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 Article
  • Published:

Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy

Nature Clinical Practice Cardiovascular Medicine volume 5, pages 715–724 (2008)Cite this article

Abstract

According to the International Diabetes Federation the number of people between the ages of 20 and 79 years diagnosed with diabetes mellitus is projected to reach 380 million worldwide by 2025. Cardiovascular disease, including heart failure, is the major cause of death in patients with diabetes. A contributing factor to heart failure in such patients is the development of diabetic cardiomyopathy—a clinical myocardial condition distinguished by ventricular dysfunction that can present independently of other risk factors such as hypertension or coronary artery disease. This disorder has been associated with both type 1 and type 2 diabetes, and is characterized by early-onset diastolic dysfunction and late-onset systolic dysfunction. The development of diabetic cardiomyopathy and the cellular and molecular perturbations associated with the pathology are complex and multifactorial. Hallmark mechanisms include abnormalities in regulation of calcium homeostasis, and associated abnormal ventricular excitation–contraction coupling, metabolic disturbances, and alterations in insulin signaling. An emerging concept is that disruptions in calcium homeostasis might be linked to diminished insulin responsiveness. An understanding of the cellular effect of these abnormalities on cardiomyocytes should be useful in predicting the maladaptive cardiac structural and functional consequences of diabetes.

Key Points

  • Diabetic cardiomyopathy is defined as a phenotypic myocardial disease distinguished by ventricular dysfunction independent of hypertension or coronary heart disease

  • Diabetic cardiomyopathy is associated with both type 1 and type 2 diabetes mellitus and is characterized by both systolic and diastolic dysfunction

  • Pathogenic factors contributing to the development of diabetic cardiomyopathy include hyperglycemia and elevated fatty acid levels

  • Abnormalities in Ca2+ handling and ventricular excitation-contraction coupling are clearly major contributors to cardiac dysfunction in diabetes, which shows considerable similarities to abnormalities seen in hypertrophic failing hearts

  • Myocardial insulin resistance is associated with abnormal cardiomyocyte excitation-contraction coupling in both type 1 and type 2 diabetes, but a definitive link has not been established

  • Management of traditional risk factors, lifestyle control and insulin treatment might be effective in preventing or delaying the progression of diabetic cardiomyopathy; however, myocardial gene delivery is being pursued as a new therapeutic modality in patients with heart failure

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: Changes in ventricular myocyte excitation–contraction coupling in diabetic cardiomyopathy.
Figure 2: Cardiac action potential waveform and schematic representation of the major contributing ionic currents.
Figure 3: Simplified insulin-receptor-mediated signaling pathways and potential inhibitory mechanisms associated with insulin resistance.

Similar content being viewed by others

References

  1. International Diabetes Federation (online 2006) Diabetes Atlas, 3rd edition [http://www.eatlas.idf.org/media]

  2. Sowers JR et al. (2001) Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 7: 1053–1059

    Article  Google Scholar 

  3. Boudina S and Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115: 3213–3223

    Article  Google Scholar 

  4. Fox CS et al. (2007) Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation 115: 1544–1550

    Article  Google Scholar 

  5. Rubler S et al. (1972) A new type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 30: 595–602

    Article  CAS  Google Scholar 

  6. Galderisi M et al. (1991) Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy (the Framingham Heart Study). Am J Cardiol 68: 85–89

    Article  CAS  Google Scholar 

  7. Severson D (2004) Diabetic cardiomyopathy: recent evidence from mouse models of type 1 and type 2 diabetes. Can J Physiol Pharmacol 82: 813–823

    Article  CAS  Google Scholar 

  8. Poornima IG et al. (2006) Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res 98: 596–605

    Article  CAS  Google Scholar 

  9. Witteles RM and Fowler MB (2008) Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options. J Am Coll Cardiol 51: 93–102

    Article  CAS  Google Scholar 

  10. An D and Rodrigues B (2006) Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 291: H1489–H1506

    Article  CAS  Google Scholar 

  11. Dillmann W (1980) Diabetes mellitus induces changes in cardiac myosin of the rat. Diabetes 29: 579–582

    Article  CAS  Google Scholar 

  12. Malhotra A et al. (1995) Molecular biology of protein kinase C signaling in cardiac myocytes. Mol Cell Biochem 151: 165–172

    Article  CAS  Google Scholar 

  13. Yaras N et al. (2007) Restoration of diabetes-induced abnormal local Ca2+ release in cardiomyocytes by angiotensin II receptor blockade. Am J Physiol Heart Circ Physiol 292: H912–H920

    Article  CAS  Google Scholar 

  14. Ren J and Davidoff AJ (1997) Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes. Am J Physiol 272: H148–H158

    CAS  PubMed  Google Scholar 

  15. Ishikawa T et al. (1999) Alterations in contractile properties and Ca2+ handling in streptozotocin-induced diabetic rat myocardium. Am J Physiol Heart Circ Physiol 277: H2185–H2194

    Article  CAS  Google Scholar 

  16. Jourdon P and Feuvray D (1993) Calcium and potassium currents in ventricular myocytes isolated from diabetic rats. J Physiol 470: 411–429

    Article  CAS  Google Scholar 

  17. Penpargkul S et al. (1981) Depressed cardiac sarcoplasmic reticulum function from diabetic rats. J Mol Cell Cardiol 13: 303–309

    Article  CAS  Google Scholar 

  18. Chattou S et al. (1999) Decrease in sodium–calcium exchange and calcium currents in diabetic rat ventricular myocytes. Acta Physiol Scanda 166: 137–144

    Article  CAS  Google Scholar 

  19. Yaras N et al. (2005) Effects of diabetes on ryanodine receptor Ca release channel (RyR2) and Ca2+ homeostasis in rat heart. Diabetes 54: 3082–3088

    Article  CAS  Google Scholar 

  20. Gando S et al. (1997) Impaired contractile response to beta adrenoceptor stimulation in diabetic rat hearts: alterations in beta adrenoceptors–G protein–adenylate cyclase system and phospholamban phosphorylation. J Pharmacol Exp Ther 282: 475–84

    CAS  PubMed  Google Scholar 

  21. Zhong Y et al. (2001) Altered SR protein expression associated with contractile dysfunction in diabetic rat hearts. Am J Physiol Heart Circ Physiol 281: H1137–H1147

    Article  CAS  Google Scholar 

  22. Shimoni Y et al. (1994) Short-term diabetes alters K+ currents in rat ventricular myocytes. Circ Res 74: 620–628

    Article  CAS  Google Scholar 

  23. Wang DW et al. (1995) Abnormalities of K+ and Ca2+ currents in ventricular myocytes from rats with chronic diabetes. Am J Physiol 269: H1288–H1296

    CAS  PubMed  Google Scholar 

  24. Lu Z et al. (2007) Decreased L-type Ca2+ current in cardiac myocytes of type 1 diabetic Akita mice due to reduced phosphatidylinositol 3-kinase signaling. Diabetes 56: 2780–2789

    Article  CAS  Google Scholar 

  25. Wold LE et al. (2005) Impaired SERCA function contributes to cardiomyocyte dysfunction in insulin resistant rats. J Mol Cell Cardiol 39: 297–307

    Article  CAS  Google Scholar 

  26. Belke DD et al. (2004) Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart. Diabetes 53: 3201–3208

    Article  CAS  Google Scholar 

  27. Trost SU et al. (2002) Overexpression of the sarcoplasmic reticulum Ca(2+)-ATPase improves myocardial contractility in diabetic cardiomyopathy. Diabetes 51: 1166–1171

    Article  CAS  Google Scholar 

  28. del Monte F et al. (1999) Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation 100: 2308–2311

    Article  CAS  Google Scholar 

  29. Hattori Y et al. (2000) Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload. J Physiol 527: 85–94

    Article  CAS  Google Scholar 

  30. Pereira L et al. (2006) Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice. Diabetes 55: 608–615

    Article  CAS  Google Scholar 

  31. Schaffer SW et al. (1997) Mechanisms underlying depressed Na+/Ca2+ exchanger activity in the diabetic heart. Cardiovasc Res 34: 129–136

    Article  CAS  Google Scholar 

  32. Ranu HK et al. (2002) Effects of Na+/Ca2+-exchanger overexpression on excitation-contraction coupling in adult rabbit ventricular myocytes. J Mol Cell Cardiol 34: 389–400

    Article  CAS  Google Scholar 

  33. Dutta K et al. (2002) Depressed PKA activity contributes to impaired SERCA function and is linked to the pathogenesis of glucose-induced cardiomyopathy. J Mol Cell Cardiol 34: 985–996

    Article  CAS  Google Scholar 

  34. Marks AR (2001) Ryanodine receptors/calcium release channels in heart failure and sudden cardiac death. J Mol Cell Cardiol 33: 615–624

    Article  CAS  Google Scholar 

  35. Boudina S and Abel ED (2006) Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology 21: 250–258

    Article  CAS  Google Scholar 

  36. Nisoli E et al. (2007). Defective mitochondrial biogenesis: a hallmark of the high cardiovascular risk in the metabolic syndrome? Circ Res 100: 795–806

    Article  CAS  Google Scholar 

  37. Szabadkai G and Duchen MR (2008) Mitochondria: the hub of cellular Ca2+ signaling. Physiology 23: 84–94

    Article  CAS  Google Scholar 

  38. Malhotra A and Sanghi V (1997) Regulation of contractile proteins in diabetic heart. Cardiovasc Res 34: 34–40

    Article  CAS  Google Scholar 

  39. Jweied EE et al. (2005) Depressed cardiac myofilament function in human diabetes mellitus. Am J Physiol Heart Circ Physiol 289: H2478–H2483

    Article  CAS  Google Scholar 

  40. Shimoni Yand Liu XF (2003) Role of PKC in autocrine regulation of rat ventricular K+ currents by angiotensin and endothelin. Am J Physiol Heart Circ Physiol 284: H1168–H1181

    Article  Google Scholar 

  41. Akella AB et al. (1995) Diminished Ca2+ sensitivity of skinned cardiac muscle contractility coincident with troponin T-band shifts in the diabetic rat. Circ Res 76: 600–606

    Article  CAS  Google Scholar 

  42. Susic D et al. (2004) Collagen cross-link breakers: a beginning of a new era in the treatment of cardiovascular changes associated with aging, diabetes, and hypertension. Curr Drug Targets Cardiovasc Haematol Disord 4: 97–101

    Article  CAS  Google Scholar 

  43. Bidasee KR et al. (2004) Diabetes increases formation of advanced glycation end products on sarco(endo)plasmic reticulum Ca2+-ATPase. Diabetes 53: 463–473

    Article  CAS  Google Scholar 

  44. Bidasee KR et al. (2003) Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/calcium-release channels. Diabetes 52: 1825–1836

    Article  CAS  Google Scholar 

  45. Fülöp N et al. (2007) Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system. Cardiovasc Res 73: 288–297

    Article  Google Scholar 

  46. Fein FS et al. (1981) Reversibility of diabetic cardiomyopathy with insulin in rats. Circ Res 49: 1251–1261

    Article  CAS  Google Scholar 

  47. Abel ED (2005) Myocardial insulin resistance and cardiac complications of diabetes. Curr Drug Targets Immune Endocr Metabol Disord 5: 219–226

    Article  CAS  Google Scholar 

  48. Davidoff AJ (2006) Convergence of glucose- and fatty acid-induced abnormal myocardial excitation-contraction coupling and insulin signalling. Clin Exp Pharmacol Physiol 33: 152–158

    Article  CAS  Google Scholar 

  49. Ouwen DM and Diamant M (2007) Myocardial insulin action and the contribution of insulin resistance to the pathogenesis of diabetic cardiomyopathy. Arch Physiol Biochem 113: 76–86

    Article  Google Scholar 

  50. Morisco C et al. (2006) Insulin resistance and cardiovascular risk: new insights from molecular and cellular biology. Trends Cardiovasc Med. 16: 183–188

    Article  CAS  Google Scholar 

  51. Belke DD et al. (2002) Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest 109: 629–639

    Article  CAS  Google Scholar 

  52. McQueen AP et al. (2005) Contractile dysfunction in hypertrophied hearts with deficient insulin receptor signaling: possible role of reduced capillary density. J Mol Cell Cardiol 39: 882–892

    Article  CAS  Google Scholar 

  53. Krook A et al. (2000) Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49: 284–292

    Article  CAS  Google Scholar 

  54. Kolter T et al. (1997) Molecular analysis of insulin resistance in isolated ventricular cardiomyocytes of obese Zucker rats. Am J Physiol Endocrinol Metab 273: E59–E67

    Article  CAS  Google Scholar 

  55. Petersen KF and Shulman GI (2006) Etiology of insulin resistance. Am J Med 119 (Suppl 1): S10–S16

    Article  Google Scholar 

  56. O'Neill BT et al. (2007) A conserved role for phosphatidylinositol 3-kinase but not Akt signaling in mitochondrial adaptations that accompany physiological cardiac hypertrophy. Cell Metab 6: 294–306

    Article  CAS  Google Scholar 

  57. Hart GW et al. (2007) Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446: 1017–1022

    Article  CAS  Google Scholar 

  58. Sakata S et al. (2006) Mechanical and metabolic rescue in a type II diabetes model of cardiomyopathy by targeted gene transfer. Mol Ther 13: 987–996

    Article  CAS  Google Scholar 

  59. Algenstaedt P et al. (1997) Insulin receptor substrate proteins create a link between the tyrosine phosphorylation cascade and the Ca2+-ATPases in muscle and heart. J Biol Chem 272: 23696–23702

    Article  CAS  Google Scholar 

  60. Ouwens DM et al. (2005) Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia 48: 1229–1237

    Article  CAS  Google Scholar 

  61. Davidoff AJ et al. (2004) Diabetic cardiomyocyte dysfunction and myocyte insulin resistance: role of glucose-induced PKC activity. Mol Cell Biochem 262: 155–163

    Article  CAS  Google Scholar 

  62. Yu J et al. (2006) Insulin improves cardiomyocyte contractile function through enhancement of SERCA2a activity in simulated ischemia/reperfusion. Acta Pharmacol Sin 27: 919–926

    Article  CAS  Google Scholar 

  63. Michael A et al. (2004) Glycogen synthase kinase-3β regulates growth, calcium homeostasis, and diastolic function in the heart. J Biol Chem 279: 21383–21393

    Article  CAS  Google Scholar 

  64. Von Lewinski D et al. (2005) Insulin causes [Ca2+]i-dependent and [Ca2+]i-independent positive inotropic effects in failing human myocardium. Circulation 111: 2588–2595

    Article  CAS  Google Scholar 

  65. Jo SH et al. (2002) Phosphatidylinositol 3-kinase functionally compartmentalizes the concurrent G(s) signaling during β2-adrenergic stimulation. Circ Res 91: 46–53

    Article  CAS  Google Scholar 

  66. Condorelli G et al. (2002) Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci USA 99: 12333–12338

    Article  CAS  Google Scholar 

  67. Crackower MA et al. (2002) Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110: 737–749

    Article  CAS  Google Scholar 

  68. Kerfant BG et al. (2005) Cardiac sarcoplasmic reticulum calcium release and load are enhanced by subcellular cAMP elevations in PI3Kgamma-deficient mice. Circ Res 96: 1079–1086

    Article  CAS  Google Scholar 

  69. Rota M et al. (2005) Nuclear targeting of Akt enhances ventricular function and myocyte contractility. Circ Res 97: 1332–1341

    Article  CAS  Google Scholar 

  70. Kim YK et al. (2003) Mechanism of enhanced cardiac function in mice with hypertrophy induced by overexpressed Akt. J Biol Chem 278: 47622–47628

    Article  CAS  Google Scholar 

  71. Sun H et al. (2006) Insulin-like growth factor-1 and PTEN deletion enhance cardiac L-type Ca2+ currents via increased PI3Kalpha/PKB signaling. Circ Res 98: 1390–1397

    Article  CAS  Google Scholar 

  72. Paternostro G et al. (1999) Insulin resistance in patients with cardiac hypertrophy. Cardiovasc Res 42: 246–253

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by the following grants from the National Institutes of Health: R01 HL078691; HL057263; HL071763; HL080498; HL083156; K01 HL076659 (DL); HL078731 (RJH, DL); and HL66895 (AJD). This work was also supported by a Leducq Transatlantic Network grant (RJH) and a grant from the American Diabetes Association (7-04-RA-23; AJD).

Author information

Authors and Affiliations

  1. D Lebeche is Assistant Professor of Medicine (Cardiology) and RJ Hajjar is the Arthur and Janet C Professor of Medicine and Director, both at the Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY.,

    Djamel Lebeche & Roger J Hajjar

  2. Department of Pharmacology, AJ Davidoff is Professor and Associate Chair of Research, at the University of New England College of Osteopathic Medicine, Biddeford, ME, USA.,

    Amy J Davidoff

Authors
  1. Djamel Lebeche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amy J Davidoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roger J Hajjar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Djamel Lebeche.

Ethics declarations

Competing interests

RJ Hajjar is a stockholder for and a patent holder/applicant for both Celladon and Nanocor. The other authors declared no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lebeche, D., Davidoff, A. & Hajjar, R. Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy. Nat Rev Cardiol 5, 715–724 (2008). https://doi.org/10.1038/ncpcardio1347

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio1347

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing