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. 1996 Nov 1;98(9):2094–2099. doi: 10.1172/JCI119015

Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease. A study with positron emission tomography.

G Paternostro 1, P G Camici 1, A A Lammerstma 1, N Marinho 1, R R Baliga 1, J S Kooner 1, G K Radda 1, E Ferrannini 1
PMCID: PMC507654  PMID: 8903329

Abstract

Patients with coronary artery disease or heart failure have been shown to be insulin resistant. Whether in these patients heart muscle participates in the insulin resistance, and whether reduced blood flow is a mechanism for such resistance is not known. We measured heart and skeletal muscle blood flow and glucose uptake during euglycemic hyperinsulinemia (insulin clamp) in 15 male patients with angiographically proven coronary artery disease and chronic regional wall motion abnormalities. Six age- and weight-matched healthy subjects served as controls. Regional glucose uptake was measured by positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose (FDG), blood flow was measured by the H2(15)O method. Myocardial glucose utilization was measured in regions with normal perfusion and wall motion as assessed by radionuclide ventriculography. Whole-body glucose uptake was 37+/-4 micromol x min(-1) x kg(-1) in controls and 14+/-2 mciromol x min(-1) x kg(-1) in patients (P = 0.001). Myocardial blood flow (1.09+/-0.06 vs. 0.97+/-0.04 ml x min(-1) x g(-1), controls vs. patients) and skeletal muscle (arm) blood flow (0.046+/-0.012 vs. 0.043+/-0.006 ml x min(-1) x g(-1)) were similar in the two groups (P = NS for both). In contrast, in patients both myocardial (0.38+/-0.03 vs. 0.70+/-0.03 micromol x min(-1) x g(-1), P = 0.0005) and muscle glucose uptake (0.026+/-0.004 vs. 0.056+/-0.006 micromol x min(-1) x g(-1), P = 0.005) were markedly reduced in comparison with controls. In the whole dataset, a direct relationship existed between insulin-stimulated glucose uptake in heart and skeletal muscle. Patients with a history of myocardial infarction and a low ejection fraction are insulin resistant. This insulin resistance affects both the myocardium and skeletal muscle and is independent of blood flow.

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Selected References

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  1. Annuzzi G., Riccardi G., Capaldo B., Kaijser L. Increased insulin-stimulated glucose uptake by exercised human muscles one day after prolonged physical exercise. Eur J Clin Invest. 1991 Feb;21(1):6–12. doi: 10.1111/j.1365-2362.1991.tb01351.x. [DOI] [PubMed] [Google Scholar]
  2. Araujo L. I., Lammertsma A. A., Rhodes C. G., McFalls E. O., Iida H., Rechavia E., Galassi A., De Silva R., Jones T., Maseri A. Noninvasive quantification of regional myocardial blood flow in coronary artery disease with oxygen-15-labeled carbon dioxide inhalation and positron emission tomography. Circulation. 1991 Mar;83(3):875–885. doi: 10.1161/01.cir.83.3.875. [DOI] [PubMed] [Google Scholar]
  3. Bonadonna R. C., Saccomani M. P., Seely L., Zych K. S., Ferrannini E., Cobelli C., DeFronzo R. A. Glucose transport in human skeletal muscle. The in vivo response to insulin. Diabetes. 1993 Jan;42(1):191–198. doi: 10.2337/diab.42.1.191. [DOI] [PubMed] [Google Scholar]
  4. DeFronzo R. A., Jacot E., Jequier E., Maeder E., Wahren J., Felber J. P. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981 Dec;30(12):1000–1007. doi: 10.2337/diab.30.12.1000. [DOI] [PubMed] [Google Scholar]
  5. DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
  6. Després J. P., Lamarche B., Mauriège P., Cantin B., Dagenais G. R., Moorjani S., Lupien P. J. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996 Apr 11;334(15):952–957. doi: 10.1056/NEJM199604113341504. [DOI] [PubMed] [Google Scholar]
  7. Devlin J. T. Effects of exercise on insulin sensitivity in humans. Diabetes Care. 1992 Nov;15(11):1690–1693. doi: 10.2337/diacare.15.11.1690. [DOI] [PubMed] [Google Scholar]
  8. Ebeling P., Bourey R., Koranyi L., Tuominen J. A., Groop L. C., Henriksson J., Mueckler M., Sovijärvi A., Koivisto V. A. Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity. J Clin Invest. 1993 Oct;92(4):1623–1631. doi: 10.1172/JCI116747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ferrannini E., Santoro D., Bonadonna R., Natali A., Parodi O., Camici P. G. Metabolic and hemodynamic effects of insulin on human hearts. Am J Physiol. 1993 Feb;264(2 Pt 1):E308–E315. doi: 10.1152/ajpendo.1993.264.2.E308. [DOI] [PubMed] [Google Scholar]
  10. Fontbonne A. Why can high insulin levels indicate a risk for coronary heart disease? Diabetologia. 1994 Sep;37(9):953–955. doi: 10.1007/BF00400954. [DOI] [PubMed] [Google Scholar]
  11. Gambhir S. S., Schwaiger M., Huang S. C., Krivokapich J., Schelbert H. R., Nienaber C. A., Phelps M. E. Simple noninvasive quantification method for measuring myocardial glucose utilization in humans employing positron emission tomography and fluorine-18 deoxyglucose. J Nucl Med. 1989 Mar;30(3):359–366. [PubMed] [Google Scholar]
  12. Hardin D. S., Azzarelli B., Edwards J., Wigglesworth J., Maianu L., Brechtel G., Johnson A., Baron A., Garvey W. T. Mechanisms of enhanced insulin sensitivity in endurance-trained athletes: effects on blood flow and differential expression of GLUT 4 in skeletal muscles. J Clin Endocrinol Metab. 1995 Aug;80(8):2437–2446. doi: 10.1210/jcem.80.8.7629239. [DOI] [PubMed] [Google Scholar]
  13. Hariharan R., Bray M., Ganim R., Doenst T., Goodwin G. W., Taegtmeyer H. Fundamental limitations of [18F]2-deoxy-2-fluoro-D-glucose for assessing myocardial glucose uptake. Circulation. 1995 May 1;91(9):2435–2444. doi: 10.1161/01.cir.91.9.2435. [DOI] [PubMed] [Google Scholar]
  14. Hicks R. J., Herman W. H., Kalff V., Molina E., Wolfe E. R., Hutchins G., Schwaiger M. Quantitative evaluation of regional substrate metabolism in the human heart by positron emission tomography. J Am Coll Cardiol. 1991 Jul;18(1):101–111. doi: 10.1016/s0735-1097(10)80225-6. [DOI] [PubMed] [Google Scholar]
  15. Huang S. C., Williams B. A., Barrio J. R., Krivokapich J., Nissenson C., Hoffman E. J., Phelps M. E. Measurement of glucose and 2-deoxy-2-[18F]fluoro-D-glucose transport and phosphorylation rates in myocardium using dual-tracer kinetic experiments. FEBS Lett. 1987 May 25;216(1):128–132. doi: 10.1016/0014-5793(87)80770-6. [DOI] [PubMed] [Google Scholar]
  16. Iida H., Rhodes C. G., de Silva R., Yamamoto Y., Araujo L. I., Maseri A., Jones T. Myocardial tissue fraction--correction for partial volume effects and measure of tissue viability. J Nucl Med. 1991 Nov;32(11):2169–2175. [PubMed] [Google Scholar]
  17. Jarrett R. J. Why is insulin not a risk factor for coronary heart disease? Diabetologia. 1994 Sep;37(9):945–947. doi: 10.1007/BF00400952. [DOI] [PubMed] [Google Scholar]
  18. Kelley D. E., Mandarino L. J. Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. J Clin Invest. 1990 Dec;86(6):1999–2007. doi: 10.1172/JCI114935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Krivokapich J., Huang S. C., Selin C. E., Phelps M. E. Fluorodeoxyglucose rate constants, lumped constant, and glucose metabolic rate in rabbit heart. Am J Physiol. 1987 Apr;252(4 Pt 2):H777–H787. doi: 10.1152/ajpheart.1987.252.4.H777. [DOI] [PubMed] [Google Scholar]
  20. Lammertsma A. A., Bench C. J., Price G. W., Cremer J. E., Luthra S. K., Turton D., Wood N. D., Frackowiak R. S. Measurement of cerebral monoamine oxidase B activity using L-[11C]deprenyl and dynamic positron emission tomography. J Cereb Blood Flow Metab. 1991 Jul;11(4):545–556. doi: 10.1038/jcbfm.1991.103. [DOI] [PubMed] [Google Scholar]
  21. Lenfant C. NHLBI funding policies. Enhancing stability, predictability, and cost control. Circulation. 1994 Jul;90(1):1–1. doi: 10.1161/01.cir.90.1.1. [DOI] [PubMed] [Google Scholar]
  22. Lenfant C. NHLBI funding policies. Enhancing stability, predictability, and cost control. Circulation. 1994 Jul;90(1):1–1. doi: 10.1161/01.cir.90.1.1. [DOI] [PubMed] [Google Scholar]
  23. Marangou A. G., Alford F. P., Ward G., Liskaser F., Aitken P. M., Weber K. M., Boston R. C., Best J. D. Hormonal effects of norepinephrine on acute glucose disposal in humans: a minimal model analysis. Metabolism. 1988 Sep;37(9):885–891. doi: 10.1016/0026-0495(88)90124-2. [DOI] [PubMed] [Google Scholar]
  24. Marshall R. C., Huang S. C., Nash W. W., Phelps M. E. Assessment of the [18F]fluorodeoxyglucose kinetic model in calculations of myocardial glucose metabolism during ischemia. J Nucl Med. 1983 Nov;24(11):1060–1064. [PubMed] [Google Scholar]
  25. Massie B. M., Conway M., Yonge R., Frostick S., Sleight P., Ledingham J., Radda G., Rajagopalan B. 31P nuclear magnetic resonance evidence of abnormal skeletal muscle metabolism in patients with congestive heart failure. Am J Cardiol. 1987 Aug 1;60(4):309–315. doi: 10.1016/0002-9149(87)90233-5. [DOI] [PubMed] [Google Scholar]
  26. Massie B., Conway M., Yonge R., Frostick S., Ledingham J., Sleight P., Radda G., Rajagopalan B. Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow. Circulation. 1987 Nov;76(5):1009–1019. doi: 10.1161/01.cir.76.5.1009. [DOI] [PubMed] [Google Scholar]
  27. Mitrakou A., Kelley D., Veneman T., Jenssen T., Pangburn T., Reilly J., Gerich J. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes. 1990 Nov;39(11):1381–1390. doi: 10.2337/diab.39.11.1381. [DOI] [PubMed] [Google Scholar]
  28. Natali A., Buzzigoli G., Taddei S., Santoro D., Cerri M., Pedrinelli R., Ferrannini E. Effects of insulin on hemodynamics and metabolism in human forearm. Diabetes. 1990 Apr;39(4):490–500. doi: 10.2337/diab.39.4.490. [DOI] [PubMed] [Google Scholar]
  29. Nguyê V. T., Mossberg K. A., Tewson T. J., Wong W. H., Rowe R. W., Coleman G. M., Taegtmeyer H. Temporal analysis of myocardial glucose metabolism by 2-[18F]fluoro-2-deoxy-D-glucose. Am J Physiol. 1990 Oct;259(4 Pt 2):H1022–H1031. doi: 10.1152/ajpheart.1990.259.4.H1022. [DOI] [PubMed] [Google Scholar]
  30. Nuutila P., Knuuti J., Ruotsalainen U., Koivisto V. A., Eronen E., Teräs M., Bergman J., Haaparanta M., Voipio-Pulkki L. M., Viikari J. Insulin resistance is localized to skeletal but not heart muscle in type 1 diabetes. Am J Physiol. 1993 May;264(5 Pt 1):E756–E762. doi: 10.1152/ajpendo.1993.264.5.E756. [DOI] [PubMed] [Google Scholar]
  31. Nuutila P., Koivisto V. A., Knuuti J., Ruotsalainen U., Teräs M., Haaparanta M., Bergman J., Solin O., Voipio-Pulkki L. M., Wegelius U. Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo. J Clin Invest. 1992 Jun;89(6):1767–1774. doi: 10.1172/JCI115780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nuutila P., Mäki M., Laine H., Knuuti M. J., Ruotsalainen U., Luotolahti M., Haaparanta M., Solin O., Jula A., Koivisto V. A. Insulin action on heart and skeletal muscle glucose uptake in essential hypertension. J Clin Invest. 1995 Aug;96(2):1003–1009. doi: 10.1172/JCI118085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Oliver M. F., Opie L. H. Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet. 1994 Jan 15;343(8890):155–158. doi: 10.1016/s0140-6736(94)90939-3. [DOI] [PubMed] [Google Scholar]
  34. Opie L. H. Glucose and the metabolism of ischaemic myocardium. Lancet. 1995 Jun 17;345(8964):1520–1521. doi: 10.1016/s0140-6736(95)91080-8. [DOI] [PubMed] [Google Scholar]
  35. Paolisso G., Gambardella A., Galzerano D., D'Amore A., Balbi V., Varricchio M., D'Onofrio F. Metabolic features of patients with and without coronary heart disease but with a superimposable cluster of cardiovascular risk factors. Coron Artery Dis. 1993 Dec;4(12):1085–1091. doi: 10.1097/00019501-199312000-00008. [DOI] [PubMed] [Google Scholar]
  36. Paolisso G., Gambardella A., Galzerano D., D'Amore A., Rubino P., Verza M., Teasuro P., Varricchio M., D'Onofrio F. Total-body and myocardial substrate oxidation in congestive heart failure. Metabolism. 1994 Feb;43(2):174–179. doi: 10.1016/0026-0495(94)90241-0. [DOI] [PubMed] [Google Scholar]
  37. Paternostro G., Clarke K., Heath J., Seymour A. M., Radda G. K. Decreased GLUT-4 mRNA content and insulin-sensitive deoxyglucose uptake show insulin resistance in the hypertensive rat heart. Cardiovasc Res. 1995 Aug;30(2):205–211. [PubMed] [Google Scholar]
  38. Patlak C. S., Blasberg R. G., Fenstermacher J. D. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983 Mar;3(1):1–7. doi: 10.1038/jcbfm.1983.1. [DOI] [PubMed] [Google Scholar]
  39. RANDLE P. J., GARLAND P. B., HALES C. N., NEWSHOLME E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785–789. doi: 10.1016/s0140-6736(63)91500-9. [DOI] [PubMed] [Google Scholar]
  40. Ratib O., Phelps M. E., Huang S. C., Henze E., Selin C. E., Schelbert H. R. Positron tomography with deoxyglucose for estimating local myocardial glucose metabolism. J Nucl Med. 1982 Jul;23(7):577–586. [PubMed] [Google Scholar]
  41. Reading J. L., Goodman J. M., Plyley M. J., Floras J. S., Liu P. P., McLaughlin P. R., Shephard R. J. Vascular conductance and aerobic power in sedentary and active subjects and heart failure patients. J Appl Physiol (1985) 1993 Feb;74(2):567–573. doi: 10.1152/jappl.1993.74.2.567. [DOI] [PubMed] [Google Scholar]
  42. Reaven G. M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595–1607. doi: 10.2337/diab.37.12.1595. [DOI] [PubMed] [Google Scholar]
  43. Reaven G. M., Laws A. Insulin resistance, compensatory hyperinsulinaemia, and coronary heart disease. Diabetologia. 1994 Sep;37(9):948–952. doi: 10.1007/BF00400953. [DOI] [PubMed] [Google Scholar]
  44. Rogers W. J., Russell R. O., Jr, McDaniel H. G., Rackley C. E. Acute effects of glucose-insulin-potassium infusion on myocardial substrates, coronary blood flow and oxygen consumption in man. Am J Cardiol. 1977 Sep;40(3):421–428. doi: 10.1016/0002-9149(77)90166-7. [DOI] [PubMed] [Google Scholar]
  45. Russell R. R., 3rd, Mrus J. M., Mommessin J. I., Taegtmeyer H. Compartmentation of hexokinase in rat heart. A critical factor for tracer kinetic analysis of myocardial glucose metabolism. J Clin Invest. 1992 Nov;90(5):1972–1977. doi: 10.1172/JCI116076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Smith S. C., Jr AHA president's letter. Circulation. 1995 Jul 1;92(1):1–1. [PubMed] [Google Scholar]
  47. Stern M. P. The insulin resistance syndrome: the controversy is dead, long live the controversy! Diabetologia. 1994 Sep;37(9):956–958. doi: 10.1007/BF00400955. [DOI] [PubMed] [Google Scholar]
  48. Sullivan M. J., Hawthorne M. H. Exercise intolerance in patients with chronic heart failure. Prog Cardiovasc Dis. 1995 Jul-Aug;38(1):1–22. doi: 10.1016/s0033-0620(05)80011-8. [DOI] [PubMed] [Google Scholar]
  49. Sun D., Nguyen N., DeGrado T. R., Schwaiger M., Brosius F. C., 3rd Ischemia induces translocation of the insulin-responsive glucose transporter GLUT4 to the plasma membrane of cardiac myocytes. Circulation. 1994 Feb;89(2):793–798. doi: 10.1161/01.cir.89.2.793. [DOI] [PubMed] [Google Scholar]
  50. Swan J. W., Walton C., Godsland I. F., Clark A. L., Coats A. J., Oliver M. F. Insulin resistance in chronic heart failure. Eur Heart J. 1994 Nov;15(11):1528–1532. doi: 10.1093/oxfordjournals.eurheartj.a060425. [DOI] [PubMed] [Google Scholar]
  51. Thomas J. A., Marks B. H. Plasma norepinephrine in congestive heart failure. Am J Cardiol. 1978 Feb;41(2):233–243. doi: 10.1016/0002-9149(78)90162-5. [DOI] [PubMed] [Google Scholar]
  52. Voipio-Pulkki L. M., Nuutila P., Knuuti M. J., Ruotsalainen U., Haaparanta M., Teräs M., Wegelius U., Koivisto V. A. Heart and skeletal muscle glucose disposal in type 2 diabetic patients as determined by positron emission tomography. J Nucl Med. 1993 Dec;34(12):2064–2067. [PubMed] [Google Scholar]
  53. Wilson C. B., Lammertsma A. A., McKenzie C. G., Sikora K., Jones T. Measurements of blood flow and exchanging water space in breast tumors using positron emission tomography: a rapid and noninvasive dynamic method. Cancer Res. 1992 Mar 15;52(6):1592–1597. [PubMed] [Google Scholar]
  54. Wilson J. R., Martin J. L., Schwartz D., Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation. 1984 Jun;69(6):1079–1087. doi: 10.1161/01.cir.69.6.1079. [DOI] [PubMed] [Google Scholar]
  55. Yki-Järvinen H., Young A. A., Lamkin C., Foley J. E. Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest. 1987 Jun;79(6):1713–1719. doi: 10.1172/JCI113011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Zaret B. L., Wackers F. J. Nuclear cardiology (2). N Engl J Med. 1993 Sep 16;329(12):855–863. doi: 10.1056/NEJM199309163291208. [DOI] [PubMed] [Google Scholar]
  57. Zelis R., Nellis S. H., Longhurst J., Lee G., Mason D. T. Abnormalities in the regional circulations accompanying congestive heart failure. Prog Cardiovasc Dis. 1975 Nov-Dec;18(3):181–199. doi: 10.1016/0033-0620(75)90010-9. [DOI] [PubMed] [Google Scholar]
  58. vom Dahl J., Herman W. H., Hicks R. J., Ortiz-Alonso F. J., Lee K. S., Allman K. C., Wolfe E. R., Jr, Kalff V., Schwaiger M. Myocardial glucose uptake in patients with insulin-dependent diabetes mellitus assessed quantitatively by dynamic positron emission tomography. Circulation. 1993 Aug;88(2):395–404. doi: 10.1161/01.cir.88.2.395. [DOI] [PubMed] [Google Scholar]

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