Skip to main content
SpringerLink
Log in

Chronic exposure to ketone bodies impairs glucose uptake in adult cardiomyocytes in response to insulin but not vanadate: the role of PI3-K

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

There is a strong positive correlation between insulin resistance and cardiac diseases. We have already shown that chronic exposure to the ketone body β-hydroxybutyrate (OHB) decreases insulin-mediated activation of protein kinase B (PKB) and glucose uptake in cardiomyocytes. To gain further insights into the mechanism underlying ketone body-induced insulin resistance, we examined whether OHB alters activation of the insulin-signaling cascade and whether the insulinomimetic agent vanadate could bypass insulin resistance and stimulate glucose uptake in these cells. Cardiomyocytes were incubated with 5 mM OHB, 50 μM vanadate or both for 16 h before the measurement of glucose uptake or the activation of insulin-signaling molecules. While chronic exposure to OHB did not alter insulin- or vanadate-mediated activation of the insulin receptor, it suppressed insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation in response to both agonists. Furthermore, this treatment decreased by 54 and 36% the phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-K) and PKB in response to insulin, whereas it did not alter vanadate-mediated activation of these enzymes. Although insulin did not significantly stimulate p38MAPK phosphorylation, vanadate increased it by 3.8-fold. Furthermore, chronic exposure to OHB potentiated vanadate’s action, resulting in a 250% increase in enzyme activation compared to control cells. Though OHB induced a 2.1-fold increase of basal ERK1/2 phosphorylation, inhibition of this enzyme with the MEK inhibitor PD98059 demonstrated that ERK1/2 did not participate in OHB-induced insulin resistance. In conclusion, ketone bodies promote insulin resistance probably through decreased activation of the PI3-K/PKB signaling cascade. Furthermore, vanadate can bypass insulin resistance and stimulate glucose uptake in OHB-treated cardiomyocytes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bonora Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, Saggiani F, Poli M, Perbellini S, Raffaelli A, Cacciatori V, Santi L, Targher G, Bonadonna R, Muggeo M HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study Diabetes Care 25: 1135–1141, 2002

    Google Scholar 

  2. Iozzo P, Chareonthaitawee P, Dutka D, Betteridge DJ, Ferrannini E, Camici PG Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance Diabetes 51: 3020–3024, 2002

    PubMed  CAS  Google Scholar 

  3. Stone PH, Muller JE, Hartwell T, York BJ, Rutherford JD, Parker CB, Turi ZG, Strauss HW, Willerson JT, Robertson T The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. The MILIS Study Group J Am Coll Cardiol 14: 49–57, 1989

    Article  PubMed  CAS  Google Scholar 

  4. Meyer C, Schwaiger M Myocardial blood flow and glucose metabolism in diabetes mellitus Am J Cardiol 80: 94A–101A, 1997

    Article  PubMed  CAS  Google Scholar 

  5. Voipio-Pulkki LM, Nuutila P, Knuuti MJ, Ruotsalainen U, Haaparanta M, Teras M, Wegelius U, Koivisto VA Heart and skeletal muscle glucose disposal in type 2 diabetic patients as determined by positron emission tomography J Nucl Med 34: 2064–2067, 1993

    PubMed  CAS  Google Scholar 

  6. Sidell RJ, Cole MA, Draper NJ, Desrois M, Buckingham RE, Clarke K Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the Zucker fatty rat heart Diabetes 51: 1110–1117, 2002

    PubMed  CAS  Google Scholar 

  7. Belke DD, Larsen TS, Gibbs EM, Severson DL Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice Am J Physiol 279: E1104–E1113, 2000

    CAS  Google Scholar 

  8. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein Nature 352: 73–77, 1991

    Article  PubMed  CAS  Google Scholar 

  9. Kaburagi Y, Yamauchi T, Yamamoto-Honda R, Ueki K, Tobe K, Akanuma Y, Yazaki Y, Kadowaki T The mechanism of insulin-induced signal transduction mediated by the insulin receptor substrate family Endocr J 46(Suppl): S25–S34, 1999

    PubMed  CAS  Google Scholar 

  10. Backer JM, Myers MCJ, Shoelson SE, Chin DJ, Sun XJ, Miralpeix M, Hu P, Margolis B, Skolnik EY, Schlessinger J, White MF Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation EMBO J 11: 3469–3479, 1992

    PubMed  CAS  Google Scholar 

  11. Khan AH, Pessin JE Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways Diabetologia 45: 1475–1483, 2002

    Article  PubMed  CAS  Google Scholar 

  12. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA Mechanism of activation of protein kinase B by insulin and IGF-1 EMBO J 15: 6541–6551, 1996

    PubMed  CAS  Google Scholar 

  13. Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo Circulation 104: 330–335, 2001

    PubMed  CAS  Google Scholar 

  14. Ceresa BP, Pessin JE Insulin regulation of the Ras activation/inactivation cycle Mol Cell Biochem 182: 23–29, 1998

    Article  PubMed  CAS  Google Scholar 

  15. Somwar R, Koterski S, Sweeney G, Sciotti R, Djuric S, Berg C, Trevillyan J, Scherer PE, Rondinone CM, Klip A A dominant-negative p38 MAPK mutant and novel selective inhibitors of p38 MAPK reduce insulin-stimulated glucose uptake in 3T3-L1 adipocytes without affecting GLUT4 translocation J Biol Chem 277: 50386–50395, 2002

    Article  PubMed  CAS  Google Scholar 

  16. Bevan AP, Drake PG, Yale J-F, Shaver A, Posner BI Peroxovanadium compounds: biological actions and mechanism of insulin-mimesis Mol Cell Biochem 153: 49–58, 1995

    Article  PubMed  CAS  Google Scholar 

  17. Ramachandran B, Kandaswamy M, Narayanan V, Subramanian S Insulin mimetic effects of macrocyclic binuclear oxovanadium complexes on streptozotocin-induced experimental diabetes in rats Diabetes Obes Metab 5: 455–461, 2003

    Article  PubMed  CAS  Google Scholar 

  18. Semiz S, McNeill JH Oral treatment with vanadium of Zucker fatty rats activates muscle glycogen synthesis and insulin-stimulated protein phosphatase-1 activity Mol Cell Biochem 236: 123–131, 2002

    Article  PubMed  CAS  Google Scholar 

  19. Boden G, Chen X, Ruiz J, van Rossum GD, Turco S Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus Metabolism 45: 1130–1135, 1996

    Article  PubMed  CAS  Google Scholar 

  20. Donthi RV, Huisamen B, Lochner A Effect of vanadate and insulin on glucose transport in isolated adult rat cardiomyocytes Cardiovasc Drugs Ther 14: 463–470, 2000

    Article  PubMed  CAS  Google Scholar 

  21. Noda C, Masuda T, Sato K, Ikeda K, Shimohama T, Matsuyama N, Izumi T Vanadate improves cardiac function and myocardial energy metabolism in diabetic rat hearts Jpn Heart J 44: 745–757, 2003

    Article  PubMed  CAS  Google Scholar 

  22. Tardif A, Julien N, Chiasson JL, Coderre L Stimulation of glucose uptake by chronic vanadate pretreatment in cardiomyocytes requires phosphatidylinositol 3-kinase and p38 MAPK activation Am J Physiol 284: E1055–E1064, 2003

    CAS  Google Scholar 

  23. Laffel LM Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes Diabetes Metab Res Rev 15: 412–426, 1999

    Article  PubMed  CAS  Google Scholar 

  24. Lommi J, Koskinen P, Naveri H, Harkonen M, Kupari M Heart failure ketosis J Intern Med 242: 231–238, 1997

    Article  PubMed  CAS  Google Scholar 

  25. Kang HC, Chung DE, Kim DW, Kim HD Early- and late-onset complications of the ketogenic diet for intractable epilepsy Epilepsia 45: 1116–1123, 2004

    Article  PubMed  Google Scholar 

  26. Best TH, Franz DN, Gilbert DL, Nelson DP, Epstein MR Cardiac complications in pediatric patients on the ketogenic diet Neurology 54: 2328–2330, 2000

    PubMed  CAS  Google Scholar 

  27. Lommi J, Kupari M, Koskinen P, Naveri H, Leinonen H, Pulkki K, Harkonen M Blood ketone bodies in congestive heart failure J Am Coll Cardiol 28: 665–672, 1996

    Article  PubMed  CAS  Google Scholar 

  28. White NH Diabetic ketoacidosis in children Endocrinol Metab Clin North Am 29: 657–682, 2000

    Article  PubMed  CAS  Google Scholar 

  29. Tardif A, Julien N, Pelletier A, Thibault G, Srivastava AK, Chiasson JL, Coderre L Chronic exposure to beta-hydroxybutyrate impairs insulin action in primary cultures of adult cardiomyocytes Am J Physiol 281: E1205–E1212, 2001

    CAS  Google Scholar 

  30. Guerci B, Floriot M, Bohme P, Durain D, Benichou M, Jellimann S, Drouin P Clinical performance of CGMS in type 1 diabetic patients treated by continuous subcutaneous insulin infusion using insulin analogs. Diabetes Care 26: 582–589, 2003

    PubMed  CAS  Google Scholar 

  31. Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor Wortmannin J Biol Chem 269: 3568–3573, 1994

    PubMed  CAS  Google Scholar 

  32. Sharma PM, Egawa K, Huang Y, Martin JL, Huvar I, Boss GR, Olefsky JM Inhibition of phosphatidylinositol 3-kinase activity by adenovirus-mediated gene transfer and its effect on insulin action J Biol Chem 273: 18528–18537, 1998

    Article  PubMed  CAS  Google Scholar 

  33. Pelletier A, Joly E, Prentki M, Coderre L Adenosine 5′-monophosphate-activated protein kinase and p38 mitogen-activated protein kinase participate in the stimulation of glucose uptake by dinitrophenol in adult cardiomyocytes Endocrinology 146: 2285–2294, 2005

    Article  PubMed  CAS  Google Scholar 

  34. Kessler A, Uphues I, Ouwens DM, Till M, Eckel J Diversification of cardiac insulin signaling involves the p85 alpha/beta subunits of phosphatidylinositol 3-kinase Am J Physiol 280: E65–E74, 2001

    CAS  Google Scholar 

  35. Andreozzi F, Laratta E, Sciacqua A, Perticone F, Sesti G Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells Circ Res 94: 1211–1218, 2004

    Article  PubMed  CAS  Google Scholar 

  36. Newton CA, Raskin P Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences Arch Intern Med 164: 1925–1931, 2004

    Article  PubMed  CAS  Google Scholar 

  37. Kupari M, Lommi J, Ventila M, Karjalainen U Breath acetone in congestive heart failure Am J Cardiol 76: 1076–1078, 1995

    Article  PubMed  CAS  Google Scholar 

  38. Pandey SK, Anand-Srivastava MB, Srivastava AK Vanadyl sulfate-stimulated glycogen synthesis is associated with activation of phosphatidyl inositol 3-kinase (PI3-K) and is independent of insulin receptor tyrosine phosphorylation Biochemistry 37: 7006–7014, 1998

    Article  PubMed  CAS  Google Scholar 

  39. Maegawa H, Shigeta Y, Egawa K, Kobayashi M Impaired autophosphorylation of insulin receptors from abdominal skeletal muscles in nonobese subjects with NIDDM Diabetes 40: 815–819, 1991

    PubMed  CAS  Google Scholar 

  40. Krook A, Björnholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG Jr, Wallberg-Henriksson H, Zierath JR Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients Diabetes 49: 284–292, 2000

    PubMed  CAS  Google Scholar 

  41. Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle J Clin Invest 105: 311–320, 2000

    Article  PubMed  CAS  Google Scholar 

  42. Petersen KF, Shulman GI Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus Am J Cardiol 90: 11G–18G, 2002

    Article  PubMed  CAS  Google Scholar 

  43. Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R Defects of the insulin receptor substrate (IRS) system in human metabolic disorders FASEB J 15: 2099–2111, 2001

    Article  PubMed  CAS  Google Scholar 

  44. Rordorf-Nikolic T, Van Horn DJ, Chen D, White MF, Backer JM Regulation of phosphatidylinositol 3′-kinase by tyrosyl phosphoproteins. Full activation requires occupancy of both SH2 domains in the 85-kDa regulatory subunit J Biol Chem 270: 3662–3666, 1995

    Article  PubMed  CAS  Google Scholar 

  45. Kriauciunas KM, Myers MG Jr, Kahn CR Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1 Mol Cell Biol 20: 6849–6859, 2000

    Article  PubMed  CAS  Google Scholar 

  46. Anai M, Ono H, Funaki M, Fukushima Y, Inukai K, Ogihara T, Sakoda H, Onishi Y, Yazaki Y, Kikuchi M, Oka Y, Asano T Different subcellular distribution and regulation of expression of insulin receptor substrate (IRS)-3 from those of IRS-1 and IRS-2 J Biol Chem 273: 29686–29692, 1998

    Article  PubMed  CAS  Google Scholar 

  47. Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation Mol Cell Biol 14: 4902–4911, 1994

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  49. Kruszynska YT, Worrall DS, Ofrecio J, Frias JP, Macaraeg G, Olefsky JM Fatty acid-induced insulin resistance: decreased muscle PI3K activation but unchanged Akt phosphorylation J Clin Endocrinol Metab 87: 226–234, 2002

    Article  PubMed  CAS  Google Scholar 

  50. Shepherd PR Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues Acta Physiol Scand 183: 3–12, 2005

    Article  PubMed  CAS  Google Scholar 

  51. Ikeda Y, Ziv E, Shafrir E, Mosthaf-Seedorf L Protein tyrosine phosphatase 1B is impaired in skeletal muscle of diabetic Psammomys obesus Int J Exp Diabetes Res 3: 205–212, 2002

    Article  PubMed  Google Scholar 

  52. Morris AJ, Martin SS, Haruta T, Nelson JG, Vollenweider P, Gustafson TA, Mueckler M, Rose DW, Olefsky JM Evidence for an insulin receptor substrate 1 independent insulin signaling pathway that mediates insulin-responsive glucose transporter (GLUT4) translocation Proc Natl Acad Sci USA 93: 8401–8406, 1996

    Article  PubMed  CAS  Google Scholar 

  53. Staubs PA, Nelson JG, Reichart DR, Olefsky JM Platelet-derived growth factor inhibits insulin stimulation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase in 3T3-L1 adipocytes without affecting glucose transport J Biol Chem 273: 25139–25147, 1998

    Article  PubMed  CAS  Google Scholar 

  54. Venable CL, Frevert EU, Kim YB, Fischer BM, Kamatkar S, Neel BG, Kahn BB Overexpression of protein-tyrosine phosphatase-1B in adipocytes inhibits insulin-stimulated phosphoinositide 3-kinase activity without altering glucose transport or Akt/Protein kinase B activation J Biol Chem 275: 18318–18326, 2000

    Article  PubMed  CAS  Google Scholar 

  55. Araki E, Lipes MY, Patti ME, Bruning JC, Hagg HB, Johnson RS, Kahn CR Alternative pathway of insulin signaling in mice with targeted disruption of the IRS-I gene Nature 372: 186–189, 1994

    Article  PubMed  CAS  Google Scholar 

  56. Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S, Sekihara H, Yoshioka S, Horikoshi H, Furuta Y, Ikawa Y, Kasuga M, Yazaki Y, Aizawa S Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1 Nature 372: 182–186, 1994

    Article  PubMed  CAS  Google Scholar 

  57. Sharma PM, Egawa K, Gustafson TA, Martin JL, Olefsky JM Adenovirus-mediated overexpression of IRS-1 interacting domains abolishes insulin-stimulated mitogenesis without affecting glucose transport in 3T3-L1 adipocytes Mol Cell Biol 17: 7386–7397, 1997

    PubMed  CAS  Google Scholar 

  58. Schreyer S, Ledwig D, Rakatzi I, Kloting I, Eckel J Insulin receptor substrate-4 is expressed in muscle tissue without acting as a substrate for the insulin receptor Endocrinology 144: 1211–1218, 2003

    Article  PubMed  CAS  Google Scholar 

  59. Patti ME, Sun XJ, Bruening JC, Araki E, Lipes MA, White MF, Kahn CR 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice J Biol Chem 270: 24670–24673, 1995

    Article  PubMed  CAS  Google Scholar 

  60. Till M, Kolter T, Eckel J Molecular mechanisms of contraction-induced translocation of GLUT4 in isolated cardiomyocytes Am J Cardiol 4(3A): 85A–89A, 1997

    Google Scholar 

  61. Sharma PM, Egawa K, Huang Y, Martin JL, Huvar I, Boss GR, Olefsky JM Inhibition of phosphatidylinositol 3-kinase activity by adenovirus-mediated gene transfer and its effect on insulin action J Biol Chem 273: 18528–18537, 1998

    Article  PubMed  CAS  Google Scholar 

  62. Van Horn DJ, Myers MG Jr, Backer JM Direct activation of the phosphatidylinositol 3′-kinase by the insulin receptor J Biol Chem 269: 29–32, 1994

    PubMed  Google Scholar 

  63. Rajala RV, McClellan ME, Chan MD, Tsiokas L, Anderson RE Interaction of the retinal insulin receptor beta-subunit with the p85 subunit of phosphoinositide 3-kinase Biochemistry 43: 5637–5650, 2004

    Article  PubMed  CAS  Google Scholar 

  64. Holgado-Madruga M, Emlet DR, Moscatello DK, Godwin AK, Wong AJ A Grb2-associated docking protein in EGF- and insulin-receptor signalling Nature 379: 560–564, 1996

    Article  PubMed  CAS  Google Scholar 

  65. Till M, Ouwens DM, Kessler A, Eckel J Molecular mechanisms of contraction-regulated cardiac glucose transport Biochem J 346: 841–847, 2000

    Article  PubMed  CAS  Google Scholar 

  66. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action J Biol Chem 277: 1531–1537, 2002

    Article  PubMed  CAS  Google Scholar 

  67. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MR, Spiegelman BM IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance Science 271: 665–668, 1996

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The editorial assistance of Mr. Ovid Da Silva, Editor, Research Support Office, Research Centre, CHUM, is acknowledged. A.P. is the recipient of a Canadian Diabetes Association/Canadian Institutes of Health Research Doctoral Student Research Award. M.-H.G. was the recipient of a University of Montreal summer studentship award (COPSE). We thank Miguel Chagnon for his advice on statistical analysis.

Author information

Authors and Affiliations

  1. Montreal Diabetes Research Centre, Centre hospitalier de l’Université de Montréal (CHUM)-Hôtel-Dieu, 3850 St. Urbain, Montreal, Que., Canada, H2W 1T7

    Amélie Pelletier, Annie Tardif, Marie-Hélène Gingras, Jean-Louis Chiasson & Lise Coderre

  2. Department of Medicine, Université de Montréal, Montreal, Que., Canada

    Amélie Pelletier, Annie Tardif, Marie-Hélène Gingras, Jean-Louis Chiasson & Lise Coderre

Authors
  1. Amélie Pelletier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annie Tardif
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marie-Hélène Gingras
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Louis Chiasson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lise Coderre
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lise Coderre.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pelletier, A., Tardif, A., Gingras, MH. et al. Chronic exposure to ketone bodies impairs glucose uptake in adult cardiomyocytes in response to insulin but not vanadate: the role of PI3-K. Mol Cell Biochem 296, 97–108 (2007). https://doi.org/10.1007/s11010-006-9303-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-006-9303-7

Keywords

Search

Navigation