Abstract
Diabetes mellitus is an epidemic condition with an impressive predictive increase in the next future. Several data suggest that activation of the sympathetic nervous system represents one of the main factors for the sustenance and progression of this pathophysiological condition. Due to the fact that usually diabetes is associated with other pathophysiological conditions, several mechanisms contribute to the hyperadrenergic tone. All these mechanisms are the objective of nonpharmacological and pharmacological approaches not only for a better control of hyperglycemic levels but also to reduce the hyperadrenergic tone and the cardiovascular risk.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047–53.
Guariguata L, Whiting D, Weil C, Unwin N. The International Diabetes Federation diabetes atlas methodology for estimating global and national prevalence of diabetes in adults. Diabetes Res Clin Pract. 2011;94:322–32.
Da Rocha FJ, Ogurtsova K, Linnekamp U, Guariguata L, Seuring T, Zhang P, et al. IDF diabetes atlas estimates of 2014 global health expenditures on diabetes. Diabetes Res Clin Pract. 2016;117:48–54.
Ogurtsova K, da Rocha FJ, Huang Y, Linnekamp U, Guariguata L, Cho NH, et al. IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Prac. 2017;128:40–50.
World Health Organization. Global report on diabetes. Geneva, Switzerland; 2016.
Entmacher PS, Marks HH. Diabetes in 1964; a world survey. Diabetes. 1965;14:212–23.
International Diabetes Federation. IDF Diabetes Atlas. 1st ed. Brussels, Belgium: International Diabetes Federation; 2000.
International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Brussels, Belgium: International Diabetes Federation; 2013.
International Diabetes Federation. IDF Diabetes Atlas. 9th ed. Brussels, Belgium: International Diabetes Federation; 2019.
Degli Esposti L, Saragoni S, Buda S, Sturani A, Degli EE. Glycemic control and diabetes-related health care costs in type 2 diabetes; retrospective analysis based on clinical and administrative databases. Clin Outcomes Res CEOR. 2013;5:193–201.
Diabetes UK. The cost of diabetes. London, United Kingdom: Diabetes UK; 2014.
Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and European Association for the Study on Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. Eur Heart J. 2007;28:88–136.
Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EAM, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. Circulation. 2009;119:351–7.
American Diabetes Association. Standards of medical care in diabetes--2011. Diabetes Care. 2011;34(Suppl 1):S11–61.
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. J Hypertens. 2018;36:1953–2041.
McCormack T, Boffa RJ, Jones NR, Carville S, McManus RJ. The 2018 ESC/ESH hypertension guidelines and the 2019 NICE hypertension guideline, how and why they differ. Eur Heart J. 2019;40:3456–8.
Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet. 2017;389:2239–51.
Roden M, Shulman GI. The integrative biology of type 2 diabetes. Nature. 2019;576:51–60.
Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol (Lausanne). 2013;4:37.
Zheng Y, Ley SH, Hu FB. Global etiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14:88–98.
Halban PA, Polonsky KS, Bowden DW, Hawkins MA, Ling C, Mather KJ, et al. Beta cells failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care. 2014;37:1751–8.
Christensen AA, Gannon M. The beta cell in type 2 diabetes. Curr Diabetes Rep. 2019;19:81.
Yamamoto WR, Bone RN, Sohn P, Syed F, Reissaus CA, Mosley AL, et al. Endoplasmatic reticulum stress alters ryanodine receptor function in the murine pancreatic beta cell. J Biol Chem. 2019;294:168–81.
Bertacca A, Ciccarone A, Cecchetti P, Vianello B, Laurenza I, Maffei M, et al. Continually high insulin levels impair Akt phosphorylation and glucose transport in human bioblasts. Metabolism. 2005;54:1687–93.
Catalano KJ, Maddux BA, Szary J, Youngren JF, Goldfine ID, Schaufele F. Insulin resistance induced by hyperinsulinemia coincides with a persistent alteration at the insulin receptor tyrosine kinase domain. PLoS One. 2014;9:e108693.
Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, et al. Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci USA. 2009;106:17787–92.
Nolan CJ, Ruderman NB, Kahn SE, Pedersen O, Prentki M. Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes. Diabetes. 2015;64:673–86.
Braccini L, Ciraolo L, Campa CC, Perino A, Dl L, Tibolla G, et al. PI3K-C2y is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling. Nat Commun. 2015;6:7400.
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–76.
Boden G, Cheung P, Kresge K, Homko C, Powers B, Ferrer L. Insulin resistance is associated with diminished endoplasmic reticulum stress responses in adipose tissue of healthy and diabetic subjects. Diabetes. 2014;63:2977–83.
Tan Y, Ichikawa T, Li J, Si Q, Yang H, Chen X, et al. Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo. Diabetes. 2011;60:625–33.
Bucris E, Beck A, Boura-Halfon S, Isaac R, Vinik Y, Rosenzweig T, et al. Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic beta cells. J Endocrinol. 2016;230:291–307.
Corkey BE. Banting lecture 2011. Hyperinsulinemia: cause or consequence. Diabetes. 2012(61):4–13.
Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. 2017;23:804–14.
Reed MA, Pories WJ, Chapman W, Pender J, Bowden R, Bakarat H, et al. Roux-en-Y gastric bypass corrects hyperinsulinemia implications for the remission of type 2 diabetes. J Clin Endocrinol Metab. 2011;96:2525–31.
Seravalle G, Colombo M, Perego P, Giardini V, Volpe M, Dell’Oro R, et al. Long-term sympathoinhibitory effects of surgically induced weight loss in severe obese patients. Hypertension. 2014;64:431–7.
Purnell JQ, Johnson GS, Wahed AS, Dalla MC, Piccinini F, Cobelli C, et al. Prospective evaluation of insulin and incretin dynamics in obese adults with and without diabetes for 2 years after Roux-en-Y gastric bypass. Diabetologia. 2018;61:1142–54.
Thomas DD, Corkey BE, Istfan NW, Apovian CM. Hyperinsulinemia: an early indicator of metabolic dysfunction. J Endocr Soc. 2019;3:1727–47.
Aasen G, Fagertun H, Halse J. Effect of loss of regional fat assessed by DXA on insulin resistance and dyslipidemia in obese men. Scand J Clin Lab Invest. 2010;70:547–53.
Grassi G, Seravalle G, Colombo M, Bolla G, Cattaneo BM, Cavagnini F, et al. Body weight reduction, sympathetic nerve traffic, and arterial baroreflex in obese normotensive humans. Circulation. 1998;97:2037–42.
Perseghin G, Price TB, Petersen KF, Roden M, Cline GW, Gerow K, et al. Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med. 1996;335:1357–62.
Rabol R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci USA. 2011;108:13705–9.
Karauti MA, Freitas-Dias R, Ferreira SM, Vettorazzi JF, Nardelli TR, Araujo HN, et al. Acute exercise improves insulin clearance and increases the expression of insulin-degrading enzyme in the liver and skeletal muscle of Swiss mice. PLoS One. 2016;11:e0160239.
Greenwood RH, Mahler RF, Hales CN. Improvement in insulin secretion in diabetes after diazoxide. Lancet. 1976;1:444–7.
Alemzadeh R, Langley G, Upchurch L, Smith P, Slonim AE. Beneficial effect of diazoxide in obese hyperinsulinemic adults. J Clin Endocrinol Metab. 1998;83:1911–5.
American Diabetes Association. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40(Suppl 1):S64–74.
Bastin M, Andreelli F. Dual GIP-GLP1R agonists in the treatment of type 2 diabetes: a short review on emerging data and therapeutic potential. Diabetes Metab Syndr Obesity Targets Ther. 2019;12:1973–85.
O’Dea K, Esler M, Leonard P, Stockigt JR, Nestel P. Noradrenaline turnover during undereating and overeating in normal weight subjects. Metabolism. 1982;896-99
Welle S, Lilavivathana U, Campbell RG. Increased plasma norepinephrine concentrations and metabolic rates following glucose ingestion in man. Metabolism. 1980;29:806–9.
Berne C, Fagius J, Niklasson F. Sympathetic response to oral carbohydrate administration: evidence from microelectrode nerve recordings. J Clin Invest. 1989;84:1403–9.
Rowe JW, Young JB, Minaker KL, Stevens AL, Pallotta J, Landsberg L. Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes. 1981;30:219–25.
Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest. 1991;87:2246–52.
Bazelmans J, Nestel PJ, O’Dea K, Esler MD. Blunted norepinephrine responsiveness to changing energy states in obese subjects. Metabolism. 1985;34:154–60.
Astrup A, Andersen T, Christensen NJ, Bulow J, Madsen J, Breum L, et al. Impaired glucose-induced thermogenesis and arterial norepinephrine response persist after weight reduction in obese humans. J Clin Nutr. 1990;51:331–7.
Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man: a novel mechanism for insulin resistance. J Clin Invest. 1991;87:2246–52.
Landsberg L. Diet, obesity and hypertension: an hypothesis involving insulin, the sympathetic nervous system, and adaptive thermogenesis. Q J Med. 1986;236:1081–90.
Ravussin E, Swinbum BA. Energy metabolism. In: Stunkard AJ, Wadden TA, editors. Obesity: theory and therapy. 2nd ed. Raven: New York; 1993. p. 97–123.
Landsberg L. Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why). J Hypertens. 2001;19:523–8.
Sartori C, Scherrer U. Insulin, nitric oxide and the sympathetic nervous system: at the crossroads of metabolic and cardiovascular regulation. J Hypertens. 1999;17:1517–25.
Grassi G, Seravalle G, Dell’Oro R, Turri C, Pasqualinotto L, Colombo M, et al. Participation of the hypothalamus-hypophysis axis in the sympathetic activation of human obesity. Hypertension. 2001;38:1316–20.
Mark AL, Anderson EA. Genetic factors determine the blood pressure response to insulin resistance and hyperinsulinemia: a call to refocus the insulin hypothesis of hypertension. Proc Soc Exp Biol Med. 1995;208:330–6.
Hausberg M, Hoffman RP, Somers VK, Sinkey CA, Mark AL, Anderson EA. Contrasting autonomic and hemodynamic effects of insulin in healthy versus young subjects. Hypertension. 1997;29:700–5.
Seravalle G, Lonati L, Buzzi S, Cairo M, Quarti Trevano F, Dell’Oro R, et al. Sympathetic nerve traffic and baroreflex function in optimal, normal, and high-normal blood pressure states. J Hypertens. 2015;33:1411–7.
Grassi G, Quarti Trevano F, Seravalle G, Arenare F, Volpe M, Furiani S, et al. Early sympathetic activation in the initial stages of chronic renal failure. Hypertension. 2011;57:846–51.
Dell’Oro R, Quarti Trevano F, Gamba P, Ciuffarella C, Seravalle G, Mancia G, et al. Sympathetic and baroreflex abnormalities in the uncomplicated prediabetic state. J Hypertens. 2018;36:1195–200.
Boden G, Chen X, Ruiz J, White JV, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest. 1994;93:2438–46.
Florian JP, Pawelczyk JA. Non-esterified fatty acids increase arterial pressure via central sympathetic activation in humans. Clin Sci. 2009;118:61–9.
Huggett RJ, Scott EM, Gilbey SG, Stoker JB, Mackintosh AF, Mary DASG. Impact of type 2 diabetes mellitus on sympathetic neural mechanisms in hypertension. Circulation. 2003;108:3097–101.
Curry TB, Hines CN, Barnes JN, Somaraju M, Basu R, Miles JM, et al. Relationship of muscle sympathetic nerve activity to insulin sensitivity. Clin Auton Res. 2014;24:77–85.
Grassi G, Biffi A, Seravalle G, Quarti Trevano F, Dell’oro R, Corrao G, et al. Sympathetic neural overdrive in the obese and overweight state: meta-analysis of published studies. Hypertension. 2019;74:349–58.
Lambert GW, Straznicky NE, Lambert EA, Dixon JB, Schlaich MP. Sympathetic nervous activation in obesity and metabolic syndrome – causes, consequences and therapeutic implications. Pharmacol Ther. 2010;126:159–72.
Grassi G, Dell’Oro R, Quarti Trevano F, Scopelliti F, Seravalle G, Paleari F, et al. Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome. Diabetologia. 2005;48:1359–65.
Thorp AA, Schlaich MP. Relevance of sympathetic nervous system activation in obesity and metabolic syndrome. J Diabetes Res. 2015;2015:341583.
Esler M, Rumantir M, Wiesner G, Kaye D, Hastings J, Lambert G. Sympathetic nervous system and insulin resistance: from obesity to diabetes. Am J Hypertens. 2001;14:304S–9.
Sharma AM, Engeli S, Pischon T. New developments in mechanisms of obesity-induced hypertension. Curr Hypertens Rep. 2001;3:152–6.
Festa A, D’Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000;102:42–7.
Christensen NJ. Catecholamines and diabetes mellitus. Diabetologia. 1979;16:211–24.
Frattola A, Parati A, Gamba P, Paleari F, Mauri G, Di Rienzo M, et al. Time and frequency domain estimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus. Diabetologia. 1997;40:1470–5.
Sucharita S, Bantwal G, Idiculla J, Ayyar V, Vaz M. Autonomic nervous system function in type 2 diabetes using conventional clinical autonomic tests, heart rate and blood pressure variability measures. Indian J Endocrinol Metab. 2011;15:198–203.
Ziegler D, Strom A, Bonhof G, Puttgen S, Bodis M, Buckart V, et al. GDS Group. Differential associations of lower cardiac vagal tone with insulin resistance and insulin secretion in recently diagnosed type 1 and type 2 diabetes. Metabolism. 2018;79:1–9.
Malpas SC. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev. 2010;90:513–57.
Miki K, Yoshomoto M. Sympathetic nerve activity during sleep, exercise, and mental stress. Auton Neurosci. 2013;174:15–20.
Yeboah J, Bertoni AG, Herrington DM, Post WS, Burke GL. Impaired fasting glucose and the risk of incident diabetes mellitus and cardiovascular events in an adult population: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2011;58:140–6.
Anand SS, Dagenais GR, Mohan V, Diaz R, Probsfield J, Freeman R, et al. Glucose levels are associated with cardiovascular disease and death in an international cohort of normal glycaemic and dysglycaemic men and women: the EpiDREAM cohort study. Eur J Prev Cardiol. 2012;19:755–64.
Huang Y, Cai X, Mai W, Li M, Hu Y. Association between prediabetes and risk of cardiovascular disease and all-cause mortality: systematic review and meta-analysis. BMJ. 2016;355:i5953.
Straznicky NE, Grima AT, Sari CI, Eikelis N, Lambert EA, Nestel PJ, et al. Neuroadrenergic dysfunction along the diabetes continuum: a comparative study in obese metabolic syndrome subjects. Diabetes. 2012;61:2506–16.
Grassi G, Biffi A, Dell’Oro R, Quarti Trevano F, Seravalle G, Corrao G, et al. Sympathetic neural abnormalities in type 1 and type 2 diabetes: a systematic review and meta-analysis. J Hypertens. 2020;38:1436–42.
Jamerson KA, Julius S, Gudbrandsson T, Andersson O, Brand DO. Reflex sympathetic activation induces insulin resistance in the human forearm. Hypertension. 1993;21:618–23.
Scherrer U, Sartori C. Insulin is a vascular and sympathoexcitatory hormone: implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity. Circulation. 1997;96:4104–13.
Wu JS, Lu FH, Yang YC, Chang SH, Huang YH, Jason Chen JJ, et al. Impaired baroreflex sensitivity in subjects with impaired glucose tolerance, but not isolated impaired fasting glucose. Acta Diabetol. 2014;51:535–41.
Zimmerman BG, Sybertz EJ, Wong PC. Interactions between sympathetic and renin-angiotensin system. J Hypertens. 1984;2:581–7.
Haynes WG, Sivitz WI, Morgan DA, Walsh SA, Mark AL. Sympathetic and cardiorenal action of leptin. Hypertension. 1997;30:619–23.
Lambert E, Lambert G, Ika-Sari C, Dawood T, Lee K, Chopra R, et al. Ghrelin modulates sympathetic nervous system and stress response in lean and overweight men. Hypertension. 2011;58:43–50.
Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75:33–59.
Mazidi M, Rezaie P, Gao HK, Kengne AP. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22528 patients. J Am Heart Assoc. 2017;6:e004007.
Baker WL, Buckley LF, Kelly MS, Bucheit JD, Pard ED, Brown R, et al. Effects of sodium-glucose cotransporter 2 inhibitors on 24-hour ambulatory blood pressure: a systematic review and meta-analysis. J Am Heart Assoc. 2017;6:e005686.
Sheen AJ, Delanaye P. Effects of reducing blood pressure on renal outcomes in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Metab. 2017;43:99–109.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canaglifozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393:31–9.
Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819–29.
Matthews VB, Elliot RH, Rudnicka C, Hricova J, Heart L, Schlaich MP. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens. 2017;35:2059–68.
Briasoulis A, Al Dhaybi O, Bakris GL. SGLT2 inhibitors and mechanisms of hypertension. Curr Cardiol Rep. 2018;20:1.
Jordan J, Tank J, Heusser K, Heise T, Wanner C, Heer M, et al. The effect of empaglifozin on muscle sympathetic nerve activity in patients with type 2 diabetes mellitus. J Am Soc Hypertens. 2017;11:604–12.
Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71:471–6.
Kiuchi S, Hisatake S, Kabuki T, Fujii T, Oka T, Dobashi S, et al. Long-term use of ipraglifozin improved cardiac sympathetic nerve activity in a patient with heart failure: a case report. Drug Discover Ther. 2018;12:51–4.
Verma S. Are the cardiorenal benefits of SGLT2 inhibitors due to inhibition of the sympathetic nervous system? JACC Basic Transl Sci. 2020;5:180–2.
Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nature Rev Cardiol. 2020;17:2108–17.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Seravalle, G., Grassi, G. (2023). Diabetes and Sympathetic Nervous System. In: Berbari, A.E., Mancia, G. (eds) Blood Pressure Disorders in Diabetes Mellitus. Updates in Hypertension and Cardiovascular Protection. Springer, Cham. https://doi.org/10.1007/978-3-031-13009-0_10
Download citation
DOI: https://doi.org/10.1007/978-3-031-13009-0_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-13008-3
Online ISBN: 978-3-031-13009-0
eBook Packages: MedicineMedicine (R0)