Cardiovascular Toxicology

, Volume 8, Issue 1, pp 15–22

Severe Impairment of Endothelial Function with the HIV-1 Protease Inhibitor Indinavir is not Mediated by Insulin Resistance in Healthy Subjects

  • Michael P. Dubé
  • Jude Christopher Gorski
  • Changyu Shen


Endothelial dysfunction may contribute to increased cardiovascular events among HIV-1-infected patients receiving antiretroviral therapy. The HIV-1 protease inhibitor indinavir causes both vascular dysfunction and insulin resistance, but the relationship between the two disturbances is not established. Endothelium-dependent vasodilation (EDV), insulin-mediated vasodilation (IMV), and whole body and leg glucose uptake during a euglycemic hyperinsulinemic clamp (40 mU/m2/min) were measured before and after four weeks of indinavir in nine healthy men. EDV fell from 270 ± 67% above basal to 124 ± 30% (P = 0.04) and IMV from 56 ± 14% above basal to 8 ± 8% (P = 0.001) with indinavir. During the clamp, arteriovenous glucose difference and leg glucose uptake were not significantly different after indinavir and whole-body glucose uptake was only modestly reduced (8.0 ± 0.8 vs. 7.2 ± 0.8 mg/kg/min, P = 0.04). The change in EDV did not correlate with the change in whole-body glucose uptake after indinavir (r = 0.21, P = 0.6). Despite marked impairment of endothelial function and IMV with indinavir, only modest, inconsistent reductions in measures of insulin-stimulated glucose uptake occurred. This suggests that indinavir’s effects on glucose metabolism are not directly related to indinavir-associated endothelial dysfunction. Studies of the vascular effects of newer protease inhibitors are needed.


Endothelial dysfunction Insulin sensitivity Indinavir HIV-1 protease inhibitors 



Endothelium-dependent vasodilation


Insulin-mediated vasodilation


Nitric oxide




Arterio-venous glucose difference


  1. 1.
    Friis-Moller, N., Sabin, C. A., Weber, R., d’Arminio Monforte, A., El-Sadr, W. M., Reiss, P., Thibaut, R., Morfeldt, L., De Wit, S., Pradier, C., Calvo, G., Law, M. G., Kirk, O., Phillips, A. N., Lundgren, J. D., & Data Collection on Adverse Events of Anti-HIV Drugs Study Group. (2003). Combination antiretroviral therapy and the risk of myocardial infarction. New England Journal of Medicine, 349, 1993–2003.Google Scholar
  2. 2.
    D. A. D. Study Group, Friis-Moller, N., Reiss, P., Sabin, C. A., Weber, R., Monforte, A. d. A., El-Sadr, W., Thiebaut, R., De Wit, S., Kirk, O., Fontas, E., Law, M. G., Phillips, A., & Lundgren, J. D. (2007). Class of antiretroviral drugs and the risk of myocardial infarction. New England Journal of Medicine, 356, 1723–1735.Google Scholar
  3. 3.
    Mary-Krause, M., Cotte, L., Simon, A., Partisani, M., & Costagliola, D. (2003). Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS, 17, 2479–2486.PubMedCrossRefGoogle Scholar
  4. 4.
    Celermajer, D. S. (1997). Endothelial dysfunction: does it matter? Is it reversible? Journal of the American College of Cardiology, 30, 325–333.PubMedCrossRefGoogle Scholar
  5. 5.
    Kinlay, S., & Ganz, P. (1997). Role of endothelial dysfunction in coronary artery disease and implications for therapy. The American Journal of Cardiology, 80, 11I–16I.PubMedCrossRefGoogle Scholar
  6. 6.
    Stein, J. H., Klein, M. A., Bellehumeur, J. L., McBride, P. E., Wiebe, D. A., Otvos, J. D., & Sosman, J. M. (2001). Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation, 104, 257–262.PubMedGoogle Scholar
  7. 7.
    Shankar, S. S., & Dubé, M. P. (2004). Clinical aspects of endothelial dysfunction associated with human immunodeficiency virus infection and antiretroviral agents. Cardiovascular Toxicology, 4, 261–269.PubMedCrossRefGoogle Scholar
  8. 8.
    Caballero, A. E., Arora, S., Saouaf, R., Lim, S. C., Smakowski, P., Park, J. Y., King, G. L., LoGerfo, F. W., Horton, E. S., & Veves, A. (1999). Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes, 48, 1856–1862.PubMedCrossRefGoogle Scholar
  9. 9.
    Paradisi, G. M., Steinberg, H. O. M., Hempfling, A. R., Cronin, J. R., Hook, G. R., Shepard, M. K. M., & Baron, A. D. M. (2001). Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation, 103, 1410–1415.PubMedGoogle Scholar
  10. 10.
    Serne, E. H. M., Stehouwer, C. D. A. M., ter Maaten, J. C. M., ter Wee, P. M. M., Rauwerda, J. A. M., Donker, A. J. M. M., & Gans, R. O. B. M. (1999). Microvascular function relates to insulin sensitivity and blood pressure in normal subjects. Circulation, 99, 896–902.PubMedGoogle Scholar
  11. 11.
    Steinberg, H. O., Chaker, H., Leaming, R., Johnson, A., Brechtel, G., & Baron, A. D. (1996). Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. The Journal of Clinical Investigation, 97, 2601–2610.PubMedCrossRefGoogle Scholar
  12. 12.
    Zizek, B., & Poredos, P. (2001). Insulin resistance adds to endothelial dysfunction in hypertensive patients and in normotensive offspring of subjects with essential hypertension. Journal of Internal Medicine, 249, 189–197.PubMedCrossRefGoogle Scholar
  13. 13.
    Baron, A. D., Brechtel-Hook, G., Johnson, A., Cronin, J., Leaming, R., & Steinberg, H. O. (1996). Effect of perfusion rate on the time course of insulin-mediated skeletal muscle glucose uptake. The American Journal of Physiology, 271, E1067–1072.PubMedGoogle Scholar
  14. 14.
    Baron, A. D., Steinberg, H. O., Chaker, H., Leaming, R., Johnson, A., & Brechtel, G. (1995). Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans. The Journal of Clinical Investigation, 96, 786–792.PubMedCrossRefGoogle Scholar
  15. 15.
    Baron, A. D., Tarshoby, M., Hook, G., Lazaridis, E. N., Cronin, J., Johnson, A., & Steinberg, H. O. (2000). Interaction between insulin sensitivity and muscle perfusion on glucose uptake in human skeletal muscle: evidence for capillary recruitment. Diabetes, 49, 768–774.PubMedCrossRefGoogle Scholar
  16. 16.
    Laine, H., Yki-Jarvinen, H., Kirvela, O., Tolvanen, T., Raitakari, M., Solin, O., Haaparanta, M., Knuuti, J., & Nuutila, P. (1998). Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity. The Journal of Clinical Investigation, 101, 1156–1162.PubMedCrossRefGoogle Scholar
  17. 17.
    Steinberg, H. O., Brechtel, G., Johnson, A., Fineberg, N., & Baron, A. D. (1994). Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. The Journal of Clinical Investigation, 94, 1172–1179.PubMedCrossRefGoogle Scholar
  18. 18.
    Utriainen, T., Makimattila, S., Virkamaki, A., Bergholm, R., & Yki-Jarvinen, H. (1996). Dissociation between insulin sensitivity of glucose uptake and endothelial function in normal subjects. Diabetologia, 39, 1477–1482.PubMedCrossRefGoogle Scholar
  19. 19.
    Scherrer, U., Randin, D., Vollenweider, P., Vollenweider, L., & Nicod, P. (1994). Nitric oxide release accounts for insulin’s vascular effects in humans. The Journal of Clinical Investigation, 94, 2511–2515.PubMedCrossRefGoogle Scholar
  20. 20.
    Shankar, S. S., Dube, M. P., Gorski, J. C., Klaunig, J. E., & Steinberg, H. O. (2005). Indinavir impairs endothelial function in healthy HIV-negative men. American Heart Journal, 150, 933.PubMedCrossRefGoogle Scholar
  21. 21.
    Steinberg, H. O., Paradisi, G., Cronin, J., Crowde, K., Hempfling, A., Hook, G., & Baron, A. D. (2000). Type II diabetes abrogates sex differences in endothelial function in premenopausal women. Circulation, 101, 2040–2046.PubMedGoogle Scholar
  22. 22.
    Noor, M. A., Lo, J. C., Mulligan, K., Schwarz, J. M., Halvorsen, R. A., Schambelan, M., & Grunfeld, C. (2001). Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS, 15, F11–18.PubMedCrossRefGoogle Scholar
  23. 23.
    Noor, M. A., Seneviratne, T., Aweeka, F. T., Lo, J. C., Schwarz, J., Mulligan, K., Schambelan, M., & Grunfeld, C. (2002). Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: A randomized, placebo-controlled study. AIDS, 16, F1–F8.PubMedCrossRefGoogle Scholar
  24. 24.
    (1997). Sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Archives of Internal Medicine, 157, 2413–2244.Google Scholar
  25. 25.
    American Diabetes Association. (2000). Screening for type 2 diabetes. Diabetes Care, 23(Supplement 1), S20–S23.Google Scholar
  26. 26.
    Expert Panel on Detection Evaluation, Treatment of High Blood Cholesterol in Adults. (2001). Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA, 285, 2486–2497.CrossRefGoogle Scholar
  27. 27.
    Baron, A. D., Brechtel, G., Wallace, P., & Edelman, S. P. (1988). Rates and tissue sites of non-insulin and insulin-mediated glucose uptake in humans. The American Journal of Physiology, 255, E769–E774.PubMedGoogle Scholar
  28. 28.
    DeFronzo, R. A., Tobin, J. D., & Andres, R. (1979). Glucose clamp technique: A method for quantifying insulin secretion and resistance. The American Journal of Physiology, 237, E214–223.PubMedGoogle Scholar
  29. 29.
    van Heeswijk, R. P., Hoetelmans, R. M., Harms, R., Meenhorst, P. L., Mulder, J. W., Lange, J. M., & Beijnen, J. H. (1998). Simultaneous quantitative determination of the HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir in human plasma by ion-pair high-performance liquid chromatography with ultraviolet detection. Journal of Chromatography. B, Biomedical Sciences & Applications, 719, 159–168.CrossRefGoogle Scholar
  30. 30.
    Hruz, P. W., Murata, H., Qiu, H., & Mueckler, M. (2002). Indinavir induces acute and reversible insulin resistance in rats. Diabetes, 51, 937–942.PubMedCrossRefGoogle Scholar
  31. 31.
    Murata, H., Hruz, P. W., & Mueckler, M. (2000). The mechanism of insulin resistance caused by HIV protease inhibitor therapy. The Journal of Biological Chemistry, 275, 20251–20254.PubMedCrossRefGoogle Scholar
  32. 32.
    Shankar, S. S., Considine, R. V., Gorski, J. C., & Steinberg, H. O. (2006). Insulin sensitivity is preserved despite disrupted endothelial function. American Journal of Physiology – Endocrinology & Metabolism, 291, E691–696.CrossRefGoogle Scholar
  33. 33.
    Laakso, M., Edelman, S. V., Brechtel, G., & Baron, A. D. (1990). Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. The Journal of Clinical Investigation, 85, 1844–1852.PubMedCrossRefGoogle Scholar
  34. 34.
    Rizza, R. A., Mandarino, L. J., & Gerich, J. E. (1981). Dose-response characteristics for effects of insulin on production and utilization of glucose in man. The American Journal of Physiology, 240, E630–639.PubMedGoogle Scholar
  35. 35.
    Grover, A., Padginton, C., Wilson, M. F., Sung, B. H., Izzo, J. L. Jr., & Dandona, P. (1995). Insulin attenuates norepinephrine-induced venoconstriction. An ultrasonographic study. Hypertension, 25, 779–784.PubMedGoogle Scholar
  36. 36.
    Serne, E. H., Ijzerman, R. G., Gans, R. O., Nijveldt, R., De Vries, G., Evertz, R., Donker, A. J., & Stehouwer, C. D. (2002). Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia. Diabetes, 51, 1515–1522.PubMedCrossRefGoogle Scholar
  37. 37.
    Aljada, A., & Dandona, P. (2000). Effect of insulin on human aortic endothelial nitric oxide synthase. Metabolism: Clinical & Experimental, 49, 147–150.Google Scholar
  38. 38.
    Zeng, G., Nystrom, F. H., Ravichandran, L. V., Cong, L.-N., Kirby, M., Mostowski, H., & Quon, M. J. (2000). Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation, 101, 1539–1545.PubMedGoogle Scholar
  39. 39.
    Zeng, G., & Quon, M. J. (1996). Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. The Journal of Clinical Investigation, 98, 894–898.PubMedCrossRefGoogle Scholar
  40. 40.
    Mueckler, M. (1994). Facilitative glucose transporters. European Journal of Biochemistry, 219, 713–725.PubMedCrossRefGoogle Scholar
  41. 41.
    Murata, H., Hruz, P. W., & Mueckler, M. (2002). Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS, 16, 859–863.PubMedCrossRefGoogle Scholar
  42. 42.
    Lee, G. A., Mafong, D. D., Noor, M. A., Lo, J. C., Mulligan, K., Schwarz, J. M., Schambelan, M., & Grunfeld, C. (2004). HIV protease inhibitors increase adiponectin levels in HIV-negative men. Journal of Acquired Immune Deficiency Syndromes: JAIDS, 36, 645–647.PubMedCrossRefGoogle Scholar
  43. 43.
    Vernochet, C., Azoulay, S., Duval, D., Guedj, R., Cottrez, F., Vidal, H., Ailhaud, G., & Dani, C. (2005). Human immunodeficiency virus protease inhibitors accumulate into cultured human adipocytes and alter expression of adipocytokines. Journal of Biological Chemistry, 280, 2238–2243.PubMedCrossRefGoogle Scholar
  44. 44.
    Lagathu, C., Bastard, J. P., Auclair, M., Maachi, M., Kornprobst, M., Capeau, J., & Caron, M. (2004). Antiretroviral drugs with adverse effects on adipocyte lipid metabolism and survival alter the expression and secretion of proinflammatory cytokines and adiponectin in vitro. Antiviral Therapy, 9, 911–920.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Michael P. Dubé
    • 1
  • Jude Christopher Gorski
    • 2
    • 3
  • Changyu Shen
    • 4
  1. 1.Department of Medicine and the Division of Infectious DiseasesIndiana University School of Medicine, Wishard Memorial HospitalIndianapolisUSA
  2. 2.Division of Clinical PharmacologyIndiana University School of MedicineIndianapolisUSA
  3. 3.Mylan Pharmaceuticals, Inc.MorgantownUSA
  4. 4.Division of BiostatisticsIndiana University School of MedicineIndianapolisUSA

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