Cardiovascular Toxicology

, Volume 5, Issue 3, pp 285–292 | Cite as

Cardiomyocyte dysfunction in models of type 1 and type 2 diabetes

  • Patricia M. Kralik
  • Gang Ye
  • Naira S. Metreveli
  • Xia Shen
  • Paul N. Epstein
Original Research


Cardiomyopathy is a major cause of mortality for both type 1 and 2 diabetic patients. However, experimental analysis of diabetic cardiomyopathy has focused on type 1 diabetes and there are few reports on cardiomyocyte dysfunction in the widely used type 2 diabetic model, db/db. In the current study, we assessed function in isolated ventricular myocytes from type 1 diabetic OVE26 mice and from type 2 diabetic db/db mice. When compared with their respective control strains, both diabetic models showed significant impairment in contractility, as assessed by percent peak shortening, maximal rate of contraction, and maximal rate of relaxation. The calcium decay rate was also significantly reduced in both types of diabetes, but the decrement was much greater in OVE26 myocytes, approx 50% vs only 20% in db/db myocytes. To understand the basis for slow calcium decay in diabetic myocytes and to understand the molecular basis for the quantitative difference between calcium decay in OVE26 and db/db myocytes, we measured cardiac content of the SERCA2a calcium pump. SERCA2a was significantly decreased in OVE26 diabetic myocytes but not reduced at all in db/db myocytes. The reduction of SERCA2a in OVE26 myocytes was completely prevented by overexpression of the antioxidant protein metallothionein, confirming that oxidative stress is an important component of diabetic cardiomyopathy. The current results demonstrate that though contractility is impaired in individual myocytes of db/db hearts and deficits are similar to what is seen in a severe model of type 1 diabetes, impairment in calcium reuptake is less severe, probably as a result of maintenance of normal levels of SERCA2a.

Key Words

Diabetes cardiomyopathy cardiomyocytes db/db mice SERCA2a oxidative stress calcium 


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  1. 1.
    Rubler, S., Dlugash, J., Yuceoglu, Y.Z., Kumral, T., Branwood, A.W., and Grishman, A. (1972). New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am. J. Cardiol. 30:595–602.PubMedCrossRefGoogle Scholar
  2. 2.
    Kannel, W.B., Hjortland, M., and Castelli, W.P. (1974). Role of diabetes in congestive heart failure: the Framingham study. Am. J. Cardiol. 34:29–34.PubMedCrossRefGoogle Scholar
  3. 3.
    Shehadeh, A. and Regan, T.J. (1995). Cardiac consequences of diabetes mellitus. Clin. Cardiol. 18:301–305.PubMedCrossRefGoogle Scholar
  4. 4.
    Uusitupa, M.I., Mustonen, J.N., and Airaksinen, K.E., (1990). Diabetic heart muscle disease. Ann. Med. 22: 377–386.PubMedGoogle Scholar
  5. 5.
    Tomlinson, K.C., Gardiner, S.M., Hebden, R.A., and Bennett, T. (1992). Functional consequences of streptozotocin-induced diabetes mellitus, with particular reference to the cardiovascular system. Pharmacol. Rev. 44:103–150.PubMedGoogle Scholar
  6. 6.
    Duan, J., Zhang, H.Y., Adkins, S.D., Ren, B.H., Norby, F.L., Zhang, X., et al. (2003). Impaired cardiac function and IGF-Iresponse in myocytes from calmodulin-diabetic mice: role of Akt and RhoA. Am. J. Physiol. Endocrinol. Metab. 284:E366-E376.PubMedGoogle Scholar
  7. 7.
    Ye, G., Metreveli, N.S., Ren, J., and Epstein, P.N. (2003). Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes 52:777–783.PubMedCrossRefGoogle Scholar
  8. 8.
    Wyse, B.M. and Dulin, W.E. (1970). The influence of age and dietary conditions on diabetes in the db mouse. Diabetologia 6:268–273.PubMedCrossRefGoogle Scholar
  9. 9.
    Belke, D.D., Larsen, T.S., Gibbs, E.M., and Severson, D.L. (2000). Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am. J. Physiol. Endocrinol. Metab. 279:E1104-E1113.PubMedGoogle Scholar
  10. 10.
    Severson, D.L., Larsen, T.S., and Belke, D.D. (1999). Cardiac function in perfused hearts from diabetic and transgenic mice. Winnipeg International Conference on Diabetes and Cardiovascular Disease, S50.Google Scholar
  11. 11.
    Aasum, E., Belke, D.D., Severson, D.L., Riemersma, R.A., Cooper, M., Andreassen, M., and Larsen, T.S. (2002). Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator. Am. J. Physiol. Heart Circ. Physiol. 283:H949-H957.PubMedGoogle Scholar
  12. 12.
    Periasamy, M. and Huke, S. (2001). SERCA pump level is a critical determinant of Ca(2+)homeostasis and cardiac contractility. J. Mol. Cell. Cardiol. 33:1053–1063.PubMedCrossRefGoogle Scholar
  13. 13.
    Pieske, B., Maier, L.S., and Schmidt-Schweda, S. (2002). Sarcoplasmic reticulum Ca2+ load in human heart failure. Basic Res. Cardiol. 97(Suppl. 1):I63-I71.PubMedGoogle Scholar
  14. 14.
    Meyer, M., Schillinger, W., Pieske, B., Holubarsch, C., Heilmann, C., Posival, H., et al. (1995). Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 92:778–784.PubMedGoogle Scholar
  15. 15.
    Ganguly, P.K., Pierce, G.N., Dhalla, K.S., and Dhalla, N.S. (1983). Detective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy. Am. J. Physiol. 244:E528-E535.PubMedGoogle Scholar
  16. 16.
    Teshima, Y., Takahashi, N., Saikawa, T., Hara, M., Yasunaga, S., Hidaka, S., et al. (2000). Diminished expression of sarcoplasmic reticulum Ca(2+)-ATPase and ryanodine sensitive Ca(2+) channel mRNA in streptozotocin-induced diabetic rat heart. J. Mol. Cell. Cardiol. 32:655–664.PubMedCrossRefGoogle Scholar
  17. 17.
    Epstein, P.N., Overbeek, P.A., and Means, A.R. (1989). Calmodulin-induced early-onset diabetes in transgenic mice. Cell 58:1067–1073.PubMedCrossRefGoogle Scholar
  18. 18.
    Liang, Q., Carlson, E.C., Donthi, R.V., Kralik, P.M., Shen, X., and Epstein, P.N. (2002). Overexpression of metallothionein reduces diabetic cardiomyopathy. Diabetes 51:174–181.PubMedCrossRefGoogle Scholar
  19. 19.
    Munch, G., Bolck, B., Hoischen, S., Brixius, K., Bloch, W., Reuter, H., et al. (1998). Unchanged protein expression of sarcoplasmic reticulum Ca2+-ATPase, phospholamban, and calsequestrin in terminally failing human myocardium. J. Mol. Med. 76:434–441.PubMedCrossRefGoogle Scholar
  20. 20.
    Ye, G., Metreveli, N.S., Donthi, R.V. Xia, S., Xu, M., Carlson, E.C., et al. (2004). Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. Diabetes 53:1336–1343.PubMedCrossRefGoogle Scholar
  21. 21.
    Ren, J., Sowers, J.R., Walsh, M.F., and Brown, R.A. (2000). Reduced contractile response to insulin and IGF-I in ventricular myocytes from genetically obese Zucker rats. Am. J. Physiol. Heart Circ. Physiol. 279:H1708-H1714.PubMedGoogle Scholar
  22. 22.
    Belke, D.D., Swanson, E.A., and Dillmann, W.H. (2004). Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart. Diabetes 53:3201–3208.PubMedCrossRefGoogle Scholar
  23. 23.
    Bidasee, K.R., Zhang, Y., Shao, C.H., Wang, M., Patel, K.P., Dincer, U.D., et al. (2004). Diabetes increases formation of advanced glycation end products on Sarco(endo) plasmic reticulum Ca2+-ATPase. Diabetes 53:463–473.PubMedCrossRefGoogle Scholar
  24. 24.
    Clark, R.J., McDonough, P.M., Swanson, E., Trost, S.U., Suzuki, M., Fukuda, M., et al. (2003). Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J. Biol. Chem. 278:44230–44237.PubMedCrossRefGoogle Scholar
  25. 25.
    Pelzer, T., Jazbutyte, V., Arias-Loza, P.A., Segerer, S., Lichtenwald, M., Law, M.P., et al. (2005). Pioglitazone reverses down-regulation of cardiac PPARgamma expression in Zucker diabetic fatty rats. Biochim. Biophys. Res. Commun. 329:726–732.CrossRefGoogle Scholar
  26. 26.
    Marfella, R., D'Amico, M., Di, F.C., Piegari, E., Nappo, F., Esposito, K., et al. (2002). Myocardial infarction in diabetic rats: role of hyperglycaemia in infarct size and early expression of hypoxia-inducible factor 1. Diabetologia 45:1172–1181.PubMedCrossRefGoogle Scholar
  27. 27.
    Nishikawa, T., Edelstein, D., Du, X.L., Yamagishi, S., Matsumura, T., Kaneda, Y., et al. (2000). Normalizing mitochondiral superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790.PubMedCrossRefGoogle Scholar
  28. 28.
    Marra, G., Cotroneo, P., Pitocco, D., Manto, A., Di Leo, M.A., Ruotolo, V., et al. (2002). Early increase of oxidative stress and reduced antioxidant defenses in patients with uncomplicated type 1 diabetes: a case for gender diffrence. Diabetes Care 25:370–375.PubMedCrossRefGoogle Scholar
  29. 29.
    Trost, S.U., Belke, D.D., Bluhm, W.F., Meyer, M., Swanson, E., and Dillmann, W.H. (2002). Overexpression of the sarcoplasmic reticulum Ca(2+)-ATPase improves myocardial contractility in diabetic cardiomyopathy. Diabetes 51:1166–1171.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Patricia M. Kralik
  • Gang Ye
  • Naira S. Metreveli
  • Xia Shen
  • Paul N. Epstein

There are no affiliations available

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