Cell Biochemistry and Biophysics

, Volume 48, Issue 2–3, pp 103–113 | Cite as

Insulin signaling and glucose transport in insulin resistant human skeletal muscle

  • Håkan K. R. Karlsson
  • Juleen R. ZierathEmail author
Original Paper


Insulin increases glucose uptake and metabolism in skeletal muscle by signal transduction via protein phosphorylation cascades. Insulin action on signal transduction is impaired in skeletal muscle from Type 2 diabetic subjects, underscoring the contribution of molecular defects to the insulin resistant phenotype. This review summarizes recent work to identify downstream intermediates in the insulin signaling pathways governing glucose homeostasis, in an attempt to characterize the molecular mechanism accounting for skeletal muscle insulin resistance in Type 2 diabetes. Furthermore, the effects of pharmaceutical treatment of Type 2 diabetic patients on insulin signaling and glucose uptake are discussed. The identification and characterization of pathways governing insulin action on glucose metabolism will facilitate the development of strategies to improve insulin sensitivity in an effort to prevent and treat Type 2 diabetes mellitus.


Skeletal Muscle Insulin action Glucose metabolism Signal transduction Type 2 diabetes Drug therapy Thiazolidinedione Metformin 



The authors are supported by grants from the Swedish Medical Research Council, the Swedish Diabetes Association, Foundation for Scientific Studies of Diabetology, the Strategic Research Foundation (INGVAR), Novo-Nordisk Foundation, and the Commission of the European Communities (Network of Excellence EUGENE2; Contract No. LSHM-CT-2004-005272 and Integrated Project EXGENESIS; Contract No. LSHM-CT-2004-005272).


  1. 1.
    DeFronzo, R. A., Jacot, E., Jequier, E., Maeder, E., Wahren, J., & Felber, J. P. (1981). The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes, 30, 1000–1007.PubMedGoogle Scholar
  2. 2.
    DeFronzo, R. A., Gunnarsson, R., Bjorkman, O., Olsson, M., & Wahren, J. (1985). Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (Type II) diabetes mellitus. Journal of Clinical Investigation, 76, 149–155.PubMedGoogle Scholar
  3. 3.
    Kelley, D., Mitrakou, A., Marsh, H., Schwenk, F., Benn, J., Sonnenberg, G., Arcangeli, M., Aoki, T., Sorensen, J., Berger, M., Sonksen, P., & Gerich, J. (1988). Skeletal muscle glycolysis, oxidation, and storage of an oral glucose load. Journal of Clinical Investigation, 81, 1563–1571.PubMedGoogle Scholar
  4. 4.
    Moore, M. C., Cherrington, A. D., & Wasserman, D. H. (2003). Regulation of hepatic and peripheral glucose disposal. Best Practice & Research. Clinical Endocrinology & Metabolism, 17, 343–364.CrossRefGoogle Scholar
  5. 5.
    Joost, H.-G., Bell, G. I., Best, J. D., Birnbaum, M. J., Charron, M. J., Chen, Y. T., Doege, H., James, D. E., Lodish, H. F., Moley, K. H., Moley, J. F., Mueckler, M., Rogers, S., Schurmann, A., Seino, S., & Thorens, B. (2002). Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. American Journal of Physiology. Endocrinology and Metabolism, 282, E974–E976.PubMedGoogle Scholar
  6. 6.
    Scheepers, A., Joost, H. G., & Schurmann, A. (2004). The glucose transporter families SGLT and GLUT: Molecular basis of normal and aberrant function. Journal of Parenteral and Enteral Nutrition, 28, 364–371.PubMedGoogle Scholar
  7. 7.
    Birnbaum, M. J. (1989). Identification of a novel gene encoding an insulin-responsive glucose transporter protein. Cell, 57, 305–315.PubMedCrossRefGoogle Scholar
  8. 8.
    Fukumoto, H., Kayano, T., Buse, J. B., Edwards, Y., Pilch, P. F., Bell, G. I., & Seino, S. (1989). Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues. Journal of Biological Chemistry, 264, 7776–7779.PubMedGoogle Scholar
  9. 9.
    James, D. E., Strube, M., & Muecdler, M. (1989). Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature, 338, 83–87.PubMedCrossRefGoogle Scholar
  10. 10.
    Douen, A. G., Ramlal, T., Rastogi, S., Bilan, P. J., Cartee, G. D., Vranic, M., Holloszy, J. O., & Klip, A. (1990). Exercise induces recruitment of the “insulin-responsive glucose transporter”. Evidence for distinct intracellular insulin- and exercise- recruitable transporter pools in skeletal muscle. Journal of Biological Chemistry, 265, 13427–13430.PubMedGoogle Scholar
  11. 11.
    Hirshman, M. F., Goodyear, L. J., Wardzala, L. J., Horton, E. D., & Horton, E. S. (1990). Identification of an intracellular pool of glucose transporters from basal and insulin-stimulated rat skeletal muscle. Journal of Biological Chemistry, 265, 987–991.PubMedGoogle Scholar
  12. 12.
    Kristiansen, S., Hargreaves, M., & Richter, E. A. (1996). Exercise-induced increase in glucose transport, G. L.,UT-4, and VAMP-2 in plasma membrane from human muscle. American Journal of Physiology. Endocrinology and Metabolism, 270, E197-201.Google Scholar
  13. 13.
    Ryder, J., Yang, J., Galuska, D., Rincon, J., Bjornholm, M., Krook, A., Lund, S., Pedersen, O., Wallberg-Henriksson, H., Zierath, J. R., & Holman, G (2000). Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 2 diabetic patients. Diabetes, 49, 647–654.PubMedCrossRefGoogle Scholar
  14. 14.
    Cline, G. W., Petersen, K. F., Krssak, M., Shen, J., Hundal, R. S., Trajanoski, Z., Inzucchi, S., Dresner, A., Rothman, D. L., & Shulman, G. I. (1999). Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in Type 2 diabetes. The New England Journal of Medicine, 341, 240–246.PubMedCrossRefGoogle Scholar
  15. 15.
    Handberg, A., Vaag, A., Damsbo, P., Beck-Nielsen, H., & Vinten, J (1990). Expression of insulin regulatable glucose transporters in skeletal muscle from type 2 (non-insulin-dependent) diabetic patients. Diabetologia, 33, 625–627.PubMedCrossRefGoogle Scholar
  16. 16.
    Pedersen, O., Bak, J. F., Andersen, P. H., Lund, S., Moller, D. E., Flier, J. S., & Kahn, B. B. (1990). Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM. Diabetes, 39, 865–870.PubMedCrossRefGoogle Scholar
  17. 17.
    Shepherd, P. R., & Kahn, B. B. (1999). Glucose transporters and insulin action: Implications for insulin resistance and diabetes mellitus. The New England Journal of Medicine, 341, 248–257.PubMedCrossRefGoogle Scholar
  18. 18.
    Cushman, S. W., & Wardzala, L. J. (1980). Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane. Journal of Biological Chemistry, 255, 4758–4762.PubMedGoogle Scholar
  19. 19.
    Suzuki, K., & Kono, T (1980). Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. Proceedings of the National Academy of Sciences of the United States of America, 77, 2542–2545.PubMedCrossRefGoogle Scholar
  20. 20.
    James, D. E., Brown, R., Navarro, J., & Pilch, P. F. (1988). Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein. Nature, 333, 183–185.PubMedCrossRefGoogle Scholar
  21. 21.
    Holman, G. D., Kozka, I. J., Clark, A. E., Flower, C. J., Saltis, J., Habberfield, A. D., Simpson, I. A., & Cushman, S. W. (1990). Cell surface labeling of glucose transporter isoform GLUT4 by bis- mannose photolabel. Correlation with stimulation of glucose transport in rat adipose cells by insulin and phorbol ester. Journal of Biological Chemistry, 265, 18172–18179.PubMedGoogle Scholar
  22. 22.
    Holman, G. D., & Sandoval, I. V. (2001). Moving the insulin-regulated glucose transporter GLUT4 into and out of storage. Trends in Cell Biology, 11, 173–179.PubMedCrossRefGoogle Scholar
  23. 23.
    Garvey, W. T., Maianu, L., Zhu, J.-H., Brechtel-Hook, G., Wallace, P., & Baron, A. D. (1998). Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance. Journal of Clinical Investigation, 101, 2377–2386.PubMedGoogle Scholar
  24. 24.
    Huang, C., Thirone, A. C. P., Huang, X., & Klip, A (2005). Differential contribution of insulin receptor substrates 1 versus 2 to insulin signaling and glucose uptake in L6 myotubes. Journal of Biological Chemistry, 280, 19426–19435.PubMedCrossRefGoogle Scholar
  25. 25.
    Kido, Y., Burks, D. J., Withers, D., Bruning, J. C., Kahn, C. R., White, M. F., & Accili, D (2000). Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. Journal of Clinical Investigation, 105, 199–205.PubMedGoogle Scholar
  26. 26.
    Withers, D. J., Gutierrez, J. S., Towery, H., Burks, D. J., Ren, J.-M., Previs, S., Zhang, Y., Bernal, D., Pons, S., Shulman, G. I., Bonner-Weir, S., & White, M. F. (1998). Disruption of IRS-2 causes type 2 diabetes in mice. Nature, 391, 900–904.PubMedCrossRefGoogle Scholar
  27. 27.
    Cantrell, D. A. (2001). Phosphoinositide 3-kinase signalling pathways. Journal of Cell Science, 114, 1439–1445.PubMedGoogle Scholar
  28. 28.
    Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 378, 785–789.PubMedCrossRefGoogle Scholar
  29. 29.
    Tanti, J. F., Grillo, S., Gremeaux, T., Coffer, P. J., Van Obberghen, E., & Le Marchand-Brustel, Y (1997). Potential role of protein kinase B in glucose transporter 4 translocation in adipocytes. Endocrinology, 138, 2005–2010.PubMedCrossRefGoogle Scholar
  30. 30.
    Ueki, K., Yamamoto-Honda, R., Kaburagi, Y., Yamauchi, T., Tobe, K., Burgering, B. M. T., Coffer, P. J., Komuro, I., Akanuma, Y., Yazaki, Y., & Kadowaki, T (1998). Potential role of protein kinase B in insulin-induced glucose transport, glycogen synthesis, and protein synthesis. Journal of Biological Chemistry, 273, 5315–5322.PubMedCrossRefGoogle Scholar
  31. 31.
    Alessi, D. R., Andjelkovic, M., Caudwell, B., Cron, P., Morrice, N., Cohen, P., & Hemmings, B. A. (1996). Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO Journal, 15, 6541–6551.PubMedGoogle Scholar
  32. 32.
    Feng, J., Park, J., Cron, P., Hess, D., & Hemmings, B. A. (2004). Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent Protein Kinase. Journal of Biological Chemistry, 279, 41189–41196.PubMedCrossRefGoogle Scholar
  33. 33.
    Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005). Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science, 307, 1098–1101.PubMedCrossRefGoogle Scholar
  34. 34.
    Dong, L. Q., & Liu, F. (2005). PDK2: The missing piece in the receptor tyrosine kinase signaling pathway puzzle. American Journal of Physiology. Endocrinology and Metabolism, 289, E187–196.PubMedCrossRefGoogle Scholar
  35. 35.
    Alessi, D. R., James, S. R., Downes, C. P., Holmes, A. B., Gaffney, P. R., Reese, C. B., & Cohen, P (1997). Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Current Biology, 7, 261–269.PubMedCrossRefGoogle Scholar
  36. 36.
    Mora, A., Komander, D., van Aalten, D. M. F., & Alessi, D. R. (2004). PDK1, the master regulator of AGC kinase signal transduction. Seminars in Cell & Developmental Biology, 15, 161–170.CrossRefGoogle Scholar
  37. 37.
    Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F., & Birnbaum, M. J. (2001). Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. Journal of Biological Chemistry, 276, 38349–38352.PubMedCrossRefGoogle Scholar
  38. 38.
    Cho, H., Mu, J., Kim, J. K., Thorvaldsen, J. L., Chu, Q., Crenshaw, E. B. III, Kaestner, K. H., Bartolomei, M. S., Shulman, G. I., & Birnbaum, M. J. (2001). Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBbeta). Science, 292, 1728–1731.PubMedCrossRefGoogle Scholar
  39. 39.
    Chou, M. M., Hou, W., Johnson, J., Graham, L. K., Lee, M. H., Chen, C. S., Newton, A. C., Schaffhausen, B. S., & Toker, A (1998). Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Current Biology, 8, 1069–1077.PubMedCrossRefGoogle Scholar
  40. 40.
    Bandyopadhyay, G., Standaert, M. L., Galloway, L., Moscat, J., & Farese, R. V. (1997). Evidence for involvement of protein kinase C (PKC)-zeta and noninvolvement of diacylglycerol-sensitive PKCs in insulin-stimulated glucose transport in L6 myotubes. Endocrinology, 138, 4721–4731.PubMedCrossRefGoogle Scholar
  41. 41.
    Cormont, M., & Le Marchand-Brustel, Y (2001). The role of small G-proteins in the regulation of glucose transport. Molecular Membrane Biology, 18, 213–220.PubMedCrossRefGoogle Scholar
  42. 42.
    Kane, S., Sano, H., Liu, S. C. H., Asara, J. M., Lane, W. S., Garner, C. C., & Lienhard, G. E. (2002). A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-Activating Protein (GAP) domain. Journal of Biological Chemistry, 277, 22115–22118.PubMedCrossRefGoogle Scholar
  43. 43.
    Sano, H., Kane, S., Sano, E., Miinea, C. P., Asara, J. M., Lane, W. S., Garner, C. W., & Lienhard, G. E. (2003). Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. Journal of Biological Chemistry, 278, 14599–14602.PubMedCrossRefGoogle Scholar
  44. 44.
    Zeigerer, A., McBrayer, M. K., & McGraw, T. E. (2004). Insulin stimulation of GLUT4 exocytosis, but not its inhibition of endocytosis, is dependent on RabGAP AS160. Molecular Biology of the Cell, 15, 4406–4415.PubMedCrossRefGoogle Scholar
  45. 45.
    Matsumoto, Y., Imai, Y., Lu Yoshida, N., Sugita, Y., Tanaka, T., Tsujimoto, G., Saito, H., & Oshida, T (2004). Upregulation of the transcript level of GTPase activating protein KIAA0603 in T cells from patients with atopic dermatitis. FEBS Letters, 572, 135–140.PubMedCrossRefGoogle Scholar
  46. 46.
    Arias, E. B., Kim, J., & Cartee, G. D. (2004). Prolonged incubation in PUGNAc results in increased protein O-linked glycosylation and insulin resistance in rat skeletal muscle. Diabetes, 53, 921–930.PubMedCrossRefGoogle Scholar
  47. 47.
    Bruss, M. D., Arias, E. B., Lienhard, G. E., & Cartee, G. D. (2005). Increased phosphorylation of Akt Substrate of 160 kDa (AS160) in rat skeletal muscle in response to insulin or contractile activity. Diabetes, 54, 41–50.PubMedCrossRefGoogle Scholar
  48. 48.
    Miinea, C. P., Sano, H., Kane, S., Sano, E., Fukuda, M., Peranen, J., Lane, W. S., & Lienhard, G. E. (2005). AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase activating protein domain. Biochemistry Journal, 391, 87–93.CrossRefGoogle Scholar
  49. 49.
    Leng, Y., Karlsson, H. K., & Zierath, J. R. (2004). Insulin signaling defects in type 2 diabetes. Reviews in Endocrine & Metabolic Disorders, 5, 111–117.CrossRefGoogle Scholar
  50. 50.
    Arner, P., Pollare, T., Lithell, H., & Livingston, J. N. (1987). Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia, 30, 437–440.PubMedCrossRefGoogle Scholar
  51. 51.
    Krook, A., Bjornholm, M., Galuska, D., Jiang, X., Fahlman, R., Myers, M., Wallberg-Henriksson, H., & Zierath, J. R. (2000). Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes, 49, 284–292.PubMedCrossRefGoogle Scholar
  52. 52.
    Ciaraldi, T., Carter, L., Rehman, N., Mohideen, P., Mudaliar, S., & Henry, R (2002). Insulin and insulin-like growth factor-1 action on human skeletal muscle: Preferential effects of insulin-like growth factor-1 in type 2 diabetic subjects. Metabolism, 51, 1171–1179.PubMedCrossRefGoogle Scholar
  53. 53.
    Caro, J. F., Sinha, M. K., Raju, S. M., Ittoop, O., Pories, W. J., Flickinger, E. G., Meelheim, D., & Dohm, G. L. (1987). Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes. Journal of Clinical Investigation, 79, 1330–1337.PubMedGoogle Scholar
  54. 54.
    Maegawa, H., Shigeta, Y., Egawa, K., & Kobayashi, M (1991). Impaired autophosphorylation of insulin receptors from abdominal skeletal muscles in non-obese subjects with NIDDM. Diabetes, 40, 815–819.PubMedCrossRefGoogle Scholar
  55. 55.
    Klein, H. H., Vestergaard, H., Kotzke, G., & Pedersen, O (1995). Elevation of serum insulin concentration during euglycemic hyperinsulinemic clamp studies leads to similar activation of insulin receptor kinase in skeletal muscle of subjects with and without NIDDM. Diabetes, 44, 1310–1317.PubMedCrossRefGoogle Scholar
  56. 56.
    Meyer, M. M., Levin, K., Grimmsmann, T., Beck-Nielsen, H., & Klein, H. H. (2002). Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease. Diabetologia, 45, 813–822.PubMedCrossRefGoogle Scholar
  57. 57.
    Kim, Y.-B., Kotani, K., Ciaraldi, T. P., Henry, R. R., & Kahn, B. B. (2003). Insulin-stimulated protein kinase C lambda/zeta activity is reduced in skeletal muscle of humans with obesity and Type 2 diabetes: Reversal with weight reduction. Diabetes, 52, 1935–1942.PubMedCrossRefGoogle Scholar
  58. 58.
    Nolan, J. J., Freidenberg, G., Henry, R., Reichart, D., & Olefsky, J. M. (1994). Role of human skeletal muscle insulin receptor kinase in the In vivo insulin resistance of non-insulin-dependent diabetes mellitus and obesity. The Journal of Clinical Endocrinology and Metabolism, 78, 471–477.PubMedCrossRefGoogle Scholar
  59. 59.
    Goodyear, L. J., Giorgino, F., Sherman, L. A., Carey, J., Smith, R. J., & Dohm, G. L. (1995). Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. Journal of Clinical Investigation, 95, 2195–2204.PubMedGoogle Scholar
  60. 60.
    Björnholm, M., Kawano, Y., Lehtihet, M., & Zierath, J. R. (1997). Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after In vivo insulin stimulation. Diabetes, 46, 524–527.PubMedCrossRefGoogle Scholar
  61. 61.
    Cusi, K., Maezono, K., Osman, A., Pendergrass, M., Patti, M. E., Pratipanawatr, T., DeFronzo, R. A., Kahn, C. R., & Mandarino, L. J. (2000). Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. Journal of Clinical Investigation, 105, 311–320.PubMedCrossRefGoogle Scholar
  62. 62.
    Bouzakri, K., Roques, M., Gual, P., Espinosa, S., Guebre-Egziabher, F., Riou, J.-P., Laville, M., Le Marchand-Brustel, Y., Tanti, J-F., & 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, 1319–1325.PubMedCrossRefGoogle Scholar
  63. 63.
    Beeson, M., Sajan, M. P., Dizon, M., Grebenev, D., Gomez-Daspet, J., Miura, A., Kanoh, Y., Powe, J., Bandyopadhyay, G., Standaert, M. L., & Farese, R. V. (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, 1926–1934.PubMedCrossRefGoogle Scholar
  64. 64.
    Lee, Y. H., Giraud, J., Davis, R. J., & White, M. F. (2003). c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. Journal of Biological Chemistry, 278, 2896–2902.PubMedCrossRefGoogle Scholar
  65. 65.
    Aguirre, V., Werner, E. D., Giraud, J., Lee, Y. H., Shoelson, S. E., & White, M. F. (2002). Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. Journal of Biological Chemistry, 277, 1531–1537.PubMedCrossRefGoogle Scholar
  66. 66.
    Kim, Y.-B., Nikoulina, S. E., Ciaraldi, T. P., Henry, R. R., & Kahn, B. B. (1999). Normal insulin-dependent activation of Akt/protein kinase B., with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. Journal of Clinical Investigation, 104, 733–741.PubMedGoogle Scholar
  67. 67.
    Tsuchida, H., Björnholm, M., Fernström, M., Galuska, D., Johansson, P., Wallberg-Henriksson, H., Zierath, J., Lake, S., & Krook, A (2002). Gene expression of the p85a regulatory subunit of phosphatidylinositol 3-kinase in skeletal muscle from type 2 diabetic subjects. Pflugers Archive European Journal of Physiology, 445, 25–31.CrossRefGoogle Scholar
  68. 68.
    Krook, A., Roth, R., Jiang, X., Zierath, J. R., & Wallberg-Henriksson, H (1998). Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. Diabetes, 47, 1281–1286.PubMedCrossRefGoogle Scholar
  69. 69.
    Brozinick, J. T. Jr, Roberts, B. R., & Dohm, G. L. (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, 935–941.PubMedCrossRefGoogle Scholar
  70. 70.
    Karlsson, H. K. R., Zierath, J. R., Kane, S., Krook, A., Lienhard, G. E., & Wallberg-Henriksson, H (2005). Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of Type 2 diabetic subjects. Diabetes, 54, 1692–1697.PubMedCrossRefGoogle Scholar
  71. 71.
    Aledo J. C., Darakhshan F., & Hundal H. S. (1995). Rab4, but not the transferrin receptor, is colocalized with GLUT4 in an insulin-sensitive intracellular compartment in rat skeletal muscle. Biochemical and Biophysical Research Communications, 215, 321–328.PubMedCrossRefGoogle Scholar
  72. 72.
    Sherman, L., Hirshman, M., Cormont, M., Le Marchand-Brustel, Y., & Goodyear, L (1996). Differential effects of insulin and exercise on Rab4 distribution in rat skeletal muscle. Endocrinology, 137, 266–273.PubMedCrossRefGoogle Scholar
  73. 73.
    Kessler, A., Tomas, E., Immler, D., Meyer, H. E., Zorzano, A., & Eckel, J (2000). Rab11 is associated with GLUT4-containing vesicles and redistributes in response to insulin. Diabetologia, 43, 1518–1527.PubMedCrossRefGoogle Scholar
  74. 74.
    Bailey, C. J., & Day, C. (2004). Metformin: Its botanical background. Practial Diabetes International, 21, 115–117.CrossRefGoogle Scholar
  75. 75.
    Bailey, C. J., & Turner, R. C. (1996). Metformin. The New England Journal of Medicine, 334, 574–579.PubMedCrossRefGoogle Scholar
  76. 76.
    Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., Musi, N., Hirshman, M. F., Goodyear, L. J., & Moller, D. E. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. Journal of Clinical Investigation, 108, 1167–1174.PubMedCrossRefGoogle Scholar
  77. 77.
    Zierath, J. R., Ryder, J. W., Doebber, T., Woods, J., Wu, M., Ventre, J., Li, Z., McCrary, C., Berger, J., Zhang, B., & Moller, D. E. (1998). Role of skeletal muscle in thiazolidinedione insulin sensitizer (PPARgamma agonist) action. Endocrinology, 139, 5034–5041.PubMedCrossRefGoogle Scholar
  78. 78.
    Patel, J., Anderson, R. J., & Rappaport, E. B. (1999). Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: A twelve-week, randomized, placebo-controlled study. Diabetes, Obesity & Metabolism, 1, 165–172.CrossRefGoogle Scholar
  79. 79.
    Fonseca, V., Rosenstock, J., Patwardhan, R., & Salzman, A (2000). Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: A randomized controlled trial. JAMA, 283, 1695–1702.PubMedCrossRefGoogle Scholar
  80. 80.
    Nolan, J. J., Jones, N. P., Patwardhan, R., & Deacon, L. F. (2000). Rosiglitazone taken once daily provides effective glycaemic control in patients with Type 2 diabetes mellitus. Diabetic Medicine, 17, 287–294.PubMedCrossRefGoogle Scholar
  81. 81.
    Raskin, P., Rappaport, E. B., Cole, S. T., Yan, Y., Patwardhan, R., & Freed, M. I. (2000). Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with type II diabetes. Diabetologia, 43, 278–284.PubMedCrossRefGoogle Scholar
  82. 82.
    Wolffenbuttel, B. H., Gomis, R., Squatrito, S., Jones, N. P., & Patwardhan, R. N. (2000). Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in Type 2 diabetic patients. Diabetic Medicine, 17, 40–47.PubMedCrossRefGoogle Scholar
  83. 83.
    Lebovitz, H. E., Dole, J. F., Patwardhan, R., Rappaport, E. B., & Freed, M. I. (2001). Rosiglitazone monotherapy is effective in patients with type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism, 86, 280–288.PubMedCrossRefGoogle Scholar
  84. 84.
    Phillips, L. S., Grunberger, G., Miller, E., Patwardhan, R., Rappaport, E. B., & Salzman, A (2001). Once- and twice-daily dosing with Rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care, 24, 308–315.PubMedCrossRefGoogle Scholar
  85. 85.
    Raskin, P., Rendell, M., Riddle, M. C., Dole, J. F., Freed, M. I., & Rosenstock, J (2001). A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated Type 2 diabetes. Diabetes Care, 24, 1226–1232.PubMedCrossRefGoogle Scholar
  86. 86.
    Karlsson, H. K., Hallsten, K., Bjornholm, M., Tsuchida, H., Chibalin, A. V., Virtanen, K. A., Heinonen, O. J., Lonnqvist, F., Nuutila, P., & Zierath, J. R. (2005). Effects of metformin and rosiglitazone treatment on insulin signaling and glucose uptake in patients with newly diagnosed type 2 diabetes: A randomized controlled study. Diabetes, 54, 1459–1467.PubMedCrossRefGoogle Scholar
  87. 87.
    Zierath, J. R. (1995). In vitro studies of human skeletal muscle: Hormonal and metabolic regulation of glucose transport. Acta physiologica Scandinavica. Supplementum, 155, 1–96.Google Scholar
  88. 88.
    Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G., & Gerich, J. E. (1995). Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. The New England Journal of Medicine, 333, 550–554.PubMedCrossRefGoogle Scholar
  89. 89.
    Hundal, R., Krssak, M., Dufour, S., Laurent, D., Lebon, V., Chandramouli, V., Inzucchi, S., Schumann, W., Petersen, K., Landau, B., & Shulman, G (2000). Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes, 49, 2063–2069.PubMedCrossRefGoogle Scholar
  90. 90.
    Inzucchi, S. E., Maggs, D. G., Spollett, G. R., Page, S. L., Rife, F. S., Walton, V., & Shulman, G. I. (1998). Efficacy and metabolic effects of Metformin and Troglitazone in type II diabetes mellitus. The New England Journal of Medicine, 338, 867–873.PubMedCrossRefGoogle Scholar
  91. 91.
    Kim, Y.-B., Ciaraldi, T. P., Kong, A., Kim, D., Chu, N., Mohideen, P., Mudaliar, S., Henry, R. R., & Kahn, B. B. (2002). Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110beta protein levels in skeletal muscle of type 2 diabetic subjects. Diabetes, 51, 443–448.PubMedCrossRefGoogle Scholar
  92. 92.
    Petersen, K., Krssak, M., Inzucchi, S., Cline, G., Dufour, S., & Shulman, G (2000). Mechanism of troglitazone action in type 2 diabetes. Diabetes, 49, 827–831.PubMedCrossRefGoogle Scholar
  93. 93.
    Carey, D. G., Cowin, G. J., Galloway, G. J., Jones, N. P., Richards, J. C., Biswas, N., & Doddrell, D. M. (2002). Effect of rosiglitazone on insulin sensitivity and body composition in Type 2 diabetic patients. Obesity Research, 10, 1008–1015.PubMedGoogle Scholar
  94. 94.
    Miyazaki, Y., He, H., Mandarino, L. J., & DeFronzo, R. A. (2003). Rosiglitazone improves downstream insulin receptor signaling in Type 2 diabetic patients. Diabetes, 52, 1943–1950.PubMedCrossRefGoogle Scholar
  95. 95.
    Miyazaki, Y., Glass, L., Triplitt, C., Matsuda, M., Cusi, K., Mahankali, A., Mahankali, S., Mandarino, L. J., & DeFronzo, R. A. (2001). Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type II diabetic patients. Diabetologia, 44, 2210–2219.PubMedCrossRefGoogle Scholar
  96. 96.
    Mayerson, A. B., Hundal, R. S., Dufour, S., Lebon, V., Befroy, D., Cline, G. W., Enocksson, S., Inzucchi, S. E., Shulman, G. I., & Petersen, K. F. (2002). The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with Type 2 diabetes. Diabetes, 51, 797–802.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Department of Molecular Medicine and Surgery, Section of Integrative PhysiologyKarolinska InstitutetStockholmSweden

Personalised recommendations