ReviewGeneral Interest

Carotid body: a metabolic sensor implicated in insulin resistance

The carotid body is now looked at as a multipurpose sensor for blood gases, blood pH, and several hormones. The matter of glucose sensing by the carotid body has been debated for several years in the literature, and these days there is a consensus that carotid body activity is modified by metabolic factors that contribute to glucose homeostasis. However, the sensing ability for glucose is still being pondered: are the carotid bodies low glucose sensors or, in contrast, are they overresponsive in high-glucose conditions? Herein, we debate the glucose and insulin sensing capabilities of the carotid body as key early events in the overactivation of the carotid body, which is increasingly recognized as an important feature of metabolic diseases. Additionally, we dedicate a final section to discuss new outside-the-box therapies designed to decrease carotid body activity that may be used for treating metabolic diseases.

REFERENCES

  • 1. Abdala AP, McBryde FD, Marina N, Hendy EB, Engelman ZJ, Fudim M, Sobotka PA, Gourine AV, Paton JF. Hypertension is critically dependent on the carotid body input in the spontaneously hypertensive rat. J Physiol 590: 4269–4277, 2012. doi:10.1113/jphysiol.2012.237800.
    Crossref | PubMed | ISIGoogle Scholar
  • 2. Almaraz L, Obeso A, Gonzalez C. Metabolic dissociation of carotid body chemoreceptors responses to different types of stimulation: preliminary findings in The Peripheral Arterial Chemoreceptors. London: Croom-Helm, 1984, p. 141–151.
    Google Scholar
  • 3. Alvarez-Buylla R, de Alvarez-Buylla ER. Carotid sinus receptors participate in glucose homeostasis. Respir Physiol 72: 347–359, 1988. doi:10.1016/0034-5687(88)90093-X.
    Crossref | PubMedGoogle Scholar
  • 4. Bergman RN. New concepts in extracellular signaling for insulin action: the single gateway hypothesis. Recent Prog Horm Res 52: 359–385, 1997.
    PubMedGoogle Scholar
  • 5. Bin-Jaliah I, Maskell PD, Kumar P. Indirect sensing of insulin-induced hypoglycaemia by the carotid body in the rat. J Physiol 556: 255–266, 2004. doi:10.1113/jphysiol.2003.058321.
    Crossref | PubMed | ISIGoogle Scholar
  • 6. Birmingham K, Gradinaru V, Anikeeva P, Grill WM, Pikov V, McLaughlin B, Pasricha P, Weber D, Ludwig K, Famm K. Bioelectronic medicines: a research roadmap. Nat Rev Drug Discov 13: 399–400, 2014. doi:10.1038/nrd4351.
    Crossref | PubMed | ISIGoogle Scholar
  • 7. Conde SV, Obeso A, Gonzalez C. Low glucose effects on rat carotid body chemoreceptor cells’ secretory responses and action potential frequency in the carotid sinus nerve. J Physiol 585: 721–730, 2007. doi:10.1113/jphysiol.2007.144261.
    Crossref | PubMed | ISIGoogle Scholar
  • 8. Conde SV, Ribeiro MJ, Melo BF, Guarino MP, Sacramento JF. Insulin resistance: a new consequence of altered carotid body chemoreflex? J Physiol 595: 31–41, 2017. doi:10.1113/JP271684.
    Crossref | PubMed | ISIGoogle Scholar
  • 9. Conde SV, Sacramento JF, Guarino MP, Gonzalez C, Obeso A, Diogo LN, Monteiro EC, Ribeiro MJ. Carotid body, insulin, and metabolic diseases: unraveling the links. Front Physiol 5: 418, 2014. doi:10.3389/fphys.2014.00418.
    Crossref | PubMed | ISIGoogle Scholar
  • 10. Cramer JA, Wiggins RH, Fudim M, Engelman ZJ, Sobotka PA, Shah LM. Carotid body size on CTA: correlation with comorbidities. Clin Radiol 69: e33–e36, 2014. doi:10.1016/j.crad.2013.08.016.
    Crossref | PubMed | ISIGoogle Scholar
  • 11. Dahan A, Nieuwenhuijs D, Teppema L. Plasticity of central chemoreceptors: effect of bilateral carotid body resection on central CO2 sensitivity. PLoS Med 4: e239, 2007. doi:10.1371/journal.pmed.0040239.
    Crossref | PubMed | ISIGoogle Scholar
  • 12. Dampney RAL. Arcuate nucleus - a gateway for insulin’s action on sympathetic activity. J Physiol 589: 2109–2110, 2011. doi:10.1113/jphysiol.2011.208579.
    Crossref | PubMed | ISIGoogle Scholar
  • 13. 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 62: 2422–2430, 2013. doi:10.1016/j.jacc.2013.07.079.
    Crossref | PubMed | ISIGoogle Scholar
  • 14. Dempsey JA, Smith CA. Do carotid chemoreceptors inhibit the hyperventilatory response to heavy exercise? Can J Appl Physiol 19: 350–359, 1994. doi:10.1139/h94-028.
    Crossref | PubMedGoogle Scholar
  • 16. European Medicines Agency. Guideline on Clinical Investigation of Medicinal Products in the Treatment or Prevention of Diabetes Mellitus, 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf.
    Google Scholar
  • 17. Famm K, Litt B, Tracey KJ, Boyden ES, Slaoui M. Drug discovery: a jump-start for electroceuticals. Nature 496: 159–161, 2013. doi:10.1038/496159a.
    Crossref | PubMed | ISIGoogle Scholar
  • 18. Forster HV, Pan LG. The role of the carotid chemoreceptors in the control of breathing during exercise. Med Sci Sports Exerc 26: 328–336, 1994. doi:10.1249/00005768-199403000-00009.
    Crossref | PubMed | ISIGoogle Scholar
  • 19. Forster HV, Pan LG, Bisgard GE, Kaminski RP, Dorsey SM, Busch MA. Hyperpnea of exercise at various PIO2 in normal and carotid body-denervated ponies. J Appl Physiol Respir Environ Exerc Physiol 54: 1387–1393, 1983.
    Link | ISIGoogle Scholar
  • 20. Fukuda Y, Sato A, Trzebski A. Carotid chemoreceptor discharge responses to hypoxia and hypercapnia in normotensive and spontaneously hypertensive rats. J Auton Nerv Syst 19: 1–11, 1987. doi:10.1016/0165-1838(87)90139-1.
    Crossref | PubMedGoogle Scholar
  • 21. Gallego-Martin T, Fernandez-Martinez S, Rigual R, Obeso A, Gonzalez C. Effects of low glucose on carotid body chemoreceptor cell activity studied in cultures of intact organs and in dissociated cells. Am J Physiol Cell Physiol 302: C1128–C1140, 2012. doi:10.1152/ajpcell.00196.2011.
    Link | ISIGoogle Scholar
  • 22. Gonzalez C, Almaraz L, Obeso A, Rigual R. Carotid body chemoreceptors: from natural stimuli to sensory discharges. Physiol Rev 74: 829–898, 1994. doi:10.1152/physrev.1994.74.4.829.
    Link | ISIGoogle Scholar
  • 23. IDF Diabetes Atlas - 7th edition, (2015). http://www.diabetesatlas.org/.
    Google Scholar
  • 24. Joyner MJ, Limberg JK. Insulin and sympathoexcitation: it is not all in your head. Diabetes 62: 2654–2655, 2013. doi:10.2337/db13-0613.
    Crossref | PubMed | ISIGoogle Scholar
  • 25. Koyama Y, Coker RH, Stone EE, Lacy DB, Jabbour K, Williams PE, Wasserman DH. Evidence that carotid bodies play an important role in glucoregulation in vivo. Diabetes 49: 1434–1442, 2000. doi:10.2337/diabetes.49.9.1434.
    Crossref | PubMed | ISIGoogle Scholar
  • 26. Lambert GW, Straznicky NE, Lambert EA, Dixon JB, Schlaich MP. Sympathetic nervous activation in obesity and the metabolic syndrome–causes, consequences and therapeutic implications. Pharmacol Ther 126: 159–172, 2010. doi:10.1016/j.pharmthera.2010.02.002.
    Crossref | PubMed | ISIGoogle Scholar
  • 27. Marcus NJ, Del Rio R, Schultz EP, Xia XH, Schultz HD. Carotid body denervation improves autonomic and cardiac function and attenuates disordered breathing in congestive heart failure. J Physiol 592: 391–408, 2014. doi:10.1113/jphysiol.2013.266221.
    Crossref | PubMed | ISIGoogle Scholar
  • 28. Marshall JM. Peripheral chemoreceptors and cardiovascular regulation. Physiol Rev 74: 543–594, 1994. doi:10.1152/physrev.1994.74.3.543.
    Link | ISIGoogle Scholar
  • 29. Matafome P, Rodrigues T, Pereira A, Letra L, Azevedo H, Paixão A, Silvério M, Almeida A, Sena C, Seiça R. Long-term globular adiponectin administration improves adipose tissue dysmetabolism in high-fat diet-fed Wistar rats. Arch Physiol Biochem 120: 147–157, 2014. doi:10.3109/13813455.2014.950590.
    Crossref | PubMed | ISIGoogle Scholar
  • 30. Matafome P, Rodrigues T, Seica R. Glycation and hypoxia: two key factors for adipose tissue dysfunction. Curr Med Chem 22: 2417–2437, 2015. doi:10.2174/0929867322666150209155633.
    Crossref | PubMed | ISIGoogle Scholar
  • 31. Narkiewicz K, Ratcliffe LE, Hart EC, Briant LJ, Chrostowska M, Wolf J, Szyndler A, Hering D, Abdala AP, Manghat N, Burchell AE, Durant C, Lobo MD, Sobotka PA, Patel NK, Leiter JC, Engelman ZJ, Nightingale AK, Paton JF. Unilateral carotid body resection in resistant hypertension: a safety and feasibility trial. JACC Basic Transl Sci 1: 313–324, 2016. doi:10.1016/j.jacbts.2016.06.004.
    Crossref | PubMedGoogle Scholar
  • 32. Niewiński P, Janczak D, Rucinski A, Jazwiec P, Sobotka PA, Engelman ZJ, Fudim M, Tubek S, Jankowska EA, Banasiak W, Hart EC, Paton JF, Ponikowski P. Carotid body removal for treatment of chronic systolic heart failure. Int J Cardiol 168: 2506–2509, 2013. doi:10.1016/j.ijcard.2013.03.011.
    Crossref | PubMed | ISIGoogle Scholar
  • 33. Niewiński P, Janczak D, Rucinski A, Tubek S, Engelman ZJ, Jazwiec P, Banasiak W, Sobotka PA, Hart EC, Paton JF, Ponikowski P. Dissociation between blood pressure and heart rate response to hypoxia after bilateral carotid body removal in men with systolic heart failure. Exp Physiol 99: 552–561, 2014. doi:10.1113/expphysiol.2013.075580.
    Crossref | PubMed | ISIGoogle Scholar
  • 34. Pardal R, López-Barneo J. Low glucose-sensing cells in the carotid body. Nat Neurosci 5: 197–198, 2002. doi:10.1038/nn812.
    Crossref | PubMed | ISIGoogle Scholar
  • 35. Paton JF, Sobotka PA, Fudim M, Engelman ZJ, Hart EC, McBryde FD, Abdala AP, Marina N, Gourine AV, Lobo M, Patel N, Burchell A, Ratcliffe L, Nightingale A. The carotid body as a therapeutic target for the treatment of sympathetically mediated diseases. Hypertension 61: 5–13, 2013. doi:10.1161/HYPERTENSIONAHA.111.00064.
    Crossref | PubMed | ISIGoogle Scholar
  • 36. Pereda SA, Eckstein JW, Abboud FM. Cardiovascular responses to insulin in the absence of hypoglycemia. Am J Physiol 202: 249–252, 1962.
    Link | ISIGoogle Scholar
  • 37. Petropavlovskaya AA. Reflex hyperglycemia, in The Pharmacology of New Therapeutic Substances. Leningrad: Medgiz, 1953, p. 30–32.
    Google Scholar
  • 38. Ponikowski P, Chua TP, Anker SD, Francis DP, Doehner W, Banasiak W, Poole-Wilson PA, Piepoli MF, Coats AJ. Peripheral chemoreceptor hypersensitivity: an ominous sign in patients with chronic heart failure. Circulation 104: 544–549, 2001. doi:10.1161/hc3101.093699.
    Crossref | PubMed | ISIGoogle Scholar
  • 39. Prabhakhar NR, Joyner MJ. Tasting arterial blood: what do the carotid chemoreceptors sense? Front Physiol 5: 524, 2015. doi:10.3389/fphys.2014.00524.
    Crossref | PubMed | ISIGoogle Scholar
  • 40. Przybylski J, Trzebski A, Czyzewski T, Jodkowski J. Responses to hyperoxia, hypoxia, hypercapnia and almitrine in spontaneously hypertensive rats. Bulletin Europeen de Physiopathologie Respiratoire – Clinical. Respir Physiol 18: 145–154, 1982.
    Google Scholar
  • 41. Rebrin K, Steil GM, Getty L, Bergman RN. Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes 44: 1038–1045, 1995. doi:10.2337/diab.44.9.1038.
    Crossref | PubMed | ISIGoogle Scholar
  • 42. Ribeiro MJ, Sacramento JF, Gonzalez C, Guarino MP, Monteiro EC, Conde SV. Carotid body denervation prevents the development of insulin resistance and hypertension induced by hypercaloric diets. Diabetes 62: 2905–2916, 2013. doi:10.2337/db12-1463.
    Crossref | PubMed | ISIGoogle Scholar
  • 43. Rondinone CM, Wang LM, Lonnroth P, Wesslau C, Pierce JH, Smith U. Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 94: 4171–4175, 1997. doi:10.1073/pnas.94.8.4171.
    Crossref | PubMed | ISIGoogle Scholar
  • 44. Sacramento JF, Chew DJ, Melo BF, Donegá M, Dopson W, Guarino MP, Robinson A, Prieto-Lloret J, Patel S, Holinski BJ, Ramnarain N, Pikov V, Famm K, Conde SV. Bioelectronic modulation of carotid sinus nerve activity in the rat: a potential therapeutic approach for type 2 diabetes. Diabetologia 61: 700–710, 2018. doi:10.1007/s00125-017-4533-7.
    Crossref | PubMed | ISIGoogle Scholar
  • 45. Sacramento JF, Ribeiro MJ, Rodrigues T, Olea E, Melo BF, Guarino MP, Fonseca-Pinto R, Ferreira CR, Coelho J, Obeso A, Seiça R, Matafome P, Conde SV. Functional abolition of carotid body activity restores insulin action and glucose homeostasis in rats: key roles for visceral adipose tissue and the liver. Diabetologia 60: 158–168, 2017. doi:10.1007/s00125-016-4133-y.
    Crossref | PubMed | ISIGoogle Scholar
  • 46. Shirahata M, Tang WY, Shin MK, Polotsky VY. Is the carotid body a metabolic monitor? Adv Exp Med Biol 860: 153–159, 2015. doi:10.1007/978-3-319-18440-1_17.
    Crossref | PubMed | ISIGoogle Scholar
  • 47. Siński M, Lewandowski J, Przybylski J, Bidiuk J, Abramczyk P, Ciarka A, Gaciong Z. Tonic activity of carotid body chemoreceptors contributes to the increased sympathetic drive in essential hypertension. Hypertens Res 35: 487–491, 2012. doi:10.1038/hr.2011.209.
    Crossref | PubMed | ISIGoogle Scholar
  • 48. Smith U. Impaired (‘diabetic’) insulin signaling and action occur in fat cells long before glucose intolerance–is insulin resistance initiated in the adipose tissue? Int J Obes Relat Metab Disord 26: 897–904, 2002. doi:10.1038/sj.ijo.0802028.
    Crossref | PubMed | ISIGoogle Scholar
  • 49. Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension 11: 608–612, 1988. doi:10.1161/01.HYP.11.6.608.
    Crossref | PubMed | ISIGoogle Scholar
  • 50. Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. J Appl Physiol (1985) 86: 1264–1272, 1999. doi:10.1152/jappl.1999.86.4.1264.
    Link | ISIGoogle Scholar
  • 51. Thompson EL, Ray CJ, Holmes AP, Pye RL, Wyatt CN, Coney AM, Kumar P. Adrenaline release evokes hyperpnoea and an increase in ventilatory CO2 sensitivity during hypoglycaemia: a role for the carotid body. J Physiol 594: 4439–4452, 2016. doi:10.1113/JP272191.
    Crossref | PubMed | ISIGoogle Scholar
  • 52. Thorp AA, Schlaich MP. Relevance of sympathetic nervous system activation in obesity and metabolic syndrome. J Diabetes Res 2015: 341583, 2015. doi:10.1155/2015/341583.
    Crossref | PubMed | ISIGoogle Scholar
  • 53. Timmers HJ, Wieling W, Karemaker JM, Lenders JW. Denervation of carotid baro- and chemoreceptors in humans. J Physiol 553: 3–11, 2003. doi:10.1113/jphysiol.2003.052415.
    Crossref | PubMed | ISIGoogle Scholar
  • 54. Trzebski A, Tafil M, Zoltowski M, Przybylski J. Increased sensitivity of the arterial chemoreceptor drive in young men with mild hypertension. Cardiovasc Res 16: 163–172, 1982. doi:10.1093/cvr/16.3.163.
    Crossref | PubMed | ISIGoogle Scholar
  • 55. Ward DS, Voter WA, Karan S. The effects of hypo- and hyperglycaemia on the hypoxic ventilatory response in humans. J Physiol 582: 859–869, 2007. doi:10.1113/jphysiol.2007.130112.
    Crossref | PubMed | ISIGoogle Scholar
  • 56. Wehrwein EA, Basu R, Basu A, Curry TB, Rizza RA, Joyner MJ. Hyperoxia blunts counterregulation during hypoglycaemia in humans: possible role for the carotid bodies? J Physiol 588: 4593–4601, 2010. doi:10.1113/jphysiol.2010.197491.
    Crossref | PubMed | ISIGoogle Scholar
  • 56a. World Health Organization. Diabetes Fact Sheet, 2016. http://www.who.int/mediacentre/factsheets/fs312/en/.
    Google Scholar
  • 57. Zhang M, Buttigieg J, Nurse CA. Neurotransmitter mechanisms mediating low-glucose signalling in cocultures and fresh tissue slices of rat carotid body. J Physiol 578: 735–750, 2007. doi:10.1113/jphysiol.2006.121871.
    Crossref | PubMed | ISIGoogle Scholar