Current Diabetes Reports

, 16:107 | Cite as

Integrated Cardio-Respiratory Control: Insight in Diabetes

  • Luciano BernardiEmail author
  • Lucio Bianchi
Microvascular Complications—Neuropathy (R Pop-Busui, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Microvascular Complications—Neuropathy


Autonomic dysfunction is a frequent and relevant complication of diabetes mellitus, as it is associated with increased morbidity and mortality. In addition, it is today considered as predictive of the most severe diabetic complications, like nephropathy and retinopathy. The classical methods of screening are the cardiovascular reflex tests and were originally interpreted as evidence of nerve damage. A more modern approach, based on the integrated control of cardiovascular and respiratory function, reveals that these abnormalities are to a great extent functional, at least in the early stage of the disease, thus suggesting new potential interventions. Therefore, this review aims to go further investigating how the imbalance of the autonomic nervous system is altered and can be influenced in many chronic pathologies through a global view of cardio-respiratory and metabolic interactions and how the same mechanisms are applicable to diabetes.


Chemoreflex Baroreflex Heart rate variability Diabetic neuropathy Hypoxia Autonomic nervous system Cardio-respiratory interactions 


Compliance with Ethical Standards

Conflict of Interest

Luciano Bernardi and Lucio Bianchi declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Ewing DJ, Campbell IW, Clarke BF. Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. Ann Intern Med. 1980;92(2 Pt 2):308–11.CrossRefPubMedGoogle Scholar
  2. 2.••
    Spallone V, Ziegler D, Freeman R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;27(7):639–53. doi: 10.1002/dmrr.1239. Review on clinical autonomic tests in diabetes.CrossRefPubMedGoogle Scholar
  3. 3.
    Maser RE, Mitchell BD, Vinik AI, et al. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care. 2003;26(6):1895–901.CrossRefPubMedGoogle Scholar
  4. 4.
    Duvnjak L, Tomić M, Blaslov K, et al. Autonomic nervous system function assessed by conventional and spectral analysis might be useful in terms of predicting retinal deterioration in persons with type 1 diabetes mellitus. Diabetes Res Clin Pract. 2016;116:111–6. doi: 10.1016/j.diabres.2016.04.042.CrossRefPubMedGoogle Scholar
  5. 5.
    Wheelock KM, Jaiswal M, Martin CL, et al. Cardiovascular autonomic neuropathy associates with nephropathy lesions in American Indians with type 2 diabetes. J Diabetes Complicat. 2016;30(5):873–9. doi: 10.1016/j.jdiacomp.2016.03.008.CrossRefPubMedGoogle Scholar
  6. 6.
    Salman IM. Cardiovascular autonomic dysfunction in chronic kidney disease: a comprehensive review. Curr Hypertens Rep. 2015;17(8):59. doi: 10.1007/s11906-015-0571-z.CrossRefPubMedGoogle Scholar
  7. 7.
    Wheeler T, Watkins PJ. Cardiac denervation in diabetes. Br Med J. 1973;4(5892):584–6.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Duchen LW, Anjorin A, Watkins PJ, et al. Pathology of autonomic neuropathy in diabetes mellitus. Ann Intern Med. 1980;92(2 Pt 2):301–3.CrossRefPubMedGoogle Scholar
  9. 9.
    Ziegler D, Voss A, Rathmann W, KORA Study Group, et al. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey. Diabetologia. 2015;58(5):1118–28. doi: 10.1007/s00125-015-3534-7.CrossRefPubMedGoogle Scholar
  10. 10.
    Sleight P, La Rovere MT, Mortara A, et al. Physiology and pathophysiology of heart rate and blood pressure variability in humans: is power spectral analysis largely an index of baroreflex gain? Clin Sci. 1995;88:103–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Bernardi L, Gabutti A, Porta C, et al. Slow breathing reduces chemoreflex response to hypoxia and hypercapnia, and increases baroreflex sensitivity. J Hypertens. 2001;19(12):2221–9.CrossRefPubMedGoogle Scholar
  12. 12.••
    Francis DA, Coats JS, Ponikowski P. Chemoreflex-baroreflex interactions in cardiovascular disease. In: Bradley TD, Floras JS, editors. Sleep apnea. Implication in cardiovascular and cerebrovascular disease. New York: Marcel Dekker; 2000. p. 261–83. Describes the reciprocal interaction between control of breathing and control of circulation.Google Scholar
  13. 13.
    Bristow JD, Honour AJ, Pickering GW, et al. Diminished baroreflex sensitivity in high blood pressure. Circulation. 1969;39(1):48–54.CrossRefPubMedGoogle Scholar
  14. 14.
    Frattola A, Parati G, Gamba P, et al. Time and frequency domain estimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus. Diabetologia. 1997;40(12):1470–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Sykora M, Diedler J, Rupp A, et al. Impaired baroreflex sensitivity predicts outcome of acute intracerebral hemorrhage. Crit Care Med. 2008;36:3074–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Laude D, Elghozi JL, Girard A, et al. Comparison of various techniques used to estimate spontaneous baroreflex sensiivity (the EuroBaVar study). Am J Physiol Regul Integr Comp Physiol. 2004;286:R226–31.CrossRefPubMedGoogle Scholar
  17. 17.•
    Bernardi L, De Barbieri G, Rosengård-Bärlund M, et al. New method to measure and improve consistency of baroreflex sensitivity values. Clin Auton Res. 2010;20(6):353–61. Describes a new method to measure baroreflex sensitivity and compare it with all other methods, showing that the new method has higher robustness and in agreement with the rest of methods.CrossRefPubMedGoogle Scholar
  18. 18.••
    Bernardi L, Spallone V, Stevens M, et al. Methods of investigation for cardiac autonomic dysfunction in human research studies. Toronto Consensus Panel on Diabetic Neuropathy. Diabetes Metab Res Rev. 2011;27(7):654–64. Review describing in critical terms the most relevant methods for research, with special emphasis to the misconceptions related to heart rate variability-based methods.CrossRefPubMedGoogle Scholar
  19. 19.
    Mirizzi G, Giannoni A, Bramanti F, et al. A simple method for measuring baroreflex sensitivity holds prognostic value in heart failure. Int J Cardiol. 2013;169(1):e9–11. doi: 10.1016/j.ijcard.2013.08.120.CrossRefPubMedGoogle Scholar
  20. 20.
    Duennwald T, Bernardi L, Gordin D, FinnDiane Study Group, et al. Effects of a single bout of interval hypoxia on cardiorespiratory control in patients with type 1 diabetes. Diabetes. 2013;62(12):4220–7. doi: 10.2337/db13-0167.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ducher M, Cerutti C, Gustin MP, et al. Noninvasive exploration of cardiac autonomic neuropathy. Four reliable methods for diabetes? Diabetes Care. 1999;22(3):388–93.CrossRefPubMedGoogle Scholar
  22. 22.••
    Rosengård-Bärlund M, Bernardi L, Fagerudd J, FinnDiane Study Group, et al. Early autonomic dysfunction in type 1 diabetes: a reversible disorder? Diabetologia. 2009;52(6):1164–72. doi: 10.1007/s00125-009-1340-9. Describes for the first time that autonomic dysfunction is potentially reversible.CrossRefPubMedGoogle Scholar
  23. 23.
    Rosengård-Bärlund M, Bernardi L, Sandelin A, et al. Baroreflex sensitivity and its response to deep breathing predict increase in blood pressure in type 1 diabetes in a 5-year follow-up. Diabetes Care. 2011;34(11):2424–30. doi: 10.2337/dc11-0629.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.••
    La Rovere MT, Bigger Jr JT, Marcus FI, et al. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998;351(9101):478–84. One of the most important papers showing the prognostic power of baroreflex sensitivity in cardiac patients.CrossRefPubMedGoogle Scholar
  25. 25.•
    Johansson M, Gao SA, Friberg P, et al. Baroreflex effectiveness index and baroreflex sensitivity predict all-cause mortality and sudden death in hypertensive patients with chronic renal failure. J Hypertens. 2007;25(1):163–8. Another important paper showing the prognostic power of baroreflex sensitivity in hypertensive patients.CrossRefPubMedGoogle Scholar
  26. 26.•
    Gerritsen J, Dekker JM, TenVoorde BJ, et al. Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease: the Hoorn Study. Diabetes Care. 2001;24(10):1793–8. This paper reports some information about the prognostic value of baroreflex sensitivity in diabetes.Google Scholar
  27. 27.
    Duffin J. The chemoreflex control of breathing and measurement. Can J Anaesth. 1990;37(S):933–42.CrossRefPubMedGoogle Scholar
  28. 28.••
    Piepoli MF, Coats AJ. The ‘skeletal muscle hypothesis in heart failure’ revised. Eur Heart J. 2013;34(7):486–8. doi: 10.1093/eurheartj/ehs463. Describes the “muscle hypothesis” in heart failure. In the paper, we describe how this seems to apply to diabetes as well.
  29. 29.
    Edelman NH, Cherniack NS, Lahiri S, et al. The effects of abnormal sympathetic nervous function upon the ventilatory response to hypoxia. J Clin Invest. 1970;49(6):1153–65.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Duffin J. Measuring the ventilatory response to hypoxia. J Physiol. 2007;584(Pt1):285–93.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bernardi L, Hilz M, Stemper B, et al. Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia. Am J Respir Crit Care Med. 2003;167(2):141–9.CrossRefPubMedGoogle Scholar
  32. 32.••
    Ponikowski P, Francis DP, Piepoli MF, et al. Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance: marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis. Circulation. 2001;103(7):967–72. Describes the prognostic significance of chemoreflex abnormalities.CrossRefPubMedGoogle Scholar
  33. 33.
    Van den Aardweg JG, Karemaker JM. Influence of chemoreflexes on respiratory variability in healthy subjects. Am J Respir Crit Care Med. 2002;165(8):1041–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Chua TP, Ponikowski P, Coats AJ, et al. Clinical characteristics of chronic heart failure patients with an augmented peripheral chemoreflex. Eur Heart J. 1997;18(3):480–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Despas F, Detis N, Pathak A, et al. Excessive sympathetic activation in heart failure with chronic renal failure: role of chemoreflex activation. J Hypertens. 2009;27(9):1849–54. doi: 10.1097/HJH.0b013e32832e8d0f.CrossRefPubMedGoogle Scholar
  36. 36.•
    Chua TP, Ponikowski P, Harrington D, et al. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1997;29(7):1585–90. Describes the prognostic significance of chemoreflex abnormalities.CrossRefPubMedGoogle Scholar
  37. 37.
    Andrade DC, Lucero C, Toledo C, et al. Relevance of the carotid body chemoreflex in the progression of heart failure. Biomed Res Int. 2015;2015:467597. doi: 10.1155/2015/467597.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Del Rio R, Marcus NJ, Schultz HD. Carotid chemoreceptor ablation improves survival in heart failure: rescuing autonomic control of cardiorespiratory function. J Am Coll Cardiol. 2013;62(25):2422–30. doi: 10.1016/j.jacc.2013.07.079.CrossRefPubMedGoogle Scholar
  39. 39.
    Schmidt H, Müller-Werdan U, Hoffmann T, et al. Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups. Crit Care Med. 2005;33(9):1994–2002.CrossRefPubMedGoogle Scholar
  40. 40.
    Mancia G. Influence of carotid baroreceptors on vascular responses to carotid chemoreceptor stimulation in the dog. Circ Res. 1975;36:270–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Somers VK, Mark AL, Zavala DC, et al. Contrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans. J Appl Physiol (1985). 1989;67(5):2101–6.Google Scholar
  42. 42.••
    Coats AJ, Clark AL, Piepoli M, et al. Symptoms and quality of life in heart failure: the muscle hypothesis. Br Heart J. 1994;72(2 Suppl):S36–9. Another key reference to the “muscle hypothesis”. In the paper we show its relevance in diabetes.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.•
    Ponikowski P, Chua TP, Piepoli M, et al. Augmented peripheral chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure. Circulation. 1997;96(8):2586–94. Describes the reciprocal interaction between chemoreflexes and baroreflexes in heart failure.CrossRefPubMedGoogle Scholar
  44. 44.
    Despas F, Lambert E, Vaccaro A, et al. Peripheral chemoreflex activation contributes to sympathetic baroreflex impairment in chronic heart failure. J Hypertens. 2012;30(4):753–60.CrossRefPubMedGoogle Scholar
  45. 45.••
    Naughton MT, Floras JS, Rahman MA, et al. Respiratory correlates of muscle sympathetic nerve activity in heart failure. Clin Sci (Lond). 1998;95(3):277–85. Describes the interaction between breathing pattern and sympathetic activity.CrossRefGoogle Scholar
  46. 46.
    Bernardi L, Spadacini G, Bellwon J, et al. Effect of breathing rate on oxygen saturation and exercise performance in chronic heart failure. Lancet. 1998;351(9112):1308–11.CrossRefPubMedGoogle Scholar
  47. 47.
    Coats AJ, Adamopoulos S, Radaelli A, et al. Controlled trial of physical training in chronic heart failure. Exercise performance, hemodynamics, ventilation, and autonomic function. Circulation. 1992;85(6):2119–31.CrossRefPubMedGoogle Scholar
  48. 48.••
    Greco C, Spallone V. Obstructive sleep apnoea syndrome and diabetes. Fortuitous association or interaction? Curr Diabetes Rev. 2015;12(2):129–55. A key review on sleep apnea syndrome.CrossRefPubMedGoogle Scholar
  49. 49.•
    Narkiewicz K, Somers VK. The sympathetic nervous system and obstructive sleep apnea: implications for hypertension. J Hypertens. 1997;15(12 Pt 2):1613–9. Describes the interaction between sympathetic activity and sleep apnea.CrossRefPubMedGoogle Scholar
  50. 50.
    Phillips BG, Somers VK. Neural and humoral mechanisms mediating cardiovascular responses to obstructive sleep apnea. Respir Physiol. 2000;119(2–3):181–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Spicuzza L, Bernardi L, Calciati A, et al. Autonomic modulation of heart rate during obstructive versus central apneas in patients with sleep-disordered breathing. Am J Respir Crit Care Med. 2003;167(6):902–10.CrossRefPubMedGoogle Scholar
  52. 52.
    Freet CS, Stoner JF, Tang X. Baroreflex and chemoreflex controls of sympathetic activity following intermittent hypoxia. Auton Neurosci. 2013;174(1–2):8–14. doi: 10.1016/j.autneu.2012.12.005.CrossRefPubMedGoogle Scholar
  53. 53.
    Narkiewicz K, Somers VK. Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand. 2003;177(3):385–90.CrossRefPubMedGoogle Scholar
  54. 54.
    Lurie A. Adv Cardiol. 2011;46:171–95. doi: 10.1159/000325109. Hemodynamic and autonomic changes in adults with obstructive sleep apnoea.CrossRefPubMedGoogle Scholar
  55. 55.
    Bonsignore MR, Parati G, Insalaco G, et al. Continuous positive airway pressure treatment improves baroreflex control of heart rate during sleep in severe obstructive sleep apnoea syndrome. Am J Respir Crit Care Med. 2002;166:279–86.CrossRefPubMedGoogle Scholar
  56. 56.
    Spicuzza L, Bernardi L, Balsamo R, et al. Effect of treatment with nasal continuous positive airway pressure on ventilatory response to hypoxia and hypercapnia in patients with sleep apnea syndrome. Chest. 2006;130(3):774–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Heindl S, Lehnert M, Criée CP, et al. Marked sympathetic activation in patients with chronic respiratory failure. Am J Respir Crit Care Med. 2001;164:597–601.CrossRefPubMedGoogle Scholar
  58. 58.
    Andreas S, Anker SD, Scanlon PD, et al. Neuro-humoral activation as a link to systemic manifestations of chronic lung disease. Chest. 2005;128:3618–24.CrossRefPubMedGoogle Scholar
  59. 59.•
    Raupach T, Bahr F, Herrmann P, et al. Slow breathing reduces sympathoexcitation in COPD. Eur Respir J. 2008;32(2):387–92. doi: 10.1183/09031936.00109607. Shows the sympathetic overactivation in COPD and its reduction with slow breathing.CrossRefPubMedGoogle Scholar
  60. 60.
    Haider T, Casucci G, Linser T, et al. Interval hypoxic training improves autonomic cardiovascular and respiratory control in patients with mild chronic obstructive pulmonary disease. J Hypertens. 2009;27(8):1648–54.CrossRefPubMedGoogle Scholar
  61. 61.
    Bartels MN, Gonzalez JM, Kim W, et al. Oxygen supplementation and cardiac autonomic modulation in COPD. Chest. 2000;118(3):691–6.CrossRefPubMedGoogle Scholar
  62. 62.••
    Bernardi L, Rosengård-Bärlund M, Sandelin A, FinnDiane Study Group, et al. Short-term oxygen administration restores blunted baroreflex sensitivity in patients with type 1 diabetes. Diabetologia. 2011;54(8):2164–73. This paper shows that the parasympathetic reduction results from functional impairment in type 1 diabetes, since it was corrected by oxygen administration, and that hypoxia could be the cause for it.Google Scholar
  63. 63.•
    Esposito P, Mereu R, De Barbieri G et al. Trained breathing-induced oxygenation acutely reverses cardiovascular autonomic dysfunction in patients with type 2 diabetes and renal disease. Acta Diabetol. 2015. This paper shows similar results as the previous, in type 2 diabetes also with renal impairment.Google Scholar
  64. 64.••
    Tantucci C, Scionti L, Bottini P, et al. Influence of autonomic neuropathy of different severities on the hypercapnic drive to breathing in diabetic patients. Chest. 1997;112(1):145–53. Describes chemoreflex impairment in diabetes.CrossRefPubMedGoogle Scholar
  65. 65.•
    Weisbrod CJ, Eastwood PR, O’Driscoll G, et al. Abnormal ventilatory responses to hypoxia in Type 2 diabetes. Diabet Med. 2005;22(5):563–8. Describes chemoreflex impairment in diabetes.CrossRefPubMedGoogle Scholar
  66. 66.•
    Nishimura M, Miyamoto K, Suzuki A, et al. Ventilatory and heart rate responses to hypoxia and hypercapnia in patients with diabetes mellitus. Thorax. 1989;44(4):251–7. Describes chemoreflex impairment in diabetes.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Bianchi L, Porta C, A. Rinaldi et al. Integrated cardiovascular/respiratory control in type 1 diabetes. Accepted abstract, EASD 2015 StockholmGoogle Scholar
  68. 68.•
    Miyata T, de Strihou C. Diabetic nephropathy: a disorder of oxygen metabolism? Nat Rev Nephrol. 2010;6:83–95. Describes how hypoxia could be responsible to diabetic neuropathy.CrossRefPubMedGoogle Scholar
  69. 69.
    Williamson JR, Chang K, Frangos M, et al. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes. 1993;42:801–13.CrossRefPubMedGoogle Scholar
  70. 70.•
    Catrina SB, Okamoto K, Pereira T, et al. Hyperglycemia regulates hypoxia-inducible factor-1 alpha protein stability and function. Diabetes. 2004;53(12):3226–32. Describes the molecular basis of hypoxia in diabetes and its impact on hypoxia-inducible factor.CrossRefPubMedGoogle Scholar
  71. 71.••
    Bento CF, Pereira P. Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes. Diabetologia. 2011;54(8):1946–56. This review describes the role of hypoxia-inducible factor in diabetes.Google Scholar
  72. 72.
    Bernardi L, Porta C, Spicuzza L, et al. Slow breathing increases arterial baroreflex sensitivity in patients with chronic heart failure. Circulation. 2002;105(2):143–5.Google Scholar
  73. 73.
    Joseph CN, Porta C, Casucci G, et al. Slow breathing improves arterial baroreflex sensitivity and decreases blood pressure in essential hypertension. Hypertension. 2005;46(4):714–8.Google Scholar
  74. 74.
    Goso Y, Asanoi H, Ishise H, et al. Respiratory modulation of muscle sympathetic nerve activity in patients with chronic heart failure. Circulation. 2001;104(4):418–23.Google Scholar
  75. 75.
    Bianchi L, Bernardi L, Ghelardi R et al. Accepted abstract, EASD Munich 2016Google Scholar
  76. 76.
    Vimercati C, Qanud K, Ilsar I, et al. Acute vagal stimulation attenuates cardiac metabolic response to β-adrenergic stress. J Physiol. 2012;590(23):6065–74. doi: 10.1113/jphysiol.2012.241943.
  77. 77.
    Gupta RC, Imai M, Jiang AJ, et al. Chronic therapy with selective electric vagus nerve stimulation normalizes plasma concentration of tissue necrosis factor-α, interleukin- 6 and B- type natriuretic peptide in dogs with heart failure. J Am Coll Cardiol. 2006;47:77A.Google Scholar
  78. 78.
    Kong SS, Liu JJ, Yu XJ, et al. Protection against ischemia-induced oxidative stress conferred by vagal stimulation in the rat heart: involvement of the AMPK-PKC pathway. Int J Mol Sci. 2012;13(11):14311–25. doi: 10.3390/ijms131114311.
  79. 79.
    Hegde SV, Adhikari P, Kotian S, et al. Effect of 3-month yoga on oxidative stress in type 2 diabetes with or without complications: a controlled clinical trial. Diabetes Care. 2011;34(10):2208–10. doi: 10.2337/dc10-2430.
  80. 80.
    Gordon L, Morrison EY, McGrowder D, et al. Effect of yoga and traditional physical exercise on hormones and percentage insulin binding receptor in patients with type 2 diabetes. Am J Biochem Biotechnol. 2008;4(1):35–42. doi: 10.3844/ajbbsp.2008.35.42.
  81. 81.
    Duennwald T, Gatterer H, Groop PH, et al. Effects of a single bout of interval hypoxia on cardiorespiratory control and blood glucose in patients with type 2 diabetes. Diabetes Care. 2013;36(8):2183–9.Google Scholar
  82. 82.
    Xiao H, Gu Z, Wang G, et al. The possible mechanisms underlying the impairment of HIF-1α pathway signaling in hyperglycemia and the beneficial effects of certain therapies. Int J Med Sci. 2013;10(10):1412–21.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Folkhälsan Institute of Genetics, Folkhälsan Research CenterUniversity of HelsinkiHelsinkiFinland
  2. 2.Research Program Unit, Diabetes and ObesityUniversity of HelsinkiHelsinkiFinland
  3. 3.Torre d’IsolaItaly
  4. 4.Department of Endocrinology-Diabetology-Nutrition, Jean Verdier Hospital, AP-HP, CRNH-IdFParis-Nord UniversityBondyFrance

Personalised recommendations