Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

High-fat load: mechanism(s) of insulin resistance in skeletal muscle

International Journal of Obesity Supplements volume 2, pages S31–S36 (2012)Cite this article

Subjects

Abstract

Skeletal muscle from sedentary obese patients is characterized by depressed electron transport activity, reduced expression of genes required for oxidative metabolism, altered mitochondrial morphology and lower overall mitochondrial content. These findings imply that obesity, or more likely the metabolic imbalance that causes obesity, leads to a progressive decline in mitochondrial function, eventually culminating in mitochondrial dissolution or mitoptosis. A decrease in the sensitivity of skeletal muscle to insulin represents one of the earliest maladies associated with high dietary fat intake and weight gain. Considerable evidence has accumulated to suggest that the cytosolic ectopic accumulation of fatty acid metabolites, including diacylglycerol and ceramides, underlies the development of insulin resistance in skeletal muscle. However, an alternative mechanism has recently been evolving, which places the etiology of insulin resistance in the context of cellular/mitochondrial bioenergetics and redox systems biology. Overnutrition, particularly from high-fat diets, generates fuel overload within the mitochondria, resulting in the accumulation of partially oxidized acylcarnitines, increased mitochondrial hydrogen peroxide (H2O2) emission and a shift to a more oxidized intracellular redox environment. Blocking H2O2 emission prevents the shift in redox environment and preserves insulin sensitivity, providing evidence that the mitochondrial respiratory system is able to sense and respond to cellular metabolic imbalance. Mitochondrial H2O2 emission is a major regulator of protein redox state, as well as the overall cellular redox environment, raising the intriguing possibility that elevated H2O2 emission from nutrient overload may represent the underlying basis for the development of insulin resistance due to disruption of normal redox control mechanisms regulating protein function, including the insulin signaling and glucose transport processes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP . The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981; 30: 1000–1007.

    Article  CAS  PubMed  Google Scholar 

  2. Wasserman DH . Four grams of glucose. Am J Physiol Endocrinol Metab 2009; 296: E11–E21.

    Article  CAS  PubMed  Google Scholar 

  3. Barrett EJ, Eggleston EM, Inyard AC, Wang H, Li G, Chai W et al. The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action. Diabetologia 2009; 52: 752–764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ayala JE, Bracy DP, Julien BM, Rottman JN, Fueger PT, Wasserman DH . Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes 2007; 56: 1025–1033.

    Article  CAS  PubMed  Google Scholar 

  5. Larance M, Ramm G, James DE . The GLUT4 code. Mol Endocrinol 2008; 22: 226–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Thong FS, Dugani CB, Klip A . Turning signals on and off: GLUT4 traffic in the insulin-signaling highway. Physiology (Bethesda) 2005; 20: 271–284.

    CAS  Google Scholar 

  7. Fueger PT, Bracy DP, Malabanan CM, Pencek RR, Granner DK, Wasserman DH . Hexokinase II overexpression improves exercise-stimulated but not insulin-stimulated muscle glucose uptake in high-fat-fed C57BL/6J mice. Diabetes 2004; 53: 306–314.

    Article  CAS  PubMed  Google Scholar 

  8. Halseth AE, Bracy DP, Wasserman DH . Overexpression of hexokinase II increases insulinand exercise-stimulated muscle glucose uptake in vivo. Am J Physiol 1999; 276: E70–E77.

    CAS  PubMed  Google Scholar 

  9. Roden M . How free fatty acids inhibit glucose utilization in human skeletal muscle. News Physiol Sci 2004; 19: 92–96.

    CAS  PubMed  Google Scholar 

  10. Shulman GI . Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. Physiology (Bethesda) 2004; 19: 183–190.

    CAS  Google Scholar 

  11. Cartee GD, Douen AG, Ramlal T, Klip A, Holloszy JO . Stimulation of glucose transport in skeletal muscle by hypoxia. J Appl Physiol 1991; 70: 1593–1600.

    Article  CAS  PubMed  Google Scholar 

  12. Zierath JR, Houseknecht KL, Gnudi L, Kahn BB . High-fat feeding impairs insulin-stimulated GLUT4 recruitment via an early insulin-signaling defect. Diabetes 1997; 46: 215–223.

    Article  CAS  PubMed  Google Scholar 

  13. Kelley DE, Mandarino LJ . Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 2000; 49: 677–683.

    Article  CAS  PubMed  Google Scholar 

  14. Moro C, Bajpeyi S, Smith SR . Determinants of intramyocellular triglyceride turnover: implications for insulin sensitivity. Am J Physiol Endocrinol Metab 2008; 294: E203–E213.

    Article  CAS  PubMed  Google Scholar 

  15. Meex RC, Schrauwen P, Hesselink MK . Modulation of myocellular fat stores: lipid droplet dynamics in health and disease. Am J Physiol Regul Integr Comp Physiol 2009; 297: R913–R924.

    Article  CAS  PubMed  Google Scholar 

  16. Digel M, Ehehalt R, Fullekrug J . Lipid droplets lighting up: insights from live microscopy. FEBS Lett 2010; 584: 2168–2175.

    Article  CAS  PubMed  Google Scholar 

  17. Unger RH . Lipotoxic diseases. Annu Rev Med 2002; 53: 319–336.

    Article  CAS  PubMed  Google Scholar 

  18. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1 H NMR spectroscopy study. Diabetologia 1999; 42: 113–116.

    Article  CAS  PubMed  Google Scholar 

  19. Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 1997; 46: 983–988.

    Article  CAS  PubMed  Google Scholar 

  20. Phillips DI, Caddy S, Ilic V, Fielding BA, Frayn KN, Borthwick AC et al. Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects. Metabolism 1996; 45: 947–950.

    Article  CAS  PubMed  Google Scholar 

  21. Goodpaster BH, Kelley DE . Skeletal muscle triglyceride: marker or mediator of obesity-induced insulin resistance in type 2 diabetes mellitus? Curr Diab Rep 2002; 2: 216–222.

    Article  PubMed  Google Scholar 

  22. Kraegen EW, Clark PW, Jenkins AB, Daley EA, Chisholm DJ, Storlien LH . Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats. Diabetes 1991; 40: 1397–1403.

    Article  CAS  PubMed  Google Scholar 

  23. Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW . Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes 1991; 40: 280–289.

    Article  CAS  PubMed  Google Scholar 

  24. Goodpaster BH, He J, Watkins S, Kelley DE . Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 2001; 86: 5755–5761.

    Article  CAS  PubMed  Google Scholar 

  25. Liu L, Zhang Y, Chen N, Shi X, Tsang B, Yu YH . Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J Clin Invest 2007; 117: 1679–1689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yi Z, Langlais P, De Filippis EA, Luo M, Flynn CR, Schroeder S et al. Global assessment of regulation of phosphorylation of insulin receptor substrate-1 by insulin in vivo in human muscle. Diabetes 2007; 56: 1508–1516.

    Article  CAS  PubMed  Google Scholar 

  27. Boura-Halfon S, Zick Y . Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab 2009; 296: E581–E591.

    Article  CAS  PubMed  Google Scholar 

  28. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787–790.

    Article  CAS  PubMed  Google Scholar 

  29. Hegarty BD, Furler SM, Ye J, Cooney GJ, Kraegen EW . The role of intramuscular lipid in insulin resistance. Acta Physiol Scand 2003; 178: 373–383.

    Article  CAS  PubMed  Google Scholar 

  30. Griffin M, Marcucci M, Cline G, Bell K, Barucci N, Lee D et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999; 48: 1270–1274.

    Article  CAS  PubMed  Google Scholar 

  31. Yu C, Chen Y, Zong H, Wang Y, Bergeron R, Kim JK et al. Mechanism by which fatty acids inhibit insulin activation of IRS-1 associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 2002; 277: 50230–50236.

    Article  CAS  PubMed  Google Scholar 

  32. Schmitz-Peiffer C, Oakes ND, Browne CL, Kraegen EW, Biden TJ . Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL-49653. Am J Physiol 1997; 273: E915–E921.

    CAS  PubMed  Google Scholar 

  33. Li Y, Soos TJ, Li X, Wu J, DeGennaro M, Sun X et al. Protein kinase C {theta} inhibits insulin signaling by phosphorylating IRS1 at ser1101. J Biol Chem 2004; 279: 45304–45307.

    Article  CAS  PubMed  Google Scholar 

  34. Wang C, Liu M, Riojas RA, Xin X, Gao Z, Zeng R et al. Protein kinase C theta (PKCtheta)-dependent phosphorylation of PDK1 at Ser504 and Ser532 contributes to palmitate-induced insulin resistance. J Biol Chem 2009; 284: 2038–2044.

    Article  CAS  PubMed  Google Scholar 

  35. Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 2004; 114: 823–827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Serra C, Federici M, Buongiorno A, Senni MI, Morelli S, Segratella E et al. Transgenic mice with dominant negative PKC-theta in skeletal muscle: a new model of insulin resistance and obesity. J Cell Physiol 2003; 196: 89–97.

    Article  CAS  PubMed  Google Scholar 

  37. Holland WL, Summers SA . Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev 2008; 29: 381–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Turinsky J, O’Sullivan DM, Bayly BP . 1,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo. J Biol Chem 1990; 265: 16880–16885.

    CAS  PubMed  Google Scholar 

  39. Hannun YA, Obeid LM . The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem 2002; 277: 25847–25850.

    Article  CAS  PubMed  Google Scholar 

  40. Gorska M, Dobrzyn A, Zendzian-Piotrowska M, Gorski J . Effect of streptozotocin-diabetes on the functioning of the sphingomyelin-signalling pathway in skeletal muscles of the rat. Horm Metab Res 2004; 36: 14–21.

    Article  CAS  PubMed  Google Scholar 

  41. Straczkowski M, Kowalska I, Nikolajuk A, Dzienis-Straczkowska S, Kinalska I, Baranowski M et al. Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. Diabetes 2004; 53: 1215–1221.

    Article  CAS  PubMed  Google Scholar 

  42. Hajduch E, Balendran A, Batty IH, Litherland GJ, Blair AS, Downes CP et al. Ceramide impairs the insulin-dependent membrane recruitment of protein kinase B leading to a loss in downstream signalling in L6 skeletal muscle cells. Diabetologia 2001; 44: 173–183.

    Article  CAS  PubMed  Google Scholar 

  43. Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 2007; 5: 167–179.

    Article  CAS  PubMed  Google Scholar 

  44. Ussher JR, Koves TR, Cadete VJJ, Zhang L, Jaswal JS, Swyrd SJ et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 2010; 59: 2453–2464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S et al. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 2011; 121: 1858–1870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Itani SI, Ruderman NB, Schmieder F, Boden G . Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002; 51: 2005–2011.

    Article  CAS  PubMed  Google Scholar 

  47. Serlie MJ, Meijer AJ, Groener JE, Duran M, Endert E, Fliers E et al. Short-term manipulation of plasma free fatty acids does not change skeletal muscle concentrations of ceramide and glucosylceramide in lean and overweight subjects. J Clin Endocrinol Metab 2007; 92: 1524–1529.

    Article  CAS  PubMed  Google Scholar 

  48. Skovbro M, Baranowski M, Skov-Jensen C, Flint A, Dela F, Gorski J et al. Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity. Diabetologia 2008; 51: 1253–1260.

    Article  CAS  PubMed  Google Scholar 

  49. Muoio DM, Neufer PD . Lipid-induced mitochondrial stress and insulin action in muscle. Cell Metab 2012; 15: 595–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Heilbronn LK, Campbell LV . Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des 2008; 14: 1225–1230.

    Article  CAS  PubMed  Google Scholar 

  51. Schenk S, Saberi M, Olefsky JM . Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 2008; 118: 2992–3002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. de Luca C, Olefsky JM . Inflammation and insulin resistance. FEBS Lett 2008; 582: 97–105.

    Article  CAS  PubMed  Google Scholar 

  53. Shoelson SE, Herrero L, Naaz A . Obesity, inflammation, and insulin resistance. Gastroenterology 2007; 132: 2169–2180.

    Article  CAS  PubMed  Google Scholar 

  54. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K et al. A central role for JNK in obesity and insulin resistance. Nature 2002; 420: 333–336.

    Article  CAS  PubMed  Google Scholar 

  55. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001; 293: 1673–1677.

    Article  CAS  PubMed  Google Scholar 

  56. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005; 11: 191–198.

    Article  CAS  PubMed  Google Scholar 

  57. Zhang X, Xu A, Chung SK, Cresser JH, Sweeney G, Wong RL et al. Selective inactivation of c-Jun NH2-terminal kinase in adipose tissue protects against diet-induced obesity and improves insulin sensitivity in both liver and skeletal muscle in mice. Diabetes 2011; 60: 486–495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 2009; 15: 914–920.

    Article  CAS  PubMed  Google Scholar 

  59. Sabio G, Kennedy NJ, Cavanagh-Kyros J, Jung DY, Ko HJ, Ong H et al. Role of muscle c-Jun NH2-terminal kinase 1 in obesity-induced insulin resistance. Mol Cell Biol 2010; 30: 106–115.

    Article  CAS  PubMed  Google Scholar 

  60. Hong EG, Ko HJ, Cho YR, Kim HJ, Ma Z, Yu TY et al. Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle. Diabetes 2009; 58: 2525–2535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007; 56: 901–911.

    Article  CAS  PubMed  Google Scholar 

  62. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005; 46: 2347–2355.

    Article  CAS  PubMed  Google Scholar 

  63. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306: 457–461.

    Article  CAS  PubMed  Google Scholar 

  64. Dasgupta J, Kar S, Liu R, Joseph J, Kalyanaraman B, Remington SJ et al. Reactive oxygen species control senescence-associated matrix metalloproteinase-1 through c-Jun-N-terminal kinase. J Cell Physiol 2010; 225: 52–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M . Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 2005; 120: 649–661.

    Article  CAS  PubMed  Google Scholar 

  66. Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med 2011; 208: 519–533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kabe Y, Ando K, Hirao S, Yoshida M, Handa H . Redox regulation of NF-kappaB activation: distinct redox regulation between the cytoplasm and the nucleus. Antioxid Redox Signal 2005; 7: 395–403.

    Article  CAS  PubMed  Google Scholar 

  68. Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 2009; 119: 573–581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chen L, Na R, Gu M, Salmon AB, Liu Y, Liang H et al. Reduction of mitochondrial H2O2 by overexpressing peroxiredoxin 3 improves glucose tolerance in mice. Aging Cell 2008; 7: 866–878.

    Article  CAS  PubMed  Google Scholar 

  70. Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ et al. Targeted Expression of Catalase to Mitochondria Prevents Age-Associated Reductions in Mitochondrial Function and Insulin Resistance. Cell Metab 2010; 12: 668–674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Forman HJ, Maiorino M, Ursini F . Signaling Functions of Reactive Oxygen Species. Biochemistry 2010; 49: 835–842.

    Article  CAS  PubMed  Google Scholar 

  72. Schafer FQ, Buettner GR . Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 2001; 30: 1191–1212.

    Article  CAS  PubMed  Google Scholar 

  73. Brand MD . The sites and topology of mitochondrial superoxide production. Exp Gerontol 2010; 45: 466–472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS et al. Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 2004; 24: 7779–7788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Starkov AA, Fiskum G . Regulation of brain mitochondrial H2O2 production by membrane potential and NAD(P)H redox state. J Neurochem 2003; 86: 1101–1107.

    Article  CAS  PubMed  Google Scholar 

  76. Korshunov SS, Skulachev VP, Starkov AA . High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 1997; 416: 15–18.

    Article  CAS  PubMed  Google Scholar 

  77. Liu Y, Fiskum G, Schubert D . Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 2002; 80: 780–787.

    Article  CAS  PubMed  Google Scholar 

  78. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 2008; 7: 45–56.

    Article  CAS  PubMed  Google Scholar 

  79. Fisher-Wellman KH, Neufer PD . Linking mitochondrial bioenergetics to the etiology of insulin resistance via redox biology. Trends Endocrinol Metab 2012; 23: 142–153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wright VP, Reiser PJ, Clanton TL . Redox modulation of global phosphatase activity and protein phosphorylation in intact skeletal muscle. J Physiol 2009; 587: 5767–5781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Furler SM, Oakes ND, Watkinson AL, Kraegen EW . A high-fat diet influences insulin-stimulated posttransport muscle glucose metabolism in rats. Metabolism 1997; 46: 1101–1106.

    Article  CAS  PubMed  Google Scholar 

  82. Halseth AE, Bracy DP, Wasserman DH . Limitations to basal and insulin-stimulated skeletal muscle glucose uptake in the high-fat-fed rat. Am J Physiol Endocrinol Metab 2000; 279: E1064–E1071.

    Article  CAS  PubMed  Google Scholar 

  83. Bonadonna RC, Del Prato S, Bonora E, Saccomani MP, Gulli G, Natali A et al. Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM. Diabetes 1996; 45: 915–925.

    Article  PubMed  Google Scholar 

  84. Vogt C, Ardehali H, Iozzo P, Yki-Jarvinen H, Koval J, Maezono K et al. Regulation of hexokinase II expression in human skeletal muscle in vivo. Metabolism 2000; 49: 814–818.

    Article  CAS  PubMed  Google Scholar 

  85. Kruszynska YT, Mulford MI, Baloga J, Yu JG, Olefsky JM . Regulation of skeletal muscle hexokinase II by insulin in nondiabetic and NIDDM subjects. Diabetes 1998; 47: 1107–1113.

    Article  CAS  PubMed  Google Scholar 

  86. Pendergrass M, Koval J, Vogt C, Yki-Jarvinen H, Iozzo P, Pipek R et al. Insulin-induced hexokinase II expression is reduced in obesity and NIDDM. Diabetes 1998; 47: 387–394.

    Article  CAS  PubMed  Google Scholar 

  87. Anflous-Pharayra K, Cai ZJ, Craigen WJ . VDAC1 serves as a mitochondrial binding site for hexokinase in oxidative muscles. Biochim Biophys Acta 2007; 1767: 136–142.

    Article  CAS  PubMed  Google Scholar 

  88. Viitanen PV, Geiger PJ, Erickson-Viitanen S, Bessman SP . Evidence for functional hexokinase compartmentation in rat skeletal muscle mitochondria. J Biol Chem 1984; 259: 9679–9686.

    CAS  PubMed  Google Scholar 

  89. Chen-Zion M, Bassukevitz Y, Beitner R . Sequence of insulin effects on cytoskeletal and cytosolic phosphofructokinase, mitochondrial hexokinase, glucose 1,6-bisphosphate and fructose 2,6-bisphosphate levels, and the antagonistic action of calmodulin inhibitors, in diaphragm muscle. Int J Biochem 1992; 24: 1661–1667.

    Article  CAS  PubMed  Google Scholar 

  90. Vogt C, Yki-Jarvinen H, Iozzo P, Pipek R, Pendergrass M, Koval J et al. Effects of insulin on subcellular localization of hexokinase II in human skeletal muscle in vivo. J Clin Endocrinol Metab 1998; 83: 230–234.

    CAS  PubMed  Google Scholar 

  91. Pastorino JG, Hoek JB, Shulga N . Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 2005; 65: 10545–10554.

    Article  CAS  PubMed  Google Scholar 

  92. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA . Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378: 785–789.

    Article  CAS  PubMed  Google Scholar 

  93. Eldar-Finkelman H, Schreyer SA, Shinohara MM, LeBoeuf RC, Krebs EG . Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice. Diabetes 1999; 48: 1662–1666.

    Article  CAS  PubMed  Google Scholar 

  94. Dokken BB, Saengsirisuwan V, Kim JS, Teachey MK, Henriksen EJ . Oxidative stress-induced insulin resistance in rat skeletal muscle: role of glycogen synthase kinase-3. Am J Physiol Endocrinol Metab 2008; 294: E615–E621.

    Article  CAS  PubMed  Google Scholar 

  95. Pearce NJ, Arch JR, Clapham JC, Coghlan MP, Corcoran SL, Lister CA et al. Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3beta on a muscle-specific promoter. Metabolism 2004; 53: 1322–1330.

    Article  CAS  PubMed  Google Scholar 

  96. Wu R, Smeele KM, Wyatt E, Ichikawa Y, Eerbeek O, Sun L et al. Reduction in hexokinase II levels results in decreased cardiac function and altered remodeling after ischemia/reperfusion injury. Circ Res 2011; 108: 60–69.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Support from the National Institutes of Health (R01-DK073488 and RO1-DK074825, PDN) is acknowledged.

Author information

Authors and Affiliations

  1. East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA

    D S Lark, K H Fisher-Wellman & P D Neufer

  2. Department of Kinesiology, East Carolina University, Greenville, NC, USA

    D S Lark, K H Fisher-Wellman & P D Neufer

  3. Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

    P D Neufer

Authors
  1. D S Lark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K H Fisher-Wellman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P D Neufer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P D Neufer.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

This article was published as part of a supplement funded with an unrestricted educational contribution from Desjardins Sécurité Financière.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lark, D., Fisher-Wellman, K. & Neufer, P. High-fat load: mechanism(s) of insulin resistance in skeletal muscle. Int J Obes Supp 2 (Suppl 2), S31–S36 (2012). https://doi.org/10.1038/ijosup.2012.20

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijosup.2012.20

Keywords

This article is cited by

Search

Advanced search

Quick links