Acta Diabetologica

, Volume 53, Issue 2, pp 217–226 | Cite as

Trained breathing-induced oxygenation acutely reverses cardiovascular autonomic dysfunction in patients with type 2 diabetes and renal disease

  • Pasquale EspositoEmail author
  • Roberto Mereu
  • Giacomo De Barbieri
  • Teresa Rampino
  • Alessandro Di Toro
  • Per-Henrik Groop
  • Antonio Dal Canton
  • Luciano Bernardi
Original Article



Cardiovascular autonomic dysfunction, evaluated as baroreflex sensitivity (BRS), could be acutely corrected by slow breathing or oxygen administration in patients with type 1 diabetes, thus suggesting a functional component of the disorder. We tested this hypothesis in patients with the type 2 diabetes with or without renal impairment.


Twenty-six patients with type 2 diabetes (aged 61.0 ± 0.8 years, mean ± SEM; duration of diabetes 10.5 ± 2 years, BMI 29.9 ± 0.7 kg/m2, GFR 68.1 ± 5.6 ml/min) and 24 healthy controls (aged 58.5 ± 1.0 years) were studied. BRS was obtained from recordings of RR interval and systolic blood pressure fluctuations during spontaneous and during slow, deep (6 breaths/min) controlled breathing in conditions of normoxia or hyperoxia (5 l/min oxygen).


During spontaneous breathing, diabetic patients had lower RR interval and lower BRS compared with the control subjects (7.1 ± 1.2 vs. 12.6 ± 2.0 ms/mmHg, p < 0.025). Deep breathing and oxygen administration significantly increased arterial saturation, reduced RR interval and increased BRS in both groups (to 9.6 ± 1.8 and 15.4 ± 2.4 ms/mmHg, respectively, p < 0.05, hyperoxia vs. normoxia). Twelve diabetic patients affected by chronic diabetic kidney disease (DKD) presented a significant improvement in the BRS during slow breathing and hyperoxia (p < 0.025 vs. spontaneous breathing during normoxia).


Autonomic dysfunction present in patients with type 2 diabetes can be partially reversed by slow breathing, suggesting a functional role of hypoxia, also in patients with DKD. Interventions known to relieve tissue hypoxia and improve autonomic function, like physical activity, may be useful in the prevention and management of complications in patients with diabetes.


Baroreflex sensitivity Cardiovascular autonomic neuropathy Diabetic kidney disease Hypoxia Oxygen Type 2 diabetes mellitus 



Pasquale Esposito received an educational grant from the Fondazione Italiana del Rene (FIR) and Italian Society of Nephrology (SIN). LB is a recipient of a grant from the Signe and Ane Gyllenberg Foundation, Helsinki.

Conflict of interest

All authors declare that there is no conflict of interest.

Ethical standard

All procedures performed in studies involving human participants were in accordance with the ethical standards of the responsible committee on human experimentation (Ethics Committee of Foundation IRCCS Policlinico “San Matteo” of Pavia, Italy) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Human and animal rights

All human rights were observed in keeping with Helsinki Declaration of 2008. There are no animal right issues as this is a clinical study.

Informed consent

Informed consent was obtained from all patients for being included in the study which has been done according to the ethical standards and keeping with Helsinki Declaration of 2008.


  1. 1.
    Mancia G, Grassi G, Giannattasio C, Seravalle G (1999) Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. Hypertension 34:724–728. doi: 10.1161/01.HYP.34.4.724 CrossRefPubMedGoogle Scholar
  2. 2.
    Tentolouris N, Liatis S, Katsilambros N (2006) Sympathetic system activity in obesity and metabolic syndrome. Ann N Y Acad Sci 1083:129–152CrossRefPubMedGoogle Scholar
  3. 3.
    Esposito P, Palmieri V, Migliaresi P, Pezzullo S, Martino S, Balletta MM (2009) Preclinical cardiovascular abnormalities in patients in early stages of renal disease without nephrotic syndrome. Hypertens Res 32(12):1155–1156. doi: 10.1038/hr.2009.141 CrossRefPubMedGoogle Scholar
  4. 4.
    Converse RL Jr, Jacobsen TN, Toto RD, Jost CM, Cosentino F, Fouad-Tarazi F, Victor RG et al (1992) Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 327:1912–1918CrossRefPubMedGoogle Scholar
  5. 5.
    Vinik AI, Ziegler D (2007) Diabetic cardiovascular autonomic neuropathy. Circulation 115:387–397CrossRefPubMedGoogle Scholar
  6. 6.
    Pop-Busui R, Evans GW, Gerstein HC et al (2010) Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of cardiac autonomic dysfunction on mortality risk in the action to control cardiovascular risk in diabetes (ACCORD) trial. Diabetes Care 33:1578–1584. doi: 10.2337/dc10-0125 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Karayannis G, Giamouzis G, Cokkinos DV, Skoularigis J, Triposkiadis F (2012) Diabetic cardiovascular autonomic neuropathy: clinical implications. Expert Rev Cardiovasc Ther 10(6):747–765. doi: 10.1586/erc.12.53 CrossRefPubMedGoogle Scholar
  8. 8.
    Maser RE, Mitchell BD, Vinik AI, Freeman R (2003) The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 26(6):1895–1901CrossRefPubMedGoogle Scholar
  9. 9.
    Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RRUKPDSGROUP (2003) Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 63(1):225–232CrossRefPubMedGoogle Scholar
  10. 10.
    Zoccali C, Mallamaci F, Parlongo S et al (2002) Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation 105:1354–1359CrossRefPubMedGoogle Scholar
  11. 11.
    Johansson M, Gao SA, Friberg P et al (2007) Baroreflex effectiveness index and baroreflex sensitivity predict all-cause mortality and sudden death in hypertensive patients with chronic renal failure. J Hypertens 25(1):163–168CrossRefPubMedGoogle Scholar
  12. 12.
    Masuo K, Lambert GW, Esler MD, Rakugi H, Ogihara T, Schlaich MP (2010) The role of sympathetic nervous activity in renal injury and end-stage renal disease. Hypertens Res 33:521–528. doi: 10.1038/hr.2010.35 CrossRefPubMedGoogle Scholar
  13. 13.
    Schönauer M, Thomas A, Morbach S, Niebauer J, Schönauer U, Thiele H (2008) Cardiac autonomic diabetic neuropathy. Diabetes Vasc Dis Res 5:336–344CrossRefGoogle Scholar
  14. 14.
    Miyata T, van Ypersele de Strihou C (2010) Diabetic nephropathy: a disorder of oxygen metabolism? Nature Rev Nephrol 6:83–95. doi: 10.1038/nrneph.2009.211 CrossRefGoogle Scholar
  15. 15.
    Hoffman RP, Hausberg M, Sinkey CA, Anderson EA (1999) Hyperglycemia without hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Diabetes Complications 13:17–22CrossRefPubMedGoogle Scholar
  16. 16.
    Vinik AI, Maser RE, Mitchell BD, Freeman R (2003) Diabetic autonomic neuropathy. Diabetes Care 26:1553–1579CrossRefPubMedGoogle Scholar
  17. 17.
    Ewen S, Ukena C, Linz D, Schmieder RE, Böhm M, Mahfoud F (2013) The sympathetic nervous system in chronic kidney disease. Curr Hypertens Rep 15(4):370–376. doi: 10.1007/s11906-013-0365-0 CrossRefPubMedGoogle Scholar
  18. 18.
    Rosengård-Bärlund M, Bernardi L, Sandelin A, Mäkinen VP, Forsblom C, Groop PH, FinnDiane Study Group (2011) Short-term oxygen administration restores blunted baroreflex sensitivity in patients with type 1 diabetes. Diabetologia 54(8):2164–2173. doi: 10.1007/s00125-011-2195-4 CrossRefPubMedGoogle Scholar
  19. 19.
    Loimaala A, Huikuri HV, Kööbi T, Rinne M, Nenonen A, Vuori I (2003) Exercise training improves baroreflex sensitivity in type 2 diabetes. Diabetes 52(7):1837–1842CrossRefPubMedGoogle Scholar
  20. 20.
    Madden KM, Lockhart C, Potter TF, Cuff D (2010) Aerobic training restores arterial baroreflex sensitivity in older adults with type 2 diabetes, hypertension, and hypercholesterolemia. Clin J Sport Med 20:312–317. doi: 10.1097/JSM.0b013e3181ea8454 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Mancia G, Fagard R, Narkiewicz K, Task Force Members et al (2013) 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 31(7):1281–1357. doi: 10.1097/ CrossRefPubMedGoogle Scholar
  22. 22.
    Stevens PE, Levin A (2013) Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease—improving global outcomes 2012 clinical practice guideline. Ann Intern Med 4, 158(11):825–30. doi:10.7326/0003-4819-158-11-201306040-00007Google Scholar
  23. 23.
    Laude D, Elghozi JL, Girard A et al (2004) Comparison of various techniques used to estimate spontaneous baroreflex sensitivity (the EuroBaVar study). Am J Physiol Regul Integr Comp Physiol 286(1):R226–R231CrossRefPubMedGoogle Scholar
  24. 24.
    Bernardi L, De Barbieri G, Rosengård-Bärlund M, Mäkinen VP, Porta C, Groop PH (2010) New method to measure and improve consistency of baroreflex sensitivity values. Clin Auton Res 20:353–361. doi: 10.1007/s10286-010-0079-1 CrossRefPubMedGoogle Scholar
  25. 25.
    Bertinieri G, Di Rienzo M, Cavallazzi A, Ferrari AU, Pedotti A, Mancia G (1985) A new approach to analysis of the arterial baroreflex. J Hypertens 3:S79–S81Google Scholar
  26. 26.
    Pagani M, Somers V, Furlan R et al (1988) Changes in autonomic regulation induced by physical training in mild hypertension. Hypertension 12(6):600–610CrossRefPubMedGoogle Scholar
  27. 27.
    Pinna GD, Maestri R (2001) Reliability of transfer function estimates in cardiovascular variability analysis. Med Biol Eng Comput 39:338–347CrossRefPubMedGoogle Scholar
  28. 28.
    Raupach T, Bahr F, Herrmann P et al (2008) Slow breathing reduces sympathoexcitation in chronic obstructive pulmonary disease. Eur Respir J 32:387–392CrossRefPubMedGoogle Scholar
  29. 29.
    Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R (2011) Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes 27(7):639–653. doi: 10.1002/dmrr.1239 Google Scholar
  30. 30.
    Gautschy B, Weidmann P, Gnadinger MP (1986) Autonomic function tests as related to age and gender in normal man. Klin Wochenschr 64:499–505CrossRefPubMedGoogle Scholar
  31. 31.
    Levey AS, Stevens LA, Schmid CH, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    American Diabetes Association (2006) Standards of medical care in diabetes—2006. Diabetes Care 29:S4–S42Google Scholar
  33. 33.
    Schlaich MP, Socratous F, Hennebry S et al (2009) Sympathetic activation in chronic renal failure. J Am Soc Nephrol 20(5):933–939. doi: 10.1681/ASN.2008040402 CrossRefPubMedGoogle Scholar
  34. 34.
    Koomans HA, Blankestijn PJ, Joles JA (2004) Sympathetic hyperactivity in chronic renal failure: a wake-up call. J Am Soc Nephrol 15(3):524–537CrossRefPubMedGoogle Scholar
  35. 35.
    Pruijm M, Hofmann L, Vogt B et al (2013) Renal tissue oxygenation in essential hypertension and chronic kidney disease. Int J Hypertens 2013. Article ID 696598. doi: 10.1155/2013/696598
  36. 36.
    Schlaich MP, Hering D, Sobotka P et al (2012) Effects of renal denervation on sympathetic activation, blood pressure, and glucose metabolism in patients with resistant hypertension. Front Physiol 3:10. doi: 10.3389/fphys.2012.00010 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Bisognano JD, Bakris G, Nadim MK et al (2011) Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 58:765–773. doi: 10.1016/j.jacc.2011.06.008 CrossRefPubMedGoogle Scholar
  38. 38.
    Krum H, Schlaich M, Whitbourn R et al (2009) Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 373(9671):1275–1281. doi: 10.1016/S0140-6736(09)60566-3 CrossRefPubMedGoogle Scholar
  39. 39.
    Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. SymplicityHTN-2 Investigators (2010) Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 376(9756):1903–1909. doi: 10.1016/S0140-6736(10)62039-9 CrossRefPubMedGoogle Scholar
  40. 40.
    Bhatt DL, Kandzari DE, O’Neill WW, SYMPLICITY HTN-3 Investigators et al (2014) A controlled trial of renal denervation for resistant hypertension. N Engl J Med 370:1393–1401. doi: 10.1056/NEJMoa1402670 CrossRefPubMedGoogle Scholar
  41. 41.
    Dimitropoulos G, Tahrani AA, Stevens MJ (2014) Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes 15, 5(1):17–39. doi: 10.4239/wjd.v5.i1.17
  42. 42.
    Pousset F, Copie X, Lechat P et al (1996) Effects of bisoprolol on heart rate variability in heart failure. Am J Cardiol 77:612–617CrossRefPubMedGoogle Scholar
  43. 43.
    Kontopoulos AG, Athyros VG, Didangelos TP et al (1997) Effect of chronic quinapril administration on heart rate variability in patients with diabetic autonomic neuropathy. Diabetes Care 20:355–361CrossRefPubMedGoogle Scholar
  44. 44.
    Wheatley CM, Baldi JC, Cassuto NA, Foxx-Lupo WT, Snyder EM (2011) Glycemic control influences lung membrane diffusion and oxygen saturation in exercise-trained subjects with type 1 diabetes: alveolar-capillary membrane conductance in type 1 diabetes. Eur J Appl Physiol 111(3):567–578. doi: 10.1007/s00421-010-1663-8 CrossRefPubMedGoogle Scholar
  45. 45.
    Guzzardi MA, Iozzo P (2011) Fatty heart, cardiac damage, and inflammation. Rev Diabet Stud 8(3):403–417. doi: 10.1900/RDS.2011.8.403 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Soni SS, Gowrishankar S, Kishan AG, Raman A (2006) Non diabetic renal disease in type 2 diabetes mellitus. Nephrology (Carlton) 11(6):533–537CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2015

Authors and Affiliations

  • Pasquale Esposito
    • 1
    Email author
  • Roberto Mereu
    • 2
  • Giacomo De Barbieri
    • 2
  • Teresa Rampino
    • 1
  • Alessandro Di Toro
    • 2
  • Per-Henrik Groop
    • 3
    • 4
    • 5
  • Antonio Dal Canton
    • 1
  • Luciano Bernardi
    • 2
    • 4
  1. 1.Department of Nephrology, Dialysis and TransplantationFondazione IRCCS Policlinico San Matteo and University of PaviaPaviaItaly
  2. 2.Department of Internal MedicineFondazione IRCCS Policlinico San Matteo and University of PaviaPaviaItaly
  3. 3.Division of Nephrology, Department of MedicineHelsinki University Central HospitalHelsinkiFinland
  4. 4.Folkhälsan Institute of GeneticsFolkhälsan Research Center Biomedicum HelsinkiHelsinkiFinland
  5. 5.Baker ID Heart and Diabetes InstituteMelbourneAustralia

Personalised recommendations