Journal of Cardiac Failure
Volume 16, Issue 9 , Pages 761-768 , September 2010

Impaired Glucose Tolerance and Insulin Resistance in Heart Failure: Underrecognized and Undertreated?

  • Mamas A. Mamas, MA, DPhil, MRCP

      Affiliations

    • Manchester Royal Infirmary, Biomedical Research Centre, Manchester, UK
    • Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
    • Corresponding Author InformationReprint requests: Dr Mamas A. Mamas, Clinical Lecturer in Cardiology, Manchester Heart Centre, Manchester Royal Infirmary, Manchester, M13 9PT, UK. Tel: +44 (0)161 275 5672; Fax: +44 (0)161 275 5669.
    • ,
  • Christi Deaton, PhD, RN

      Affiliations

    • Manchester Royal Infirmary, Biomedical Research Centre, Manchester, UK
    • Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
    • ,
  • Martin K. Rutter, MD, MRCP

      Affiliations

    • Manchester Royal Infirmary, Biomedical Research Centre, Manchester, UK
    • Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
    • Manchester Diabetes Centre, Manchester, UK
    • ,
  • Martin Yuille, MA, PhD, FRCPath

      Affiliations

    • Centre for Integrated Genomic Medical Research, University of Manchester, UK
    • ,
  • Simon G. Williams, MD, MRCP

      Affiliations

    • University Hospital of South Manchester, Wythenshawe Hospital, Manchester, UK
    • ,
  • Simon G. Ray, MD, FRCP

      Affiliations

    • Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
    • University Hospital of South Manchester, Wythenshawe Hospital, Manchester, UK
    • ,
  • John New, MD, MRCP

      Affiliations

    • Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
    • Salford Royal NHS Foundation Trust, Salford, UK
    • ,
  • J. Martin Gibson, MD, PhD, FRCP

      Affiliations

    • Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
    • Salford Royal NHS Foundation Trust, Salford, UK
    • ,
  • Ludwig Neyses, MD, FRCP

      Affiliations

    • Manchester Royal Infirmary, Biomedical Research Centre, Manchester, UK
    • Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

Received 2 October 2009 ,Revised 12 May 2010 ,Accepted 18 May 2010.

References 

  1. Leyden E. Asthma and diabetes mellitus. Zeutschr Klin Med. 1881;3:358–364
  2. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: The Framingham study. Am J Cardiol. 1974;34:29–34
  3. Thrainsdottir IS, Aspelund T, Thorgeirsson G, Gudnason V, Hardarson T, Malmberg K, et al. The association between glucose abnormalities and heart failure in the population-based Reykjavik study. Diabetes Care. 2005;28:612–616
  4. Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey1988-1994. Diabetes Care. 1998;21:518–524
  5. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola VP, et al. EuroHeart Survey Investigators; Heart Failure Association, European Society of Cardiology EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;27:2725–2736
  6. Adams KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, et al. ADHERE Scientific Advisory Committee and Investigators Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005;149:209–216
  7. MacDonald MR, Petrie MC, Hawkins NM, Petrie JR, Fisher M, McKelvie R, et al. Diabetes, left ventricular systolic dysfunction, and chronic heart failure. Eur Heart J. 2008;29:1224–1240
  8. MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, et al. CHARM Investigators Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J. 2008;29:1377–1385
  9. Domanski M, Krause-Steinrauf H, Deedwania P, Follmann D, Ghali JK, Gilbert E, et al. The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial. J Am Coll Cardiol. 2003;42:914–922
  10. Shindler DM, Kostis JB, Yusuf S, Quinones MA, Pitt B, Stewart D, et al. Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) Trials and Registry. Am J Cardiol. 1996;77:1017–1020
  11. Suskin N, McKelvie RS, Burns RJ, Latini R, Pericak D, Probstfield J, et al. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J. 2000;21:1368–1375
  12. Witteles RM, Tang WH, Jamali AH, Chu JW, Reaven GM, Fowler MB. Insulin resistance in idiopathic dilated cardiomyopathy: a possible etiologic link. J Am Coll Cardiol. 2004;44:78–81
  13. Swan JW, Anker SD, Walton C, Godsland IF, Clark AL, Leyva F, et al. Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure. J Am Coll Cardiol. 1997;30:527–532
  14. Goode KM, John J, Rigby AS, Kilpatrick ES, Atkin SL, Bragadeesh T, et al. Elevated glycated haemoglobin is a strong predictor of mortality in patients with left ventricular systolic dysfunction who are not receiving treatment for diabetes mellitus. Heart. 2009;95:917–923
  15. Berry C, Brett M, Stevenson K, McMurray JJ, Norrie J. Nature and prognostic importance of abnormal glucose tolerance and diabetes in acute heart failure. Heart. 2008;94:296–304
  16. Dunkelgrun M, Schreiner F, Schockman DB, Hoeks SE, Feringa HH, Goei D, et al. Usefulness of preoperative oral glucose tolerance testing for perioperative risk stratification in patients scheduled for elective vascular surgery. Am J Cardiol. 2008;101:526–529
  17. Lankisch M, Futh R, Schotes D, Rose B, Lapp H, Rathmann W, et al. High prevalence of undiagnosed impaired glucose regulation and diabetes mellitus in patients scheduled for an elective coronary angiography. Clin Res Cardiol. 2006;95:80–87
  18. Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Hata T, et al. Is admission hyperglycemia in non-diabetic patients with acute myocardial infarction a surrogate for previously undiagnosed abnormal glucose tolerance?. Eur Heart J. 2006;27:2413–2419
  19. Motala AA, Omar MA. The value of glycosylated haemoglobin as a substitute for the oral glucose tolerance test in the detection of impaired glucose tolerance (IGT). Diabetes Res Clin Pract. 1992;17:199–207
  20. Salmasi AM, Dancy M. The glucose tolerance test, but not HbA(1c), remains the gold standard in identifying unrecognized diabetes mellitus and impaired glucose tolerance in hypertensive subjects. Angiology. 2005;56:571–579
  21. Mannucci E, Ognibene A, Sposato I, Brogi M, Gallori G, Bardini G, et al. Fasting plasma glucose and glycated haemoglobin in the screening of diabetes and impaired glucose tolerance. Acta Diabetol. 2003;40:181–186
  22. Doehner W, Rauchhaus M, Ponikowski P, Godsland IF, von Haehling S, Okonko DO, et al. Impaired insulin sensitivity as an independent risk factor for mortality in patients with stable chronic heart failure. J Am Coll Cardiol. 2005;46:1019–1026
  23. Tassone F, Gianotti L, Rolfo F, Visconti G, Borretta G, Feola M. B-type natriuretic peptide levels and insulin resistance in patients with severe ischemic myocardial dysfunction. J Endocrinol Invest. 2009 Mar 25;[Epub ahead of print]
  24. Gerstein HC, Swedberg K, Carlsson J, McMurray JJ, Michelson EL, Olofsson B, et al. CHARM Program Investigators The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program. Arch Intern Med. 2008;168:1699–1704
  25. Kosiborod M, Inzucchi SE, Spertus JA, Wang Y, Masoudi FA, Havranek EP, et al. Elevated admission glucose and mortality in elderly patients hospitalized with heart failure. Circulation. 2009;119:1899–1907
  26. Knudsen EC, Seljeflot I, Abdelnoor M, Eritsland J, Mangschau A, Arnesen H, et al. Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction—a cohort study on 224 patients. Cardiovasc Diabetol. 2009;8:6
  27. Ingelsson E, Sundström J, Arnlöv J, Zethelius B, Lind L. Insulin resistance and risk of congestive heart failure. JAMA. 2005;294:334–341
  28. Thrainsdottir IS, Aspelund T, Hardarson T, Malmberg K, Sigurdsson G, Thorgeirsson G, et al. Glucose abnormalities and heart failure predict poor prognosis in the population-based Reykjavík Study. Eur J Cardiovasc Prev Rehabil. 2005;12:465–471
  29. Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L, Anderson C, et al. ONTARGET/TRANSCEND Investigators Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk. Circulation. 2007;115:1371–1375
  30. Amato L, Paolisso G, Cacciatore F, Ferrara N, Ferrara P, Canonico S, et al. Congestive heart failure predicts the development of non-insulin-dependent diabetes mellitus in the elderly. The Osservatorio Geriatrico Regione Campania Group. Diabetes Metab. 1997;23:213–218
  31. Yusuf S, Ostergren JB, Gerstein HC, Pfeffer MA, Swedberg K, Granger CB, et al. Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity Program Investigators Effects of candesartan on the development of a new diagnosis of diabetes mellitus in patients with heart failure. Circulation. 2005;112:48–53
  32. Tenenbaum A, Motro M, Fisman EZ, Leor J, Freimark D, Boyko V, et al. Functional class in patients with heart failure is associated with the development of diabetes. Am J Med. 2003;114:271–275
  33. Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005;96:939–949
  34. Mamas MA, Neyses L. Cardiac metabolism; from bench to bedside diabetic cardiomyopathy, a disease of cardiac metabolism?. In:  Rowlands D,  Clarke B editor. Recent Advances in Cardiology. London, UK: Royal Society of Medicine Press Ltd; 2007;p. 27–39
  35. Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation. 2007;116:434–448
  36. Witteles RM, Fowler MB. Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options. J Am Coll Cardiol. 2008;51:93–102
  37. Matsuzawa Y. Therapy insight: adipocytokines in metabolic syndrome and related cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2006;3:35–42
  38. Katagiri H, Yamada T, Oka Y. Adiposity and cardiovascular disorders: disturbance of the regulatory system consisting of humoral and neuronal signals. Circ Res. 2007;101:27–39
  39. Mathieu P, Lemieux I, Després JP. Obesity, inflammation, and cardiovascular risk. Clin Pharmacol Ther. 2010;87:407–416
  40. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409:307–312
  41. Jung HS, Park KH, Cho YM, Chung SS, Cho HJ, Cho SY, et al. Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardiovasc Res. 2006;69:76–85
  42. Bertrand L, Horman S, Beauloye C, Vanoverschelde JL. Insulin signalling in the heart. Cardiovasc Res. 2008;79:238–248
  43. Luo Z, Zhang Y, Li F, He J, Ding H, Yan L, et al. Resistin induces insulin resistance by both AMPK-dependent and AMPK-independent mechanisms in HepG2 cells. Endocrine. 2009;36:60–69
  44. Gentile MT, Vecchione C, Marino G, Aretini A, Di Pardo A, Antenucci G, et al. Resistin impairs insulin-evoked vasodilation. Diabetes. 2008;57:577–583
  45. Frankel DS, Vasan RS, Sr D'Agostino RB, Benjamin EJ, Levy D, Wang TJ, et al. Resistin, adiponectin, and risk of heart failure the Framingham offspring study. J Am Coll Cardiol. 2009;53:754–762
  46. Butler J, Kalogeropoulos A, Georgiopoulou V, de Rekeneire N, Rodondi N, Smith AL, et al. Health ABC Study Serum resistin concentrations and risk of new onset heart failure in older persons: the health, aging, and body composition (Health ABC) study. Arterioscler Thromb Vasc Biol. 2009;29:1144–1149
  47. Takeishi Y, Niizeki T, Arimoto T, Nozaki N, Hirono O, Nitobe J, et al. Serum resistin is associated with high risk in patients with congestive heart failure—a novel link between metabolic signals and heart failure. Circ J. 2007;71:460–464
  48. Kim M, Oh JK, Sakata S, Liang I, Park W, Hajjar RJ, et al. Role of resistin in cardiac contractility and hypertrophy. J Mol Cell Cardiol. 2008;45:270–280
  49. An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2006;291:H1489–H1506
  50. Luiken JJ, Coort SL, Koonen DP, van der Horst DJ, Bonen A, Zorzano A, et al. Regulation of cardiac long-chain fatty acid and glucose uptake by translocation of substrate transporters. Pflugers Arch. 2004;448:1–15
  51. Grundleger ML, Thenen SW. Decreased insulin binding, glucose transport, and glucose metabolism in soleus muscle of rats fed a high fat diet. Diabetes. 1982;31:232–237
  52. Finck BN, Kelly DP. Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart. J Mol Cell Cardiol. 2002;34:1249–1257
  53. Finck BN. The role of the peroxisome proliferator-activated receptor alpha pathway in pathological remodeling of the diabetic heart. Curr Opin Clin Nutr Metab Care. 2004;7:391–396
  54. Pillutla P, Hwang YC, Augustus A, Yokoyama M, Yagyu H, Johnston TP, et al. Perfusion of hearts with triglyceride-rich particles reproduces the metabolic abnormalities in lipotoxic cardiomyopathy. Am J Physiol Endocrinol Metab. 2005;288:E1229–E1235
  55. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A. 2000;97:1784–1789
  56. Tuunanen H, Engblom E, Naum A, Scheinin M, Nagren K, Airaksinen J, et al. Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction. J Card Fail. 2006;12:644–652
  57. Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, Kisrieva-Ware Z, et al. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation. 2004;109:2191–2196
  58. Yazaki Y, Isobe M, Takahashi W, Kitabayashi H, Nishiyama O, Sekiguchi M, et al. Assessment of myocardial fatty acid metabolic abnormalities in patients with idiopathic dilated cardiomyopathy using 123I BMIPP SPECT: correlation with clinicopathological findings and clinical course. Heart. 1999;81:153–159
  59. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007;100:328–341
  60. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854–865
  61. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation. 2005;111:583–590
  62. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005;28:2345–2351
  63. EMC. Glucophage 500 mg and 850 mg film coated tablets. Available online at: http://emc.medicines.org.uk/document.aspx?documentId=1043#contraindications. Accessed July 3, 2009.
  64. Shaw JS, Wilmot RL, Kilpatrick ES. Establishing pragmatic estimated GFR thresholds to guide metformin prescribing. Diabet Med. 2007;24:1160–1163
  65. Wong AK, AlZadjali MA, Choy AM, Lang CC. Insulin resistance: a potential new target for therapy in patients with heart failure. Cardiovasc Ther. 2008;26:203–213
  66. Kay L, Finelli C, Aussedat J, et al. Improvement of long-term preservation of the isolated arrested rat heart by trimetazidine: effects on the energy state and mitochondrial function. Am J Cardiol. 1995;76:45B–49B
  67. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000;86:580–588
  68. Tuunanen H, Engblom E, Naum A, Någren K, Scheinin M, Hesse B, et al. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation. 2008;118:1250–1258
  69. Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, et al. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol. 2006;48:992–998
  70. Nauck MA. Unraveling the science of incretin biology. Am J Med. 2009;122:S3–10
  71. Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L, et al. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004;110:955–961
  72. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006;12:694–699

 See page 766 for disclosure information.

PII: S1071-9164(10)00249-6

doi: 10.1016/j.cardfail.2010.05.027

Journal of Cardiac Failure
Volume 16, Issue 9 , Pages 761-768 , September 2010

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