Skip to main content
Log in

Insulin resistance and autonomic function in traumatic lower limb amputees

  • Research Paper
  • Published:
Clinical Autonomic Research Aims and scope Submit manuscript

Abstract

This study examined plasma insulin response to oral glucose load and autonomic nervous system activity in male lower limb amputees (n = 52) aged 50–65 years, compared to matched controls (n = 53). The groups had similar body mass index, blood pressure and plasma lipid levels. The amputees had higher mean fasting plasma insulin levels (18.4 ± 9.7 (SD) versus 13.7 ± 5.1 m U/l,p = 0.005) and during an oral glucose tolerance test (OGTT) (1 h levels 88.1 ± 45.3 versus 62.1 ± 42.7,p = 0.016) with similar plasma glucose levels, indicating insulin resistance. At baseline with the subjects supine, there were no group differences in low- or high-frequency power of heart rate variability or in plasma levels of norepinephrine (NE) or epinephrine (EPI). In response to orthostasis, the groups had similarly increased plasma NE levels. During the OGTT, amputees had significantly larger increments in low-frequency power than did controls (2.2 ± 1.3 versus 1.6 ± 0.9 (beats/min)2 respectively,p < 0.01) and plasma NE levels increased significantly in amputees (1595 ± 849 versus 1941 ± 986 pM,p = 0.0008) but not in controls. At 1 h after glucose administration, plasma EPI levels were decreased significantly from baseline in both groups; at both 1 and 2 h after glucose administration, plasma EPI levels were higher in the amputees than controls. Amputees appear to have a combination of enhanced sympathoneural responsiveness and attenuated suppression of adrenomedullary secretion during glucose challenge. As catecholamines antagonize insulin effects, one possible explanation for insulin resistance in amputees is hyperglycaemia-induced sympathoneural activation and a failure of hyperglycaemia to decrease adrenomedullary secretion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Troisi RJ, Weiss ST, Parker DR, Sparrow D, Young JB, Landsberg L. Relation of obesity and diet to sympathetic nervous system activity.Hypertension 1991;17: 669–677.

    Google Scholar 

  2. Landsberg L. Hyperinsulinaemia: possible role in obesity-induced hypertension.Hypertension 1992;19: 161–166.

    PubMed  Google Scholar 

  3. Hrubec Z, Ryder RA. Traumatic limb amputations and subsequent mortality from cardiovascular disease and other causes.J Chron Dis 1980;233: 239–250.

    Google Scholar 

  4. Rose HG, Yalow RS, Schweitzer P, Schwartz E. Insulin as a potential factor influencing BP in amputees.Hypertension 1986;8: 793–800.

    PubMed  Google Scholar 

  5. Loebenstein BG, Korn A, Waldhausl W. The role of adrenergic mechanisms in the BP regulation of leg-amputees.Basic Res Cardiol 1981;76: 267–275.

    PubMed  Google Scholar 

  6. Singh RB, Singh NK, Rastogi SS, Mani UV, Niaz MA. Effects of diet and lifestyle changes on atherosclerotic risk factors after 24 weeks on the Indian Diet Heart Study.Am J Cardiol 1993;71: 1283–1288.

    PubMed  Google Scholar 

  7. Kannel WB, D'Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking and risk of cardiovascular disease: insights from the Framingham study.Am Heart J 1987;113: 1006–1010.

    PubMed  Google Scholar 

  8. Folkow B. Psychosocial and central nervous influences in primary hypertension.Circulation 1987;76: I10-I19.

    PubMed  Google Scholar 

  9. James SA. Psychosocial precursors of hypertension: A review of epidemiologic evidence.Circulation 1987;76: I60-I66.

    PubMed  Google Scholar 

  10. Moriguchi A, Otsuka A, Kohara Ket al. Spectral change in HR variability in response to mental arithmetic before and after the betaadrenoceptor blocker, carteolol.Clin Autonom Res 1992;2: 267–270.

    Google Scholar 

  11. Modan M, Lubin F, Lusky A, Chetrit A, Fuchs Z, Halkin H. Interrelationships of obesity, habitual diet, physical activity and glucose tolerance in the four main Israeli Jewish ethnic groups: the Israel Glucose Intolerance, Obesity and Hypertension (GOH) Study. In: Berry EM, Blondheim SH, Eliahou EII, Shamir E, eds.Recent Advances in Obesity Research. London, Libbey, 1987: 46–59.

    Google Scholar 

  12. Olefsky J, Reaven GM, Farquhar JW. Effects of weight reduction on obesity: studies of lipid and carbohydrate metabolism in normal and hyperinsulinemic subjects.J Clin Invest 1974;53: 64–76.

    PubMed  Google Scholar 

  13. Krotkiewski M, Bjorntorp P, Sjostrom L, Smith V. Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution.J Clin Invest 1983;72: 1150–1162.

    PubMed  Google Scholar 

  14. Berglund G, Anderson O. Body composition metabolic and hormonal characteristics in unselected male hypertensives.Int J Obes 1981;5: 143–150.

    PubMed  Google Scholar 

  15. Cambien F, Jacqueson A, Richard JL, Rosseline G, Ducimetiere P. Associations between systolic BP, HR, and post load glucose and insulin: the Paris Prospective Study. In: Eschwege E, ed.Advances in Diabetes Epidemiology. Amsterdam; Elsevier, 1982: 189–196 (INSERM Symp. no. 22).

    Google Scholar 

  16. Akselrod S, Gordon D, Madwed JB, Snidman NC, Shannon DC, Cohen RJ. Hemodynamic regulation: investigation by spectral analysis.Am J Physiol 1985;249: H867-H875.

    PubMed  Google Scholar 

  17. Hyndman BW, Kitney RI, Sayers BM. Spontaneous rhythms in physiological control systems.Nature 1971;233: 339–341.

    PubMed  Google Scholar 

  18. Eisenhofer G, Goldstein DS, Stull Ret al. Simultaneous liquid chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma and their responses to inhibition of monoamine oxidase.Clin Chem 1986;32: 2030–2033.

    PubMed  Google Scholar 

  19. Yamamoto Y, Hughson RL, Peterson JC. Autonomic control of HR during exercise studied by HR variability spectral analysis.J Appl Physiol 1991;71: 1136–1142.

    PubMed  Google Scholar 

  20. Saul JP, Rea RF, Eckberg DL, Berger RD, Cohen RJ. Heart rate and muscle sympathetic nerve variability during reflex changes of autonomic activity.Am J Physiol 1990;258: H713-H721.

    PubMed  Google Scholar 

  21. Burke D, Sundlof G, Wallin G. Postural effects on muscle nerve sympathetic activity in man.J Physiol Lond 1977;272: 399–414.

    PubMed  Google Scholar 

  22. Eisenhofer G, Goldstein DS, Ropchak TG, Nguyen HQ, Keiser HR, Kopin IJ. Source and physiological significance of plasma 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol.J Auton Nerv Syst 1988;24: 1–14.

    PubMed  Google Scholar 

  23. Goldstein DS, Eisenhofer G, Stull R, Folio CJ, Keiser HR, Kopin IJ. Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans.J Clin Invest 1988;81: 213–220.

    PubMed  Google Scholar 

  24. Goldstein DS, Cannon RO, Quyyumi Aet al. Regional extraction of circulating norepinephrine, DOPA and dihydroxyphenylglycol in human.J Auton Nerv Syst 1991;34: 17–35.

    PubMed  Google Scholar 

  25. Anderson EA, Wallin BG, Mark AL. Dissociation of sympathetic nerve activity in arm and leg muscle during mental stress.Hypertension 1987;9 (3): 114–119.

    Google Scholar 

  26. National Heart, Lung and Blood Institute (1974).Manual of Laboratory Operation. Lipid Research Clinics Program, Vol. 1.Lipid and Lipoprotein Analysis. Bethesda: NIH, DHEW publication No. (NIH) 75-678.

    Google Scholar 

  27. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance.Diabetes 1979;28: 1039–1057.

    Google Scholar 

  28. Oppenheim AV, Schafer RW.Digital Signal Processing. Englewood Cliffs: Prentice Hall, 1975.

    Google Scholar 

  29. Holmes C, Eisenhofer G, Goldstein DS. Improved assay for plasma dihydroxyphenyl acetic acid and other catechols using high-performance liquid chromatography with electrochemical detection.J Chromatogr Biomed Appl 1994;653: 131–138.

    Google Scholar 

  30. Modan M, Halkin H, Almog Set al. Hyperinsulinaemia: a link between hypertension, obesity and glucose intolerance.J Clin Invest 1985;75: 809–817.

    PubMed  Google Scholar 

  31. Modan M, Halkin H, Lusky A, Segal P, Fuchs Z, Chetrit A. Hyperinsulinaemia is characterized by jointly disturbed plasma VLDL, LDL and HDL levels. A population-based study.Arteriosclerosis 1988;8: 227–236.

    PubMed  Google Scholar 

  32. Polonsky K, Rubenstein AH. C-Peptide as a measure of the secretion and hepatic extraction of insulin.Diabetes 1984;33: 486.

    PubMed  Google Scholar 

  33. Polonsky K, Frank B, Pugh Wet al. The limitations to and valid use of C-peptide as a marker of the secretion of insulin.Diabetes 1986;35: 379–386.

    PubMed  Google Scholar 

  34. Giugliano D, Quatraro A, Minei A, De Rosa N, Coppola L, D'Onofrio F. Hyperinsulinaemia in hypertension: increased secretion, reduced clearance or both?J Endocrinol Invest 1993;16: 315–321.

    PubMed  Google Scholar 

  35. Van Gaal L, Vansant G, Van Acker K, De Leeuw I. Decreased hepatic insulin extraction in upper body obesity: relationship to unbound androgens and sex hormone binding globulin.Diabetes Res Clin Pract 1991;12: 99–106.

    PubMed  Google Scholar 

  36. Ikeda T, Fujiyama K, Takeuchi Tet al. Decreased plasma C-peptide to insulin molar ratio after oral glucose in elderly subjects.Exp Clin Endocrinol 1989;94: 351–356.

    PubMed  Google Scholar 

  37. Kautzky WA, Pacini G, Ludvik B, Schernthaner G, Prager R. Beta cell hypersecretion and not reduced hepatic insulin extraction is the main cause of hyperinsulinaemia in obese nondiabetic subjects.Metabolism 1992;41: 1304–1312.

    PubMed  Google Scholar 

  38. Polonsky KS, Given BD, Hirsch Let al. Quantitative study of insulin secretion and clearance in normal and obese subjects.J Clin Invest 1988;81: 435–441.

    PubMed  Google Scholar 

  39. Kautzky WA, Pacini G, Weissel M, Capek M, Ludvik B, Prager R. Elevated hepatic insulin extraction in essential hypertension.Hypertension 1993;21: 646–653.

    PubMed  Google Scholar 

  40. Lager I. The insulin-antagonistic effect of the counterregulatory hormones.J Intern Med Suppl 1991;735: 41–47.

    PubMed  Google Scholar 

  41. Peles E, Goldstein DS, Akselrod Set al. Interrelationships among measures of autonomic activity and cardiovascular risk factors during orthostasis and the oral glucose test.Clin Autonom Res 1995;5: 271–278.

    Google Scholar 

  42. Kaye DM, Esler M, Kingwell B, McPherson G, Esmore D, Jennings G. Functional and neurochemical evidence for partial cardiac sympathetic reinnervation after cardiac transplantation in humans.Circulation 1993;88: 1110–1118.

    PubMed  Google Scholar 

  43. Lipsitz LA, Jonsson PV, Kelley MM, Koestner JS. Causes and correlates of recurrent falls in ambulatory frail elderly.J Gerontol 1991;46: M114-M122.

    PubMed  Google Scholar 

  44. Rokowski RJ, Spodick DH. Prandial effects on cardiac function and responses.Am Heart J 1989;118: 1078–1082.

    PubMed  Google Scholar 

  45. Jansen RWMM, Penterman BJ, Van Iier HJ, Hoefnagels WHL. Blood pressure reduction after oral glucose loading and its relation to age, BP and insulin.Am J Cardiol 1987;60: 1087–1091.

    PubMed  Google Scholar 

  46. Jansen RWMM, Hoefnagels WHL. The influence of oral glucose loading on baroreflex function in the elderly.Am Geriatr Soc 1989;37: 1017–1022.

    Google Scholar 

  47. Berne C, Fagius J, Niklasson F. Sympathetic response to oral carbohydrate administration. Evidence from microelectrode nerve recordings.J Clin Invest 1989;84: 1403–1409.

    PubMed  Google Scholar 

  48. RH Unger DW Foster. Diabetes mellitus. In: Wilson SD, Foster DW eds.Williams Textbook of Endocrinology. Philadelphia: WB Sanders, 1992: 1277–1278

    Google Scholar 

  49. Diamond MP, Hallarman L, Starick-zych Ket al. Suppression of counterregulatory hormone response to hypoglycemia by insulinper se.J Clin Endocrinol Metab 1991;72: 1388–1390.

    PubMed  Google Scholar 

  50. Lechin F, van der Dijs B, Lechin Met al. Effects of an oral glucose load on plasma neurotransmitters in humans: Involvement of REM sleep?Neuropsychobiology 1992;26: 4–11.

    PubMed  Google Scholar 

  51. Genter P, Ipp E. Plasma glucose thresholds for counterregulation after an oral glucose load.Metabolism 1994;43: 98–103.

    PubMed  Google Scholar 

  52. Berne C, Fagius J, Pollare T, Hjemdahl P. The sympathetic response to euglycaemic hyperinsulinaemia. Evidence from microelectrode nerve recordings in healthy subjects.Diabetologia 1992;35: 873–879.

    PubMed  Google Scholar 

  53. Laakso M, Edelman SV, Olefsky JM, Brechtel G, Wallace P, Baron AD. Kinetics ofin vivo muscle insulin-mediated glucose uptake in human obesity.Diabetes 1990;39: 965–974.

    PubMed  Google Scholar 

  54. Kaneto A, Kosaka K, Nakao K. Effects of stimulation of the vagus nerve on insulin secretion.Endocrinology 1967;80: 530–536.

    PubMed  Google Scholar 

  55. Lee HC, Curry DL, Stern JS. Direct effect of CNS on insulin hypersecretion in obese Zucker rats: involvement of the vagus nerve.Am J Physiol 1989;256: E439-E444.

    PubMed  Google Scholar 

  56. Nacht CA, Christin L, Temler E, Chiolero R, Jequier E, Acheson KJ. Thermic effect of food: possible implication of the parasympathetic nervous system.Am J Physiol 1987;253: E481-E488.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to E. Peles MSc.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peles, E., Akselrod, S., Goldstein, D.S. et al. Insulin resistance and autonomic function in traumatic lower limb amputees. Clinical Autonomic Research 5, 279–288 (1995). https://doi.org/10.1007/BF01818893

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01818893

Keywords

Navigation