peroni OD, Franke TF, Kahn BB (2000) Divergent regulation of Akt1 and Akt2 isoforms in insulin target tissues of obese Zucker rats. Diabetes 49:847–856PubMedGoogle Scholar
  214. 214.
    Kahn CR (1978) Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction. Metabolism 27(12 Suppl 2):1893–1902Google Scholar
  215. 215.
    Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T, Dixon JE, Donner DB (2001) A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci USA 98:4640–4645PubMedGoogle Scholar
  216. 216.
    Paz K, Hemi R, LeRoith D, Karasik A, Elhanany E, Kanety H, Zick Y (1997) A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem 272:29911–29918PubMedGoogle Scholar
  217. 217.
    Aguirre V, Uchida T, Yenush L, Davis R, White MF (2000) The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem 275:9047–9054PubMedPubMedCentralGoogle Scholar
  218. 218.
    Greene MW, Sakaue H, Wang L, Alessi DR, Roth RA (2003) Modulation of insulin-­stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. J Biol Chem 278:8199–8211PubMedGoogle Scholar
  219. 219.
    Zhang J, Gao Z, Yin J, Quon MJ, Ye J (2008) S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. J Biol Chem 283:35375–35382PubMedPubMedCentralGoogle Scholar
  220. 220.
    Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, Hotamisligil GS, Van OE (2001) SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 276:47944–47949PubMedGoogle Scholar
  221. 221.
    Ueki K, Kondo T, Kahn CR (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24:5434–5446PubMedPubMedCentralGoogle Scholar
  222. 222.
    Rui L, Yuan M, Frantz D, Shoelson S, White MF (2002) SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 277:42394–42398PubMedGoogle Scholar
  223. 223.
    Kerouz NJ, Horsch D, Pons S, Kahn CR (1997) Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J Clin Investig 100:3164–3172PubMedGoogle Scholar
  224. 224.
    Gum RJ, Gaede LL, Koterski SL, Heindel M, Clampit JE, Zinker BA, Trevillyan JM, Ulrich RG, Jirousek MR, Rondinone CM (2003) Reduction of protein tyrosine phosphatase 1B increases insulin-dependent signaling in ob/ob mice. Diabetes 52:21–28PubMedGoogle Scholar
  225. 225.
    Yaspelkis BB III, Kvasha IA, Figueroa TY (2009) High-fat feeding increases insulin receptor and IRS-1 coimmunoprecipitation with SOCS-3, IKKalpha/beta phosphorylation and decreases PI-3 kinase activity in muscle. Am J Physiol Regul Integr Comp Physiol 296:R1709–R1715PubMedPubMedCentralGoogle Scholar
  226. 226.
    Liberman Z, Plotkin B, Tennenbaum T, Eldar-Finkelman H (2008) Coordinated phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 and protein kinase C betaII in the diabetic fat tissue. Am J Physiol Endocrinol Metab 294:E1169–E1177PubMedGoogle Scholar
  227. 227.
    Liberman Z, Eldar-Finkelman H (2005) Serine 332 phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 attenuates insulin signaling. J Biol Chem 280:4422–4428PubMedGoogle Scholar
  228. 228.
    Kovacs P, Hanson RL, Lee YH, Yang X, Kobes S, Permana PA, Bogardus C, Baier LJ (2003) The role of insulin receptor substrate-1 gene (IRS1) in type 2 diabetes in Pima Indians. Diabetes 52:3005–3009PubMedGoogle Scholar
  229. 229.
    Carlson CJ, Koterski S, Sciotti RJ, Poccard GB, Rondinone CM (2003) Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. Diabetes 52:634–641PubMedGoogle Scholar
  230. 230.
    Danielsson A, Ost A, Lystedt E, Kjolhede P, Gustavsson J, Nystrom FH, Stralfors P (2005) Insulin resistance in human adipocytes occurs downstream of IRS1 after surgical cell isolation but at the level of phosphorylation of IRS1 in type 2 diabetes. FEBS J 272:141–151PubMedGoogle Scholar
  231. 231.
    Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL (1995) Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Investig 95:2195–2204PubMedGoogle Scholar
  232. 232.
    Bjornholm M, Kawano Y, Lehtihet M, Zierath JR (1997) Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 46:524–527PubMedGoogle Scholar
  233. 233.
    Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG Jr, Wallberg-Henriksson H, Zierath JR (2000) Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49:284–292PubMedGoogle Scholar
  234. 234.
    Beeson M, Sajan MP, Dizon M, Grebenev D, Gomez-Daspet J, Miura A, Kanoh Y, Powe J, Bandyopadhyay G, Standaert ML, Farese RV (2003) Activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 is defective in muscle in type 2 diabetes and impaired glucose tolerance: amelioration by rosiglitazone and exercise. Diabetes 52:1926–1934PubMedGoogle Scholar
  235. 235.
    Casaubon L, Sajan MP, Rivas J, Powe JL, Standaert ML, Farese RV (2006) Contrasting insulin dose-dependent defects in activation of atypical protein kinase C and protein kinase B/Akt in muscles of obese diabetic humans. Diabetologia 49:3000–3008PubMedGoogle Scholar
  236. 236.
    Rondinone CM, Carvalho E, Wesslau C, Smith UP (1999) Impaired glucose transport and protein kinase B activation by insulin, but not okadaic acid, in adipocytes from subjects with Type II diabetes mellitus. Diabetologia 42:819–825PubMedGoogle Scholar
  237. 237.
    Rondinone CM, Wang LM, Lonnroth P, Wesslau C, Pierce JH, Smith U (1997) 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 94:4171–4175PubMedGoogle Scholar
  238. 238.
    Rieusset J, Bouzakri K, Chevillotte E, Ricard N, Jacquet D, Bastard JP, Laville M, Vidal H (2004) Suppressor of cytokine signaling 3 expression and insulin resistance in skeletal muscle of obese and type 2 diabetic patients. Diabetes 53:2232–2241PubMedGoogle Scholar
  239. 239.
    Smith U (2002) Impaired (‘diabetic’) insulin signaling and action occur in fat cells long before glucose intolerance – is insulin resistance initiated in the adipose tissue? Int J Obes Relat Metab Disord 26:897–904PubMedGoogle Scholar
  240. 240.
    Kim YB, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB (1999) Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Investig 104:733–741PubMedGoogle Scholar
  241. 241.
    Avruch J (1998) Insulin signal transduction through protein kinase cascades. Mol Cell Biochem 182:31–48PubMedPubMedCentralGoogle Scholar
  242. 242.
    Matozaki T, Murata Y, Saito Y, Okazawa H, Ohnishi H (2009) Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci 100(10):1786–1793PubMedGoogle Scholar
  243. 243.
    Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J (1993) Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363:85–88PubMedGoogle Scholar
  244. 244.
    Ravichandran KS, Lorenz U, Shoelson SE, Burakoff SJ (1995) Interaction of Shc with Grb2 regulates association of Grb2 with mSOS. Mol Cell Biol 15:593–600PubMedPubMedCentralGoogle Scholar
  245. 245.
    Holgado-Madruga M, Emlet DR, Moscatello DK, Godwin AK, Wong AJ (1996) A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Nature 379:560–564PubMedGoogle Scholar
  246. 246.
    Baltensperger K, Kozma LM, Cherniack AD, Klarlund JK, Chawla A, Banerjee U, Czech MP (1993) Binding of the Ras activator son of sevenless to insulin receptor substrate-1 ­signaling complexes. Science 260:1950–1952PubMedGoogle Scholar
  247. 247.
    Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286:1358–1362PubMedGoogle Scholar
  248. 248.
    Dunn KL, Espino PS, Drobic B, He S, Davie JR (2005) The Ras-MAPK signal transduction pathway, cancer and chromatin remodeling. Biochem Cell Biol 83:1–14PubMedGoogle Scholar
  249. 249.
    Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310PubMedGoogle Scholar
  250. 250.
    Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10:307–318PubMedGoogle Scholar
  251. 251.
    Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945PubMedGoogle Scholar
  252. 252.
    Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N (2009) Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab 296:E592–E602PubMedGoogle Scholar
  253. 253.
    Anjum R, Blenis J (2008) The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol 9:747–758PubMedGoogle Scholar
  254. 254.
    Memmott RM, Dennis PA (2009) Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal 21:656–664PubMedPubMedCentralGoogle Scholar
  255. 255.
    Bouzakri K, Roques M, Gual P, Espinosa S, Guebre-Egziabher F, Riou JP, Laville M, Le Marchand-Brustel Y, Tanti JF, Vidal H (2003) Reduced activation of phosphatidylinositol-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 52:1319–1325PubMedGoogle Scholar
  256. 256.
    Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205PubMedGoogle Scholar
  257. 257.
    Tremblay F, Gagnon A, Veilleux A, Sorisky A, Marette A (2005) Activation of the mammalian target of rapamycin pathway acutely inhibits insulin signaling to Akt and glucose transport in 3T3-L1 and human adipocytes. Endocrinology 146:1328–1337PubMedGoogle Scholar
  258. 258.
    Katz H, Butler P, Homan M, Zerman A, Caumo A, Cobelli C, Rizza R (1993) Hepatic and extrahepatic insulin action in humans: measurement in the absence of non-steady-state error. Am J Physiol 264:E561–E566PubMedGoogle Scholar
  259. 259.
    Olson AL, Pessin JE (1996) Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Annu Rev Nutr 16:235–256PubMedGoogle Scholar
  260. 260.
    Dentin R, Pegorier JP, Benhamed F, Foufelle F, Ferre P, Fauveau V, Magnuson MA, Girard J, Postic C (2004) Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression. J Biol Chem 279:20314–20326PubMedGoogle Scholar
  261. 261.
    Sibrowski W, Seitz HJ (1984) Rapid action of insulin and cyclic AMP in the regulation of functional messenger RNA coding for glucokinase in rat liver. J Biol Chem 259:343–346PubMedGoogle Scholar
  262. 262.
    Kim SY, Kim HI, Kim TH, Im SS, Park SK, Lee IK, Kim KS, Ahn YH (2004) SREBP-1c mediates the insulin-dependent hepatic glucokinase expression. J Biol Chem 279:30823–30829PubMedGoogle Scholar
  263. 263.
    Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, Shelton KD, Lindner J, Cherrington AD, Magnuson MA (1999) Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem 274:305–315PubMedGoogle Scholar
  264. 264.
    Frame S, Cohen P (2001) GSK3 takes centre stage more than 20 years after its discovery. Biochem J 359:1–16PubMedPubMedCentralGoogle Scholar
  265. 265.
    Imazu M, Strickland WG, Chrisman TD, Exton JH (1984) Phosphorylation and inactivation of liver glycogen synthase by liver protein kinases. J Biol Chem 259:1813–1821PubMedGoogle Scholar
  266. 266.
    Sharfi H, Eldar-Finkelman H (2008) Sequential phosphorylation of insulin receptor ­substrate-2 by glycogen synthase kinase-3 and c-Jun NH2-terminal kinase plays a role in hepatic insulin signaling. Am J Physiol Endocrinol Metab 294:E307–E315PubMedGoogle Scholar
  267. 267.
    MacAulay K, Doble BW, Patel S, Hansotia T, Sinclair EM, Drucker DJ, Nagy A, Woodgett JR (2007) Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism. Cell Metab 6:329–337PubMedGoogle Scholar
  268. 268.
    Patel S, Doble BW, MacAulay K, Sinclair EM, Drucker DJ, Woodgett JR (2008) Tissue-specific role of glycogen synthase kinase 3beta in glucose homeostasis and insulin action. Mol Cell Biol 28:6314–6328PubMedPubMedCentralGoogle Scholar
  269. 269.
    Aiston S, Coghlan MP, Agius L (2003) Inactivation of phosphorylase is a major component of the mechanism by which insulin stimulates hepatic glycogen synthesis. Eur J Biochem 270:2773–2781PubMedGoogle Scholar
  270. 270.
    Aiston S, Hampson LJ, Arden C, Iynedjian PB, Agius L (2006) The role of protein kinase B/Akt in insulin-induced inactivation of phosphorylase in rat hepatocytes. Diabetologia 49:174–182PubMedGoogle Scholar
  271. 271.
    Cohen P (2006) The twentieth century struggle to decipher insulin signalling. Nat Rev Mol Cell Biol 7:867–873PubMedGoogle Scholar
  272. 272.
    Munro S, Ceulemans H, Bollen M, Diplexcito J, Cohen PT (2005) A novel glycogen-­targeting subunit of protein phosphatase 1 that is regulated by insulin and shows differential tissue distribution in humans and rodents. FEBS J 272:1478–1489PubMedGoogle Scholar
  273. 273.
    Alemany S, Cohen P (1986) Phosphorylase a is an allosteric inhibitor of the glycogen and microsomal forms of rat hepatic protein phosphatase-1. FEBS Lett 198:194–202PubMedGoogle Scholar
  274. 274.
    Moorhead G, MacKintosh C, Morrice N, Cohen P (1995) Purification of the hepatic glycogen-associated form of protein phosphatase-1 by microcystin-Sepharose affinity chromatography. FEBS Lett 362:101–105PubMedGoogle Scholar
  275. 275.
    Bollen M, Keppens S, Stalmans W (1998) Specific features of glycogen metabolism in the liver. Biochem J 336:19–31PubMedPubMedCentralGoogle Scholar
  276. 276.
    Doherty MJ, Cadefau J, Stalmans W, Bollen M, Cohen PT (1998) Loss of the hepatic glycogen-binding subunit (GL) of protein phosphatase 1 underlies deficient glycogen synthesis in insulin-dependent diabetic rats and in adrenalectomized starved rats. Biochem J 333:253–257PubMedPubMedCentralGoogle Scholar
  277. 277.
    Lam TK, Carpentier A, Lewis GF, van de Werve G, Fantus IG, Giacca A (2003) Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab 284:E863–E873PubMedGoogle Scholar
  278. 278.
    O’Brien RM, Granner DK (1996) Regulation of gene expression by insulin. Physiol Rev 76:1109–1161PubMedGoogle Scholar
  279. 279.
    Schmoll D, Walker KS, Alessi DR, Grempler R, Burchell A, Guo S, Walther R, Unterman TG (2000) Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity. J Biol Chem 275:36324–36333PubMedGoogle Scholar
  280. 280.
    Gabbay RA, Sutherland C, Gnudi L, Kahn BB, O’Brien RM, Granner DK, Flier JS (1996) Insulin regulation of phosphoenolpyruvate carboxykinase gene expression does not require activation of the Ras/mitogen-activated protein kinase signaling pathway. J Biol Chem 271:1890–1897PubMedGoogle Scholar
  281. 281.
    Accili D (2004) Lilly lecture 2003: the struggle for mastery in insulin action: from triumvirate to republic. Diabetes 53:1633–1642PubMedGoogle Scholar
  282. 282.
    Puigserver P, Spiegelman BM (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 24:78–90PubMedPubMedCentralGoogle Scholar
  283. 283.
    Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM (2003) Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423:550–555PubMedGoogle Scholar
  284. 284.
    Zhang W, Patil S, Chauhan B, Guo S, Powell DR, Le J, Klotsas A, Matika R, Xiao X, Franks R, Heidenreich KA, Sajan MP, Farese RV, Stolz DB, Tso P, Koo SH, Montminy M, Unterman TG (2006) FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem 281:10105–10117PubMedGoogle Scholar
  285. 285.
    Rena G, Guo S, Cichy SC, Unterman TG, Cohen P (1999) Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem 274:17179–17183PubMedGoogle Scholar
  286. 286.
    Guo S, Rena G, Cichy S, He X, Cohen P, Unterman T (1999) Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem 274:17184–17192PubMedGoogle Scholar
  287. 287.
    Zhang X, Gan L, Pan H, Guo S, He X, Olson ST, Mesecar A, Adam S, Unterman TG (2002) Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic shuttling and DNA binding. J Biol Chem 277:45276–45284PubMedGoogle Scholar
  288. 288.
    Li X, Monks B, Ge Q, Birnbaum MJ (2007) Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature 447:1012–1016PubMedPubMedCentralGoogle Scholar
  289. 289.
    Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24:7410–7425PubMedGoogle Scholar
  290. 290.
    Zhao X, Gan L, Pan H, Kan D, Majeski M, Adam SA, Unterman TG (2004) Multiple elements regulate nuclear/cytoplasmic shuttling of FOXO1: characterization of phosphorylation- and 14-3-3-dependent and -independent mechanisms. Biochem J 378:3–49Google Scholar
  291. 291.
    Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A (2003) Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci USA 100:11285–11290PubMedGoogle Scholar
  292. 292.
    Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131–138PubMedGoogle Scholar
  293. 293.
    Daitoku H, Yamagata K, Matsuzaki H, Hatta M, Fukamizu A (2003) Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. Diabetes 52:642–649PubMedGoogle Scholar
  294. 294.
    Hirota K, Sakamaki J, Ishida J, Shimamoto Y, Nishihara S, Kodama N, Ohta K, Yamamoto M, Tanimoto K, Fukamizu A (2008) A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding. J Biol Chem 283:32432–32441PubMedGoogle Scholar
  295. 295.
    Dentin R, Liu Y, Koo SH, Hedrick S, Vargas T, Heredia J, Yates J III, Montminy M (2007) Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449:366–369PubMedGoogle Scholar
  296. 296.
    Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, Hedrick S, Xu W, Boussouar F, Brindle P, Takemori H, Montminy M (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437:1109–1111PubMedGoogle Scholar
  297. 297.
    Lewis GF, Zinman B, Groenewoud Y, Vranic M, Giacca A (1996) Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in humans. Diabetes 45:454–462PubMedGoogle Scholar
  298. 298.
    Lewis GF, Vranic M, Harley P, Giacca A (1997) Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans. Diabetes 46:1111–1119PubMedGoogle Scholar
  299. 299.
    Lewis GF, Vranic M, Giacca A (1997) Glucagon enhances the direct suppressive effect of insulin on hepatic glucose production in humans. Am J Physiol 272:E371–E378Google Scholar
  300. 300.
    Lewis GF, Vranic M, Giacca A (1998) Role of free fatty acids and glucagon in the peripheral effect of insulin on glucose production in humans. Am J Physiol 275:E177–E186Google Scholar
  301. 301.
    McCall RH, Wiesenthal SR, Shi ZQ, Polonsky K, Giacca A (1998) Insulin acutely suppresses glucose production by both peripheral and hepatic effects in normal dogs. Am J Physiol 274:E346–E356Google Scholar
  302. 302.
    Edgerton DS, Lautz M, Scott M, Everett CA, Stettler KM, Neal DW, Chu CA, Cherrington AD (2006) Insulin’s direct effects on the liver dominate the control of hepatic glucose production. J Clin Investig 116:521–527PubMedGoogle Scholar
  303. 303.
    Gupta N, Sandhu H, Goh T, Shah K, Wiesenthal SR, Yoshii H, Chong V, Lam TK, Haber CA, Williams W, Tchipashvili V, Giacca A (2002) Insulin inhibits glucose production by a direct effect in diabetic depancreatized dogs during euglycemia. Am J Physiol Endocrinol Metab 283:E1002–E1007PubMedGoogle Scholar
  304. 304.
    Lewis GF, Carpentier A, Vranic M, Giacca A (1999) Resistance to insulin’s acute direct hepatic effect in suppressing steady-state glucose production in individuals with type 2 diabetes. Diabetes 48:570–576PubMedGoogle Scholar
  305. 305.
    Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Guilar-Bryan L, Rossetti L (2005) Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434:1026–1031PubMedGoogle Scholar
  306. 306.
    Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382PubMedGoogle Scholar
  307. 307.
    Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML (2000) Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci 3:757–758PubMedGoogle Scholar
  308. 308.
    Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L (2002) Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5:566–572PubMedGoogle Scholar
  309. 309.
    Buettner C, Camacho RC (2008) Hypothalamic control of hepatic glucose production and its potential role in insulin resistance. Endocrinol Metab Clin North Am 37:825–840PubMedGoogle Scholar
  310. 310.
    Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, Teshigawara K, Matsuki Y, Watanabe E, Hiramatsu R, Notohara K, Katayose K, Okamura H, Kahn CR, Noda T, Takeda K, Akira S, Inui A, Kasuga M (2006) Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab 3:267–275PubMedGoogle Scholar
  311. 311.
    Inoue H, Ogawa W, Ozaki M, Haga S, Matsumoto M, Furukawa K, Hashimoto N, Kido Y, Mori T, Sakaue H, Teshigawara K, Jin S, Iguchi H, Hiramatsu R, LeRoith D, Takeda K, Akira S, Kasuga M (2004) Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat Med 10:168–174PubMedGoogle Scholar
  312. 312.
    Sakamoto K, Holman GD (2008) Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Am J Physiol Endocrinol Metab 295:E29–E37PubMedPubMedCentralGoogle Scholar
  313. 313.
    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 USA 92:10247–10251PubMedGoogle Scholar
  314. 314.
    Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, Garner CW, Lienhard GE (2003) Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 278:14599–14602PubMedGoogle Scholar
  315. 315.
    Randhawa VK, Ishikura S, Talior-Volodarsky I, Cheng AW, Patel N, Hartwig JH, Klip A (2008) GLUT4 vesicle recruitment and fusion are differentially regulated by Rac, AS160, and Rab8A in muscle cells. J Biol Chem 283:27208–27219PubMedGoogle Scholar
  316. 316.
    Bandyopadhyay G, Standaert ML, Sajan MP, Karnitz LM, Cong L, Quon MJ, Farese RV (1999) Dependence of insulin-stimulated glucose transporter 4 translocation on 3-phosphoinositide-dependent protein kinase-1 and its target threonine-410 in the activation loop of protein kinase C-zeta. Mol Endocrinol 13:1766–1772PubMedGoogle Scholar
  317. 317.
    Bandyopadhyay G, Kanoh Y, Sajan MP, Standaert ML, Farese RV (2000) Effects of adenoviral gene transfer of wild-type, constitutively active, and kinase-defective protein kinase C-lambda on insulin-stimulated glucose transport in L6 myotubes. Endocrinology 141:4120–4127PubMedGoogle Scholar
  318. 318.
    Garvey WT, Maianu L, Zhu JH, Brechtel-Hook G, Wallace P, Baron AD (1998) Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance. J Clin Investig 101:2377–2386PubMedGoogle Scholar
  319. 319.
    Cline GW, Petersen KF, Krssak M, Shen J, Hundal RS, Trajanoski Z, Inzucchi S, Dresner A, Rothman DL, Shulman GI (1999) Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med 341:240–246PubMedGoogle Scholar
  320. 320.
    Ren JM, Marshall BA, Mueckler MM, McCaleb M, Amatruda JM, Shulman GI (1995) Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice. J Clin Investig 95:429–432PubMedGoogle Scholar
  321. 321.
    Kelley DE, Mokan M, Mandarino LJ (1992) Intracellular defects in glucose metabolism in obese patients with NIDDM. Diabetes 41:698–706PubMedGoogle Scholar
  322. 322.
    Kim YI, Lee FN, Choi WS, Lee S, Youn JH (2006) Insulin regulation of skeletal muscle PDK4 mRNA expression is impaired in acute insulin-resistant states. Diabetes 55:2311–2317PubMedGoogle Scholar
  323. 323.
    Bouskila M, Hirshman MF, Jensen J, Goodyear LJ, Sakamoto K (2008) Insulin promotes glycogen synthesis in the absence of GSK3 phosphorylation in skeletal muscle. Am J Physiol Endocrinol Metab 294:E28–E35PubMedGoogle Scholar
  324. 324.
    Vaag A, Alford F, Henriksen FL, Christopher M, Beck-Nielsen H (1995) Multiple defects of both hepatic and peripheral intracellular glucose processing contribute to the hyperglycaemia of NIDDM. Diabetologia 38:326–336PubMedGoogle Scholar
  325. 325.
    Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L, Henry RR (2000) Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes 49:263–271PubMedGoogle Scholar
  326. 326.
    Dokken BB, Henriksen EJ (2006) Chronic selective glycogen synthase kinase-3 inhibition enhances glucose disposal and muscle insulin action in prediabetic obese Zucker rats. Am J Physiol Endocrinol Metab 291:E207–E213PubMedGoogle Scholar
  327. 327.
    Krssak M, Falk PK, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, Shulman GI (1999) Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42:113–116PubMedGoogle Scholar
  328. 328.
    Dobbins RL, Szczepaniak LS, Bentley B, Esser V, Myhill J, McGarry JD (2001) Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes 50:123–130PubMedGoogle Scholar
  329. 329.
    Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140–1142PubMedPubMedCentralGoogle Scholar
  330. 330.
    Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671PubMedPubMedCentralGoogle Scholar
  331. 331.
    Rasmussen BB, Holmback UC, Volpi E, Morio-Liondore B, Paddon-Jones D, Wolfe RR (2002) Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle. J Clin Investig 110:1687–1693PubMedGoogle Scholar
  332. 332.
    Gaster M, Beck-Nielsen H (2006) Triacylglycerol accumulation is not primarily affected in myotubes established from type 2 diabetic subjects. Biochim Biophys Acta 1761:100–110PubMedGoogle Scholar
  333. 333.
    Morino K, Petersen KF, Shulman GI (2006) Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55(Suppl 2):S9–S15PubMedPubMedCentralGoogle Scholar
  334. 334.
    Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, Zhang XM, Monia BP, Bhanot S, Shulman GI (2007) Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Investig 117:739–745PubMedGoogle Scholar
  335. 335.
    Befroy DE, Petersen KF, Dufour S, Mason GF, de Graaf RA, Rothman DL, Shulman GI (2007) Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 56:1376–1381PubMedPubMedCentralGoogle Scholar
  336. 336.
    Turner N, Heilbronn LK (2008) Is mitochondrial dysfunction a cause of insulin resistance? Trends Endocrinol Metab 19:324–330PubMedGoogle Scholar
  337. 337.
    Zhang D, Liu ZX, Choi CS, Tian L, Kibbey R, Dong J, Cline GW, Wood PA, Shulman GI (2007) Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci USA 104:17075–17080PubMedGoogle Scholar
  338. 338.
    Galgani JE, Moro C, Ravussin E (2008) Metabolic flexibility and insulin resistance. Am J Physiol Endocrinol Metab 295:E1009–E1017PubMedPubMedCentralGoogle Scholar
  339. 339.
    Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio DM (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7:45–56PubMedGoogle Scholar
  340. 340.
    Bandyopadhyay G, Standaert ML, Kikkawa U, Ono Y, Moscat J, Farese RV (1999) Effects of transiently expressed atypical (zeta, lambda), conventional (alpha, beta) and novel (delta, epsilon) protein kinase C isoforms on insulin-stimulated translocation of epitope-tagged GLUT4 glucose transporters in rat adipocytes: specific interchangeable effects of protein kinases C-zeta and C-lambda. Biochem J 337:461–470PubMedPubMedCentralGoogle Scholar
  341. 341.
    Ducluzeau PH, Fletcher LM, Vidal H, Laville M, Tavare JM (2002) Molecular mechanisms of insulin-stimulated glucose uptake in adipocytes. Diab Metab 28:85–92Google Scholar
  342. 342.
    Watson RT, Kanzaki M, Pessin JE (2004) Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr Rev 25:177–204PubMedGoogle Scholar
  343. 343.
    Gonzalez E, McGraw TE (2006) Insulin signaling diverges into Akt-dependent and -independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane. Mol Biol Cell 17:4484–4493PubMedPubMedCentralGoogle Scholar
  344. 344.
    Chiang SH, Baumann CA, Kanzaki M, Thurmond DC, Watson RT, Neudauer CL, Macara IG, Pessin JE, Saltiel AR (2001) Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 410:944–948PubMedGoogle Scholar
  345. 345.
    Liu J, DeYoung SM, Hwang JB, O’Leary EE, Saltiel AR (2003) The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport. J Biol Chem 278:36754–36762PubMedGoogle Scholar
  346. 346.
    Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, Minnemann T, Shulman GI, Kahn BB (2001) Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409:729–733PubMedPubMedCentralGoogle Scholar
  347. 347.
    Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Investig 116:1793–1801PubMedGoogle Scholar
  348. 348.
    Lewis GF, Carpentier A, Adeli K, Giacca A (2002) Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 23:201–229PubMedGoogle Scholar
  349. 349.
    Kershaw EE, Flier JS (2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89:2548–2556PubMedGoogle Scholar
  350. 350.
    Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G (2001) Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 280:E745–E751PubMedGoogle Scholar
  351. 351.
    Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM (1995) Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Investig 95:2409–2415PubMedGoogle Scholar
  352. 352.
    Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935PubMedGoogle Scholar
  353. 353.
    Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83PubMedGoogle Scholar
  354. 354.
    Nieto-Vazquez I, Fernandez-Veledo S, de Alvero C, Lorenzo M (2008) Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes 57:3211–3221PubMedPubMedCentralGoogle Scholar
  355. 355.
    Nguyen MT, Satoh H, Favelyukis S, Babendure JL, Imamura T, Sbodio JI, Zalevsky J, Dahiyat BI, Chi NW, Olefsky JM (2005) JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem 280:35361–35371PubMedGoogle Scholar
  356. 356.
    Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, Liu ZX, Soos TJ, Cline GW, O’Brien WR, Littman DR, Shulman GI (2004) PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Investig 114:823–827PubMedGoogle Scholar
  357. 357.
    Schmitz-Peiffer C, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW, Biden TJ (1997) Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes 46:169–178PubMedGoogle Scholar
  358. 358.
    Perseghin G, Petersen K, Shulman GI (2003) Cellular mechanism of insulin resistance: potential links with inflammation. Int J Obes Relat Metab Disord 27(Suppl 3):S6–S11PubMedGoogle Scholar
  359. 359.
    Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI (2002) Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 277:50230–50236PubMedGoogle Scholar
  360. 360.
    Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, Shulman GI (1999) Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 48:1270–1274PubMedGoogle Scholar
  361. 361.
    Itani SI, Ruderman NB, Schmieder F, Boden G (2002) Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51:2005–2011PubMedGoogle Scholar
  362. 362.
    Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI (2004) Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279:32345–32353PubMedGoogle Scholar
  363. 363.
    Talior I, Tennenbaum T, Kuroki T, Eldar-Finkelman H (2005) PKC-delta-dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase. Am J Physiol Endocrinol Metab 288:E405–E411PubMedGoogle Scholar
  364. 364.
    Kamata H, Manabe T, Oka S, Kamata K, Hirata H (2002) Hydrogen peroxide activates IkappaB kinases through phosphorylation of serine residues in the activation loops. FEBS Lett 519:231–237PubMedGoogle Scholar
  365. 365.
    Wang X, Martindale JL, Liu Y, Holbrook NJ (1998) The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J 333:291–300PubMedPubMedCentralGoogle Scholar
  366. 366.
    Ravichandran LV, Esposito DL, Chen J, Quon MJ (2001) 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 276:3543–3549PubMedGoogle Scholar
  367. 367.
    Bollag GE, Roth RA, Beaudoin J, Mochly-Rosen D, Koshland DE Jr (1986) Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity. Proc Natl Acad Sci USA 83:5822–5824PubMedGoogle Scholar
  368. 368.
    Lam TK, Yoshii H, Haber CA, Bogdanovic E, Lam L, Fantus IG, Giacca A (2002) Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-delta. Am J Physiol Endocrinol Metab 283:E682–E691PubMedGoogle Scholar
  369. 369.
    Boden G, She P, Mozzoli M, Cheung P, Gumireddy K, Reddy P, Xiang X, Luo Z, Ruderman N (2005) Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes 54:3458–3465PubMedGoogle Scholar
  370. 370.
    Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2003) Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 52:1–8PubMedGoogle Scholar
  371. 371.
    Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11:183–190PubMedPubMedCentralGoogle Scholar
  372. 372.
    Yin MJ, Yamamoto Y, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396:77–80PubMedGoogle Scholar
  373. 373.
    Kopp E, Ghosh S (1994) Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 265:956–959PubMedGoogle Scholar
  374. 374.
    Fleischman A, Shoelson SE, Bernier R, Goldfine AB (2008) Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 31:289–294PubMedGoogle Scholar
  375. 375.
    Gilgore SG, Rupp JJ (1961) Response of blood glucose to intravenous salicylate. Metab Clin Exp 10:419–421PubMedGoogle Scholar
  376. 376.
    Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, Shulman GI (2002) Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Investig 109:1321–1326PubMedGoogle Scholar
  377. 377.
    Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Investig 108:437–446PubMedGoogle Scholar
  378. 378.
    Xiao C, Giacca A, Lewis GF (2009) The effect of high-dose sodium salicylate on chronically elevated plasma nonesterified fatty acid-induced insulin resistance and Beta-cell dysfunction in overweight and obese nondiabetic men. Am J Physiol Endocrinol Metab 297:E1205–E1211PubMedGoogle Scholar
  379. 379.
    Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198PubMedGoogle Scholar
  380. 380.
    Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J (2002) Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 277:48115–48121PubMedGoogle Scholar
  381. 381.
    Ueki K, Kondo T, Kahn CR (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24:5434–5446PubMedPubMedCentralGoogle Scholar
  382. 382.
    Seifert R, Schachtele C, Rosenthal W, Schultz G (1988) Activation of protein kinase C by cis- and trans-fatty acids and its potentiation by diacylglycerol. Biochem Biophys Res Commun 154:20–26PubMedGoogle Scholar
  383. 383.
    Ghosh S, Baltimore D (1990) Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature 344:678–682PubMedGoogle Scholar
  384. 384.
    Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Investig 116:3015–3025PubMedGoogle Scholar
  385. 385.
    Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2002) Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 23:599–622PubMedGoogle Scholar
  386. 386.
    Solinas G, Naugler W, Galimi F, Lee MS, Karin M (2006) Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci USA 103:16454–16459PubMedGoogle Scholar
  387. 387.
    Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336PubMedPubMedCentralGoogle Scholar
  388. 388.
    Kaneto H, Nakatani Y, Miyatsuka T, Kawamori D, Matsuoka TA, Matsuhisa M, Kajimoto Y, Ichijo H, Yamasaki Y, Hori M (2004) Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. Nat Med 10:1128–1132PubMedGoogle Scholar
  389. 389.
    Nakatani Y, Kaneto H, Kawamori D, Hatazaki M, Miyatsuka T, Matsuoka TA, Kajimoto Y, Matsuhisa M, Yamasaki Y, Hori M (2004) Modulation of the JNK pathway in liver affects insulin resistance status. J Biol Chem 279:45803–45809PubMedGoogle Scholar
  390. 390.
    Yang R, Wilcox DM, Haasch DL, Jung PM, Nguyen PT, Voorbach MJ, Doktor S, Brodjian S, Bush EN, Lin E, Jacobson PB, Collins CA, Landschulz KT, Trevillyan JM, Rondinone CM, Surowy TK (2007) Liver-specific knockdown of JNK1 up-regulates proliferator-activated receptor gamma coactivator 1 beta and increases plasma triglyceride despite reduced glucose and insulin levels in diet-induced obese mice. J Biol Chem 282:22765–22774PubMedGoogle Scholar
  391. 391.
    Kumashiro N, Tamura Y, Uchida T, Ogihara T, Fujitani Y, Hirose T, Mochizuki H, Kawamori R, Watada H (2008) Impact of oxidative stress and peroxisome proliferator-activated receptor gamma coactivator-1alpha in hepatic insulin resistance. Diabetes 57:2083–2091PubMedPubMedCentralGoogle Scholar
  392. 392.
    Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H (2000) High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C–dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49:1939–1945PubMedGoogle Scholar
  393. 393.
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–461PubMedGoogle Scholar
  394. 394.
    Hung JH, Su IJ, Lei HY, Wang HC, Lin WC, Chang WT, Huang W, Chang WC, Chang YS, Chen CC, Lai MD (2004) Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp 38 mitogen-activated protein kinase. J Biol Chem 279:46384–46392PubMedGoogle Scholar
  395. 395.
    Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633PubMedPubMedCentralGoogle Scholar
  396. 396.
    Cardozo AK, Ortis F, Storling J, Feng YM, Rasschaert J, Tonnesen M, Van EF, Mandrup-Poulsen T, Herchuelz A, Eizirik DL (2005) Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. Diabetes 54:452–461PubMedGoogle Scholar
  397. 397.
    Hennige AM, Lembert N, Wahl MA, Ammon HP (2000) Oxidative stress increases potassium efflux from pancreatic islets by depletion of intracellular calcium stores. Free Radic Res 33:507–516PubMedGoogle Scholar
  398. 398.
    Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247Google Scholar
  399. 399.
    Dang PM, Stensballe A, Boussetta T, Raad H, Dewas C, Kroviarski Y, Hayem G, Jensen ON, Gougerot-Pocidalo MA, El-Benna J (2006) A specific p47phox -serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites. J Clin Investig 116:2033–2043PubMedGoogle Scholar
  400. 400.
    Hansen LL, Ikeda Y, Olsen GS, Busch AK, Mosthaf L (1999) Insulin signaling is inhibited by micromolar concentrations of H(2)O(2). Evidence for a role of H(2)O(2) in tumor necrosis factor alpha-mediated insulin resistance. J Biol Chem 274:25078–25084PubMedGoogle Scholar
  401. 401.
    Tirosh A, Potashnik R, Bashan N, Rudich A (1999) Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation. J Biol Chem 274:10595–10602PubMedPubMedCentralGoogle Scholar
  402. 402.
    Houstis N, Rosen ED, Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440:944–948PubMedGoogle Scholar
  403. 403.
    Maddux BA, See W, Lawrence JC Jr, Goldfine AL, Goldfine ID, Evans JL (2001) Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by mircomolar concentrations of alpha-lipoic acid. Diabetes 50:404–410PubMedGoogle Scholar
  404. 404.
    Kawamori D, Kaneto H, Nakatani Y, Matsuoka TA, Matsuhisa M, Hori M, Yamasaki Y (2006) The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J Biol Chem 281:1091–1098PubMedGoogle Scholar
  405. 405.
    Essers MA, Weijzen S, de Vries-Smits AM, Saarloos I, de Ruiter ND, Bos JL, Burgering BM (2004) FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J 23:4802–4812PubMedPubMedCentralGoogle Scholar
  406. 406.
    Suliman HB, Welty-Wolf KE, Carraway M, Tatro L, Piantadosi CA (2004) Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis. Cardiovasc Res 64:279–288PubMedGoogle Scholar
  407. 407.
    Puigserver P, Rhee J, Lin J, Wu Z, Yoon JC, Zhang CY, Krauss S, Mootha VK, Lowell BB, Spiegelman BM (2001) Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol Cell 8:971–982PubMedGoogle Scholar
  408. 408.
    Kyriakis JM, Avruch J (1996) Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem 271:24313–24316PubMedGoogle Scholar
  409. 409.
    Collins QF, Xiong Y, Lupo EG Jr, Liu HY, Cao W (2006) p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes. J Biol Chem 281:24336–24344PubMedGoogle Scholar
  410. 410.
    Liu HY, Collins QF, Xiong Y, Moukdar F, Lupo EG Jr, Liu Z, Cao W (2007) Prolonged treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase. J Biol Chem 282:14205–14212PubMedGoogle Scholar
  411. 411.
    Dersch K, Ichijo H, Bhakdi S, Husmann M (2005) Fatty acids liberated from low-density lipoprotein trigger endothelial apoptosis via mitogen-activated protein kinases. Cell Death Differ 12:1107–1114PubMedGoogle Scholar
  412. 412.
    Wang XL, Zhang L, Youker K, Zhang MX, Wang J, LeMaire SA, Coselli JS, Shen YH (2006) Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Diabetes 55:2301–2310PubMedGoogle Scholar
  413. 413.
    Miller TA, LeBrasseur NK, Cote GM, Trucillo MP, Pimentel DR, Ido Y, Ruderman NB, Sawyer DB (2005) Oleate prevents palmitate-induced cytotoxic stress in cardiac myocytes. Biochem Biophys Res Commun 336:309–315PubMedGoogle Scholar
  414. 414.
    Koistinen HA, Chibalin AV, Zierath JR (2003) Aberrant p38 mitogen-activated protein kinase signalling in skeletal muscle from Type 2 diabetic patients. Diabetologia 46:1324–1328PubMedGoogle Scholar
  415. 415.
    Asada S, Daitoku H, Matsuzaki H, Saito T, Sudo T, Mukai H, Iwashita S, Kako K, Kishi T, Kasuya Y, Fukamizu A (2007) Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Cell Signal 19:519–527PubMedGoogle Scholar
  416. 416.
    Maehama T, Taylor GS, Dixon JE (2001) PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem 70:247–279PubMedGoogle Scholar
  417. 417.
    Li G, Barrett EJ, Barrett MO, Cao W, Liu Z (2007) Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. Endocrinology 148:3356–3363PubMedGoogle Scholar
  418. 418.
    de Alvero C, Teruel T, Hernandez R, Lorenzo M (2004) Tumor necrosis factor alpha produces insulin resistance in skeletal muscle by activation of inhibitor kappaB kinase in a p38 MAPK-dependent manner. J Biol Chem 279:17070–17078Google Scholar
  419. 419.
    Aguilar V, Alliouachene S, Sotiropoulos A, Sobering A, Athea Y, Djouadi F, Miraux S, Thiaudiere E, Foretz M, Viollet B, Diolez P, Bastin J, Benit P, Rustin P, Carling D, Sandri M, Ventura-Clapier R, Pende M (2007) S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase. Cell Metab 5:476–487PubMedGoogle Scholar
  420. 420.
    Vona-Davis L, Howard-McNatt M, Rose DP (2007) Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. Obes Rev 8:395–408Google Scholar
  421. 421.
    Godsland I (2010) Insulin resistance and hyperinsulinemia in the development and progression of cancer. Clin Sci 118:315–332Google Scholar
  422. 422.
    Taliaferro-Smith L, Nagalingam A, Zhong D, Zhou W, Saxena NK, Sharma D (2009) LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and inhibition of migration and invasion of breast cancer cells. Oncogene 28:2621–2633PubMedPubMedCentralGoogle Scholar
  423. 423.
    Ziemke F, Mantzoros CS (2010) Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr 91:258S–261SPubMedGoogle Scholar
  424. 424.
    Wang C, Mao X, Wang L, Liu M, Wetzel MD, Guan KL, Dong LQ, Liu F (2007) Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. J Biol Chem 282:7991–7996PubMedGoogle Scholar
  425. 425.
    Grant S (2008) Cotargeting survival signaling pathways in cancer. J Clin Invest 118:3003–3006PubMedPubMedCentralGoogle Scholar
  426. 426.
    Jia S, Roberts TM, Zhao JJ (2009) Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol 21:199–208PubMedPubMedCentralGoogle Scholar
  427. 427.
    Wiesenthal SR, Sandhu H, McCall RH, Tchipashvili V, Yoshii H, Polonsky K, Shi ZQ, Lewis GF, Mari A, Giacca A (1999) Free fatty acids impair hepatic insulin extraction in vivo. Diabetes 48:766–774PubMedGoogle Scholar
  428. 428.
    DeFronzo RA (1992) Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia 35:389–397PubMedGoogle Scholar
  429. 429.
    Semple RK, Sleigh A, Murgatroyd PR, Adams CA, Bluck L, Jackson S, Vottero A, Kanabar D, Charlton-Menys V, Durrington P, Soos MA, Carpenter TA, Lomas DJ, Cochran EK, Gorden P, O’Rahilly S, Savage DB (2009) Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Investig 119:315–322PubMedGoogle Scholar
  430. 430.
    George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL, Dunger DB, Barford D, Umpleby AM, Wareham NJ, Davies HA, Schafer AJ, Stoffel M, O’Rahilly S, Barroso I (2004) A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304:1325–1328PubMedPubMedCentralGoogle Scholar
  431. 431.
    Montagnani M, Golovchenko I, Kim I, Koh GY, Goalstone ML, Mundhekar AN, Johansen M, Kucik DF, Quon MJ, Draznin B (2002) Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 277:1794–1799PubMedGoogle Scholar
  432. 432.
    Draznin B (2010) Mitogenic action of insulin: friend, foe or ‘frenemy’? Diabetologia 53:229–233PubMedGoogle Scholar
  433. 433.
    Goalstone ML, Leitner JW, Wall K, Dolgonos L, Rother KI, Accili D, Draznin B (1998) Effect of insulin on farnesyltransferase. Specificity of insulin action and potentiation of nuclear effects of insulin-like growth factor-1, epidermal growth factor, and platelet-derived growth factor. J Biol Chem 273:23892–23896PubMedGoogle Scholar
  434. 434.
    Giovannucci E, Michaud D (2007) The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 132:2208–2225PubMedGoogle Scholar
  435. 435.
    Dandona P, Chaudhuri A, Mohanty P, Ghanim H (2007) Anti-inflammatory effects of insulin. Curr Opin Clin Nutr Metab Care 10:511–517PubMedGoogle Scholar
  436. 436.
    Tran TT, Naigamwalla D, Oprescu AI, Lam L, Keown-Eyssen G, Bruce WR, Giacca A (2006) Hyperinsulinemia, but not other factors associated with insulin resistance, acutely enhances colorectal epithelial proliferation in vivo. Endocrinology 147:1830–1837PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of PhysiologyUniversity of TorontoTorontoCanada

Personalised recommendations