Current Hypertension Reports

, Volume 5, Issue 3, pp 247–254

Insulin resistance and the sympathetic nervous system

  • Brent M. Egan
Article

Abstract

The obesity epidemic is driving metabolic (insulin resistance) syndrome-related health problems including an approximately threefold increased coronary heart disease risk. Sympathetic hyperfunction may participate in the pathogenesis and complications of the metabolic syndrome including higher blood pressure, a more active renin-angiotensin system, insulin resistance, faster heart rates, and excess cardiovascular disease including sudden death. Possible factors augmenting sympathetic activation in the metabolic syndrome include alterations of insulin, leptin, nonesterified fatty acids (NEFAs), cytokines, tri-iodothyronine, eicosanoids, sleep apnea, nitric oxide, endorphins, and neuropeptide Y. Of note, high plasma NEFAs are a risk factor for hypertension and sudden death. In shortterm human studies, NEFAs can raise blood pressure, heart rate, and α1-adrenoceptor vasoreactivity, while reducing baroreflex sensitivity, endothelium-dependent vasodilatation, and vascular compliance. Efforts to further identify the mechanisms and consequences of sympathetic dysfunction in the metabolic syndrome may provide insights for therapeutic advances to ameliorate the excess cardiovascular risk and adverse outcomes.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Ferrannini E, Natali A, Bell P, et al.: Insulin resistance and hypersecretion in obesity. J Clin Invest 1997, 100:1166–1173.PubMedGoogle Scholar
  2. 2.
    Bunker CH, Ukoli FA, Matthews KA, et al.: Weight threshold and blood pressure in a lean black population. Hypertension 1995, 26:616–623.PubMedGoogle Scholar
  3. 3.
    Lipton RB, Liao Y, Cao G, et al.: Determinants of incident noninsulin-dependent diabetes mellitus among blacks and whites in a national sample. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 1993, 138:826–839.PubMedGoogle Scholar
  4. 4.
    Prebble WE: Obesity: observations on one thousand cases. Boston Med Surg J 1923, 88:617–621.Google Scholar
  5. 5.
    Mokdad AH, Ford ES, Bowman BA, et al.: Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003, 289:76–79.PubMedCrossRefGoogle Scholar
  6. 6.
    Kannel WB, Wilson PW, Nam BH, D’Agostino RB: Risk stratification of obesity as a coronary risk factor. Am J Cardiol 2002, 90:697–701.PubMedCrossRefGoogle Scholar
  7. 7.
    Hubert HB, Feinleib M, McNamara PM, Castelli WP: Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983, 67:968–977.PubMedGoogle Scholar
  8. 8.
    Messerli FH, Nunez BD, Ventura HO, Snyder DW: Overweight and sudden death: Increased ventricular ectopy in cardiopathy of obesity. Arch Intern Med 1987, 147:1725–1728.PubMedCrossRefGoogle Scholar
  9. 9.
    Flegal KM, Carroll MD, Ogden CL, Johnson CL: Prevalence and trends in obesity among US adults, 1999–20. JAMA 2002, 288:1723–1727.PubMedCrossRefGoogle Scholar
  10. 10.
    Ford ES, Giles WH, Dietz WH: Prevalence of the metabolic syndrome among US adults: Findings from the Third National Health and Nutrition Examination Survey. JAMA 2002, 287:356–359.PubMedCrossRefGoogle Scholar
  11. 11.
    Obesity: preventing and managing the global epidemic. In Report of a WHO Consultation on Obesity. Geneva: World Health Organization, 1998.Google Scholar
  12. 12.
    Lakka H-M, Laaksonen DE, Lakka TA, et al.: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002, 288:2709–2716.PubMedCrossRefGoogle Scholar
  13. 13.
    Wolf AM, Colditz GA: Current estimates of the economic cost of obesity in the United States. Obes Res 1998, 6:97–106.PubMedGoogle Scholar
  14. 14.
    Sturm R: The effects of obesity, smoking, and drinking on medical problems and costs. Obesity outranks both smoking and drinking in its deleterious effects on health and health costs. Health Affairs 2002, 21:245–253.PubMedCrossRefGoogle Scholar
  15. 15.
    Quesenberry CP, Caan B, Jacabson A: Obesity, health services use, and health care costs among members of a health maintenance organization. Arch Intern Med 1998, 158:466–472.PubMedCrossRefGoogle Scholar
  16. 16.
    Field AE, Coakley EH, Must A, et al.: Impact of overweight on the risk of developing common chronic disease during a 10-year period. Arch Intern Med 2001, 161:1581–1586.PubMedCrossRefGoogle Scholar
  17. 17.
    National Task Force on the Prevention and Treatment of Obesity: Weight cycling. JAMA 1994, 272:1196–1202.Google Scholar
  18. 18.
    Snitker S, Macdonald I, Ravussin E, Astrup A: The sympathetic nervous system and obesity: role in aetiology and treatment. Obes Rev 2000, 1:5–15.PubMedCrossRefGoogle Scholar
  19. 19.
    Esler M, Magdalena R, Wiesner G, et al.: Sympathetic nervous system and insulin resistance: From obesity to diabetes. Am J Hypertens 2001, 14:304S-309S. This review article summarizes a substantial body of work on regional norepinephrine kinetics in healthy volunteers, obese subjects, and hypertensive patients by a very productive group of scientific investigators.PubMedCrossRefGoogle Scholar
  20. 20.
    Grassi G, Seravalle G, Dell-Oro R, et al.: Adrenergic and reflex abnormalities in obesity-related hypertension. Hypertension 2000, 36:538–542. This is an original article comparing MSNA in lean and obese normotensive and hypertensive patients. The results indicate separate and essentially additive effects of obesity and hypertension on MSNA.PubMedGoogle Scholar
  21. 21.
    Egan B, Panis R, Hinderliter A, et al.: Mechanism of increased a-adrenergic vasoconstriction in human essential hypertension. J Clin Invest 1987, 80:812–817.PubMedGoogle Scholar
  22. 22.
    Quillot D, Fluckiger L, Zannad F, et al.: Impaired autonomic control of heart rate and blood pressure in obesity: role of age and of insulin-resistance. Clin Autonom Res 2001, 11:79–86.CrossRefGoogle Scholar
  23. 23.
    Gao YY, Lovejoy, Spart An, et al.: Autonomic activity assessed by heart rate spectral analysis varies with fat distribution in obese women. Obes Res 1996, 4:55–63.PubMedGoogle Scholar
  24. 24.
    Pollare T, Lithell H, Selinus I, Berne C: Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia 1988, 31:415–420.PubMedCrossRefGoogle Scholar
  25. 25.
    Jamerson KA, Julius S, Gudbrandsson T, et al.: Reflex sympathetic activation induces acute insulin resistance in the human forearm. Hypertension 1993, 21:618–623.PubMedGoogle Scholar
  26. 26.
    Rocchini AP, Mao HZ, Babu K, et al.: Clonidine prevents insulin resistance and hypertension in obese dogs. Hypertension 1999, 33(part 2):548–553. This paper represents an important extension of a large body of work on obesity-induced hypertension by this investigative team. The results demonstrate a critical role for the sympathetic nervous system in the blood pressure elevation and hyperinsulinemia that occur with overfeeding in dogs.PubMedGoogle Scholar
  27. 27.
    Hall JE, Brands MW, Hildebrandt DA, et al.: Role of sympathetic nervous system and neuropeptides in obesity hypertenson. Brazil J Med Biol Res 2000, 33:605–618.Google Scholar
  28. 28.
    Wofford MR, Anderson DC, Brown CA, et al.: Antihypertensive -effect of a- and b-adrenergic blockade in obese and lean hypertensive subjects. Am J Hypertens 2001, 14:694–698.PubMedCrossRefGoogle Scholar
  29. 29.
    Sower JR, Nyby M, Stern N, et al.: Blood pressure and hormone changes associated with weight reduction in the obese. Hypertension 1982, 4:686–691.Google Scholar
  30. 30.
    Esler M, Zweifler A, Randall O, et al.: The determinants of plasma-renin activity in essential hypertension. Ann Intern Med 1978, 88:746–752.PubMedGoogle Scholar
  31. 31.
    Egan BM, Stepniakowski K, Goodfriend TL: Renin and aldosterone are higher and the hyperinsulinemic effects of salt restriction greater in subjects with risk factor clustering. Am J Hypertens 1994, 7:886–893.PubMedGoogle Scholar
  32. 32.
    Rothwell NJ: Central regulation of thermogenesis. Crit Rev Neurobiol 1994, 8:1–10.PubMedGoogle Scholar
  33. 33.
    Carroll JF, Hunag M, Hester RL, et al.: Hemodynamic alterations in hypertensive obese rabbits. Hypertension 1995, 26:465–470.PubMedGoogle Scholar
  34. 34.
    Mark AL, Correia M, Morgan DA, et al.: State-of-the-art lecture: Obesity-induced hypertension: New concepts from the emerging biology of obesity. Hypertension 1999, 33(part 2):537–541. The review article represents an insightful perspective on the biologic variables linking obesity to blood pressure control, with a focus on central neurogenic action of selected peptides and the peripheral extension of the central effects.PubMedGoogle Scholar
  35. 35.
    Hwang I-S, Ho H, Hoffman BB, Reaven GM: Fructose-induced insulin resistance and hypertension in rats. Hypertension 1987, 10:512–516.PubMedGoogle Scholar
  36. 36.
    Tuck ML: Obesity, the sympathetic nervous system, and essential hypertension. Hypertension 1992, 19(Suppl 1):I67-I77.PubMedGoogle Scholar
  37. 37.
    Rocchini AP, Key J, Bondie D, et al.: The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 1989, 321:580–585.PubMedCrossRefGoogle Scholar
  38. 38.
    Esler M, Ferrier C, Lambert G, et al.: Biochemical evidence of sympathetic hyperactivity in human hypertension. Hypertension 1991, 17(Suppl III):III29-III35.PubMedGoogle Scholar
  39. 39.
    Guyton AC: Blood pressure control—special role of the kidneys and body fluids. Science 1991, 252:1813–1816.PubMedCrossRefGoogle Scholar
  40. 40.
    Grassi G, Seravalle G, Dell’Oro R, et al.: Adrenergic and reflex abnormalities in obesity-related hypertension. Hypertension 2000, 36:538–542.PubMedGoogle Scholar
  41. 41.
    Grassi G, Seravalle G, Colombo M, et al.: Body weight reduction, sympathetic nerve activity, and arterial baroreflex in obese normotensive humans. Circulation 1998, 97:2037–2042.PubMedGoogle Scholar
  42. 42.
    Laakso M, Edelman SV, Brechtel G, Baron AD: Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. J Clin Invest 1990, 85:1844–1852.PubMedGoogle Scholar
  43. 43.
    Andersson B, Elam M, Wallin BG, et al.: Effect of energyrestricted diet on sympathetic muscle nerve activity in obese women. Hypertension 1991, 18:783–789.PubMedGoogle Scholar
  44. 44.
    Jones PP, Snitker S, Skinner JS, Ravussin E: Gender differences in muscle sympathetic nerve activity: effect of body fat distribution. Am J Physiol 1996, 270:E363-E366.PubMedGoogle Scholar
  45. 45.
    Kissebah AH, Krakower GR: Regional adiposity and morbidity. Physiol Rev 1994, 74:761–811.PubMedGoogle Scholar
  46. 46.
    Stern M, Haffner S: Body fat distribution and hyperinsulinemia as risk factors for diabetes and cardiovascular disease. Arteriosclerosis 1986, 6:123–129.PubMedGoogle Scholar
  47. 47.
    Heitmann BL: Body fat distribution in the adult Danish population aged 35 – 65 years: an epidemiological study. Int J Obes 1991, 58:535–545.Google Scholar
  48. 48.
    MacMahon SW, Blacket RB, Macdonald GJ, Hall W: Obesity, alcohol consumption and blood pressure in Australian men and women. The National Heart Foundation of Australia Risk Factor Prevalence Study. J Hypertens 1984, 2:85–91.PubMedCrossRefGoogle Scholar
  49. 49.
    Emdin M, Gastaldelli A, Muscelli E, et al.: Hyperinsulinemia and autonomic nervous system dysfunction in obesity: Effects of weight loss. Circulation 2001, 103:513–519.PubMedGoogle Scholar
  50. 50.
    Hirsch J, Leibel RL, Mackintosh R, Aguirre A: Heart rate variability as a measure of autonomic function during weight change in humans. Am J Physiol 1991, 261:R1418-R1423.PubMedGoogle Scholar
  51. 51.
    Hausberg M, Hoffman RP, Somers VK, et al.: Contrasting autonomic and hemodynamic effects of insulin in health elderly versus young subjects. Hypertension 1997, 29:700–705.PubMedGoogle Scholar
  52. 52.
    Anderson EA, Balon TW, Hoffman RP, et al.: Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans. Hypertension 1992, 19:621–627.PubMedGoogle Scholar
  53. 53.
    Wollenweider P, Tappy L, Randin D, et al.: Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest 1993, 92:147–154.Google Scholar
  54. 54.
    Monroe MB, Van Pelt RE, Schiller BC, et al.: Relation of leptin and inslin to adiposity-associated elevations in sympathetic activity with age in humans. Int J Obes 2000, 24:1183–1187. Leptin and insulin are able to activate the sympathetic nervous system and both peptides tend to cosegregate. This study used MSNA and multivariate analysis in an attempt to separate the individual contributions of leptin and insulin on sympathetic activity and found evidence for the predominance of leptin.CrossRefGoogle Scholar
  55. 55.
    Jensen MD, Haymond MW, Rizza RA, et al.: Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Invest 1989, 83:1168–1173.PubMedGoogle Scholar
  56. 56.
    Reaven GM, Hollenbeck C, Jeng CY, et al.: Measurement of plasma glucose, free fatty acids, lactate, and insulin for 24 hours in patients with NIDDM. Diabetes 1988, 37:1020–1024.PubMedCrossRefGoogle Scholar
  57. 57.
    Ferrannini E, Barrett EJ, Bevilacqua S: Effects of fatty acids on glucose production and utilization in man. J Clin Invest 1983, 72:1737–1747.PubMedGoogle Scholar
  58. 58.
    Cabezas MC, deBruin TWA, deValk HW, et al.: Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating apolipoprotein B overproduction and insulin resistance. J Clin Invest 1993, 92:160–168.CrossRefGoogle Scholar
  59. 59.
    Bülow J, Madsen J, Hojgaard L: Reversibility of the effects on local circulation of high lipid concentrations in blood. Scand J Clin Lab Invest 1990, 50:291–296.PubMedGoogle Scholar
  60. 60.
    Grekin RJ, Dumont CJ, Vollmer AP, et al.: Mechanisms in the pressor effects of hepatic portal venous fatty acid infusion. Am J Physiol 1997, 273:R324-R330.PubMedGoogle Scholar
  61. 61.
    Hildebrandt DA, Kirk D, Hall JE: Renal and cardiovascular responses to chronic increases in cerebrovascular free fatty acids. Fed Proc 1999, 13:780.Google Scholar
  62. 62.
    Stojiljkovic MP, Zhang D, Lopes HF, et al.: Hemodynamic effects of lipids in humans. Am J Physiol 2001, R280:1674–1679.Google Scholar
  63. 63.
    Steinberg HO, Tarshoby M, Monestel R, et al.: Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 1997, 100:1230–1239.PubMedGoogle Scholar
  64. 64.
    Haastrup T, Stepniakowski KT, Goodfriend TL, Egan BM: Lipids enhance a1-adrenergic receptor mediated pressor reactivity. Hypertension 1998, 32:693–698.PubMedGoogle Scholar
  65. 65.
    Thomas GD, Sander M, Lau KS, et al.: Impaired metabolic modulation of alpha-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle. Proc Natl Acad Sci U S A 1998, 95:15090–15095.PubMedCrossRefGoogle Scholar
  66. 66.
    Fagot-Campagna A, Balkau B, Simon D, et al.: High free fatty acid concentration: An independent risk factor for hypertension in the Paris Prospective Study. Int J Epidemiol 1998, 27:808–813.PubMedCrossRefGoogle Scholar
  67. 67.
    Gadegbeku CA, Dhandayuthapani A, Sadler JE, Egan BM: Raising lipids acutely reduces baroreflex sensitivity. Am J Hypertens 2002, 15:479–485.PubMedCrossRefGoogle Scholar
  68. 68.
    Paolisso G, Manzella D, Rosaria MR, et al.: Elevated plasma fatty acid concentrations stimulate the cardiac autonomic nervous system in healthy subjects. Am J Clin Nutr 2000, 72:723–730. This paper summarizes a thoughtfully designed study that shows that a rise in plasma NEFAs alters the neural control of heart rate variability. These findings may provide one link between elevated fatty acids and sudden death.PubMedGoogle Scholar
  69. 69.
    Jouven X, Charles M-A, Desnos M, Ducimetière P: Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation 2001, 104:756–761.PubMedGoogle Scholar
  70. 70.
    Chan JC, Cheung JC, Stehouwer CD, et al.: The central roles of obesity-associated dyslipidaemia, endothlelial activation and cytokines in the metabolic syndrome—an analysis by structural equation modeling. Int J Obes 2002, 26:994–1008.CrossRefGoogle Scholar
  71. 71.
    Maguri SR, Hauser R, Schwartz J, et al.: Association of heart rate variability with occupational and environmental exposure to particulate air pollution. Circulation 2001, 104:986–991.Google Scholar
  72. 72.
    Vgontzas AN, Papanicolaou DA, Bixler EO, et al.: Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000, 85:1151–1158.PubMedCrossRefGoogle Scholar
  73. 73.
    O’Dea K, Esler M, Leonard P, et al.: Noradrenaline turnover during under- and over-eating in normal weight subjects. Metabolism 1982, 31:896–899.PubMedCrossRefGoogle Scholar
  74. 74.
    Engeli S, Sharma AM: Role of adipose tissue for cardiovascular-renal regulation in health and disease. Horm Metab Res 2000, 21:485–499.Google Scholar
  75. 75.
    Brody MJ, Kadowitz PJ: Prostaglandins as modulators of autonomic nervous system. Fed Proc 1974, 33:48–60.PubMedGoogle Scholar
  76. 76.
    Stjärne L: Enhancement by indomethacin of cold-induced hypersecretion of noradrenaline in the rat in vivo by suppression of PGE mediated feedback control? Acta Physiol Scand 1972, 86:388–397.PubMedCrossRefGoogle Scholar
  77. 77.
    Qadri F, Carretero OA, Scicli AG: Centrally produced nitric oxide in the control of baroreceptor reflex sensitivity and blood pressure in normotensive and hypertensive spontaneously hypertensive rats. Jpn J Pharmacol 1999, 81:279–285.PubMedCrossRefGoogle Scholar
  78. 78.
    Tanioka H, Nakamura K, Fujimura S, et al.: Facilitatory role of NO in neural norepinephrine release in the rat kidney. Am J Physiol 2002, 282:R1436-R1442.Google Scholar
  79. 79.
    Kuo JJ, Jones OB, Hall JE: Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin. Hypertension 2001, 37(part 2):670–676.PubMedGoogle Scholar
  80. 80.
    Konishi S, Tsunoo A, Otsuka M: Enkephalins presynaptically inhibit cholinergic transmission in sympathetic ganglia. Nature 1979, 282:515–516.PubMedCrossRefGoogle Scholar
  81. 81.
    Paquali R, Cantobelli S, Casimirri F, et al.: The role of opioid peptides in the development of hyperinsulinemia in obese women with abdominal fat distribution. Metabolism 1992, 41:763–767.CrossRefGoogle Scholar
  82. 82.
    McCubbin JA, Survit RS, Williams RB, et al.: Altered pituitary hormone response to naloxone in hypertension development. Hypertension 1989, 14:636–644.PubMedGoogle Scholar
  83. 83.
    Ramirez-Gonzalez MD, Tchakarov L, Garcia RM, Kunos G: bendorphin acting on the brainstem is involved in the antihypertensive action of clonidine and a-methyldopa in rats. Circ Res 1983, 53:150–157.PubMedGoogle Scholar
  84. 84.
    Bouloux P-M, Grossman A, Al-Damluji S, et al.: Enhancement of the sympathoadrenal response to the cold-pressor test by naloxone in man. Clin Sci 1985, 69:365–368.PubMedGoogle Scholar
  85. 85.
    Rothman RB, Xu H, Char GU, et al.: Phenylpiperidine opioid antagonists that promote weight loss in rats have high affinity for the k2B (enkephalin-sensitive) binding site. Peptides 1993, 14:17–20.PubMedCrossRefGoogle Scholar
  86. 86.
    Balasubramaniam A: Clinical potential of neuropeptide Y family of hormones. Am J Surg 2002, 183:430–434.PubMedCrossRefGoogle Scholar
  87. 87.
    Silverberg DS, Oksenberg A: Are sleep-related breathing disorders important contributing factors to the production of essential hypertension? Curr Hypertens Rep 2001, 3:209–215.PubMedGoogle Scholar
  88. 88.
    Roux F, D’Ambrosio C, Mohsenin V: Sleep-related breathing disorders and cardiovascular disease. Am J Med 2000, 108:396–402.PubMedCrossRefGoogle Scholar
  89. 89.
    Fletcher EC, Lesske J, Behm R, et al.: Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol 1992, 72:1978–1984.PubMedGoogle Scholar
  90. 90.
    Ries DJ, Morrison S, Ruggiero DA: The C1 area of the brainstem in tonic and reflex control of blood pressure: state of the art lecture. Hypertension 1988, 11(Suppl 1):I8-I13.Google Scholar
  91. 91.
    Johnson EH: Interrelationships between psychological factors, overweight, and blood pressure in adolescents. J Adolesc Health Care 1990, 11:310–318.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2003

Authors and Affiliations

  • Brent M. Egan
    • 1
  1. 1.Division of General Internal MedicineMedical University of South CarolinaCharlestonUSA

Personalised recommendations