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A New Paradigm in the Understanding and Treatment of the Metabolic Syndrome, Part 2

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Elevated sympathetic tone is a major driver of insulin resistance syndrome and increased cardiovascular disease risk in humans

Reduction of neuronal dopaminergic activity at the hypothalamic clock pacemaker (suprachiasmatic nuclei; SCN) induces increases in sympathetic tone and hypothalamo-pituitary-adrenal axis activity to precipitate insulin resistance syndrome

As concluded in the previous newsletter in this series, “Evolutionary selection for insulin resistance in a cyclic environment: brain clocks and control of peripheral metabolism” the brain is equipped with circadian neurophysiological mechanisms to induce (and reverse) the insulin resistant state that evolved as a survival strategy against ensuing environmental stresses such as prolonged (seasonal) lack of food availability.  A central facilitator of this insulin resistance induction is a diminution of the circadian peak in dopaminergic activity at the SCN.  Neurotoxin induced destruction of these dopaminergic projections to the clock of insulin sensitive animals induces marked insulin resistance and glucose intolerance without alterations in food consumption [1, 2] (Figure 12).

What do we know of how this circadian dopaminergic activity peak at the SCN functions to regulate metabolism?

The loss of the circadian dopaminergic peak activity at the clock signals the clock to adjust its output signaling that regulates peripheral metabolism to drive an insulin resistant condition.  Such alterations in output signaling to induce insulin resistance include specific neurophysiological changes at the ventromedial hypothalamus (VMH) and hypothalamic paraventricular nuclei (PVN) to potentiate increases in sympathetic nervous system (SNS) tone and the hypothalamic-pituitary-adrenal (HPA) axis activity [3,4].  Decreased circadian peak dopaminergic activity at the SCN is coupled to and manifests an increase in noradrenergic (and serotonergic) activity at the VMH [5-10] (Figure 3), which in turn induces the insulin resistance syndrome in seasonal and laboratory animals via its output signals to the autonomic and endocrine systems. This effect is characterized by hyperinsulinemia, hyperglucagonemia, hyperleptinemia, insulin resistance, glucose intolerance, and the hypertensive – elevated sympathetic tone state [11-14] (Figure 4, 5, 6).  Concurrent with such VMH alterations induced by a diminution of hypothalamic dopaminergic activity are elevations in PVN corticotropin releasing hormone (CRH) and neuropeptide Y (NPY) levels.  Such simultaneous increases in PVN CRH and NPY activities potentiate an increase in sympathetic tone, HPA axis activity, and beta cell hypersecretory response to glucose (leading to hyperinsulinemia) (reviewed in [15]).  Consequently, such changes in PVN and VMH activities potentiated by the reduction of dopaminergic circadian peak activity at the clock facilitate the induction and maintenance of the obese-insulin resistant- hypertensive state without any alteration of food consumption.  The composite of these changes at the SCN, VMH, and PVN are sufficient to “lock” the animal in the insulin resistant state even while maintained on a low fat diet.

What is the relevance of this programmable hypothalamic circuitry to human insulin resistance syndrome?

The literature is now replete with clinical studies indicating a causative role for elevated sympathetic nervous system tone in the induction of both insulin resistance syndrome and increased CVD event rate (see reference list on elevated sympathetic tone in human metabolic syndrome, [16-42]).  Increased SNS tone induces increased free fatty acid mobilization, inflammation, and inflammatory cytokine secretion from adipose, increased hepatic insulin resistance, inflammation, and inflammatory cytokine secretion, muscle insulin resistance, and postprandial dysglycemia and dyslipidemia that all in turn act on the vasculature (including kidney vasculature) to precipitate arteriosclerosis (vessel stiffness and inflammation).  Importantly, these studies indicate that elevated SNS tone contributes to CVD risk at the level of the vasculature not only by increasing vascular resistance (hypertension) [24,33,43-48], but more forcefully by directly inducing reactive oxygen species (ROS) generation and inflammation in the vasculature and myocardium [49-52].

Similarly a mounting body of scientific literature is amassing that implicates elevated HPA axis activity (particularly aberrant elevations in the circadian rhythm of plasma cortisol level) as potentiating insulin resistance syndrome [53-60].  The combination of elevated SNS tone and HPA axis activity can be a powerful and persistent pathophysiology for the induction and maintenance of metabolic syndrome and CVD in that each pathophysiology facilitates the existence of the other (reviewed in [4,61]).

A simple means of reversing the VMH and PVN neurophysiology that initiates and maintains elevated SNS and HPA axis activities is the administration of a dopamine (D2) receptor agonist (e.g., bromocriptine) at the appropriate circadian time of day to reinstate the normal circadian peak of dopaminergic activity at the biological clock SCN.  Such treatment reduces overactive VMH NE and S activities and PVN NPY and CRH levels and reverses the metabolic syndrome [4,10,62,63]  (Figure 7, 8, 9).



  1. Suprachiasmatic nuclei monoamine metabolism of glucose tolerant versus intolerant hamsters. Luo S, Luo J, Cincotta AH. Neuroreport. 1999;10(10):2073-7.
  2. Dopaminergic neurotoxin administration to the area of the suprachiasmatic nuclei induces insulin resistance. Luo S, Luo J, Meier AH, Cincotta AH. Neuroreport. 1997;8(16):3495-9.
  3. Bromocriptine-QR therapy for the management of type 2 diabetes mellitus: developmental basis and therapeutic profile summary. Raskin P, Cincotta AH., Expert Review of Endocrinology & Metabolism 2016;11:2,113-48.
  4. Hypothalamic Role in the Insulin Resistance Syndrome. In Insulin Resistance and Insulin Resistance Syndrome. Cincotta A. Hansen B, Shafrir E, Eds. London, Taylor and Francis, 2002,p. 271–312.
  5. Norepinephrine mediates glucoprivic-induced increase in GABA in the ventromedial hypothalamus of rats. Beverly JL, de Vries MG, Beverly MF, Arseneau LM. Am J Physiol Regul Integr Comp Physiol. 2000;279(3):R990-6.
  6. Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release. Borg WP, Sherwin RS, During MJ, Borg MA, Shulman GI. Diabetes 1995;44:180–184.
  7. Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats. Borg MA, Sherwin RS, Borg WP, Tamborlane WV, Shulman GI. J Clin Invest 1997;99:361–365.
  8. Circulating free fatty acids, insulin, and glucose during chemical stimulation of hypothalamus in rats. Steffens AB, Damsma G, van der Gugten J, Luiten PG. Am J Physiol. 1984;247(6Pt1):E765-71.
  9. Hypothalamically-induced insulin release and its potentiation during oral and intravenous glucose loads. Steffens AB, Flik G, Kuipers F, Lotter EC, Luiten PG. Brain Res. 1984;301(2):351-61.
  10. Bromocriptine reduces obesity, glucose intolerance and extracellular monoamine metabolite levels in the ventromedial hypothalamus of Syrian hamsters. Luo S, Meier AH, Cincotta AH. Neuroendocrinology. 1998;68(1):1-10.
  11. Chronic ventromedial hypothalamic infusion of norepinephrine and serotonin promotes insulin resistance and glucose intolerance. Luo S, Luo J, Cincotta AH. Neuroendocrinology. 1999;70(6):460-5.
  12. Chronic infusion of norepinephrine into the VMH of normal rats induces the obese glucose-intolerant state. Cincotta AH, Luo S, Zhang Y, Liang Y, Bina KG, Jetton TL, Scislowski PW. Am J Physiol Regul Integr Comp Physiol. 2000;278(2):R435-44.
  13. Elevation of Norepinephrine (NE) Activity at the Ventromedial Hypothalamus (VMH) of Normal Rats Induces the Obese Hypertensive Insulin Resistant State without Altering Feeding. Luo S, Ezrokhi M, Trubitsyna Y, Li Y, Cincotta AH. Diabetes 2015;64(Suppl1):A540.
  14. Chronic infusion of norepinephrine into the VMH of normal rats induces the obese glucose-intolerant state. Cincotta AH, Luo S, Zhang Y, Liang Y, Bina KG, Jetton TL, Scislowski PW. Am J Physiol Regul Integr Comp Physiol. 2000;278(2):R435-44.
  15. Dopaminergic agonists normalize elevated hypothalamic neuropeptide Y and corticotropin-releasing hormone, body weight gain, and hyperglycemia in ob/ob mice. Bina KG, Cincotta AH. Neuroendocrinology. 2000;71(1):68-78.
  16. Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans.
    Anderson EA1, Balon TW, Hoffman RP, Sinkey CA, Mark AL. Hypertension. 1992;19(6 Pt 2):621-7.
  17. The sympathetic nervous system in hypertension and renal disease. Saruta T, Kumagai H. Curr Opin Nephrol Hypertens. 1996;5(1):72-9.
  18. Role of sympathetic nervous system in hypertension and effects of cardiovascular drugs.
    Noll G, Wenzel RR, Binggeli C, Corti C, Lüscher TF. Eur Heart J. 1998;19(Suppl F):F32-8.
  19. Basal sympathetic nerve activity is enhanced with augmentation of baroreceptor reflex in Wistar fatty rats: a model of obesity-induced NIDDM. Suzuki H, Nishizawa M, Ichikawa M, Kumagai K, Ryuzaki M, Kumagai H, Saruta T, Ikeda H. J Hypertens. 1999;17(7):959-64.
  20. Role of sympathetic nervous system and neuropeptides in obesity hypertension.
    Hall JE, Brands MW, Hildebrandt DA, Kuo J, Fitzgerald S. Braz J Med Biol Res. 2000;33(6):605-18.
  21. Insulin resistance and the sympathetic nervous system. Egan BM. Curr Hypertens Rep. 2003;5(3):247-54.
  22. Elevated sympathetic nerve activity: the link between low birth size and adult-onset metabolic syndrome? Hausberg M, Barenbrock M, Kosch M. J Hypertens. 2004;22(6):1087-9.
  23. High serum high-sensitivity C-reactive protein concentrations are associated with relative cardiac sympathetic overactivity during the early morning period in type 2 diabetic patients with metabolic syndrome. Aso Y, Wakabayashi S, Nakano T, Yamamoto R, Takebayashi K, Inukai T. Metabolism. 2006;55(8):1014-21.
  24. Sympathetic overdrive and cardiovascular risk in the metabolic syndrome. Grassi G. Hypertens Res. 2006;29(11):839-47.
  25. Insulin resistance and sympathetic overactivity in women. Kaaja RJ, Pöyhönen-Alho MK. J Hypertens. 2006;24(1):131-41.
  26. Sympathetic system activity in obesity and metabolic syndrome. Tentolouris N, Liatis S, Katsilambros N. Ann N Y Acad Sci. 2006;1083:129-52.
  27. Cardiovascular risk and adrenergic overdrive in the metabolic syndrome. Grassi G, Quarti-Trevano F, Seravalle G, Dell’Oro R. Nutr Metab Cardiovasc Dis. 2007;17(6):473-81.
  28. The sympathetic nervous system and the metabolic syndrome. Mancia G, Bousquet P, Elghozi JL, Esler M, Grassi G, Julius S, Reid J, Van Zwieten PA. J Hypertens. 2007;25(5):909-20.
  29. Mediators of sympathetic activation in metabolic syndrome obesity. Straznicky NE, Eikelis N, Lambert EA, Esler MD. Curr Hypertens Rep. 2008;10(6):440-7.
  30. Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study. Flaa A, Aksnes TA, Kjeldsen SE, Eide I, Rostrup M. Metabolism. 2008;57(10):1422-7.
  31. The role of norepinephrine and insulin resistance in an early stage of hypertension. Penesova A, Radikova Z, Cizmarova E, Kvetnanský R, Blazicek P, Vlcek M, Koska J, Vigas M. Ann N Y Acad Sci. 2008;1148:490-4.
  32. Association between the sympathetic firing pattern and anxiety level in patients with the metabolic syndrome and elevated blood pressure Lambert E, Dawood T, Straznicky N, Sari C, Schlaich M, Esler M, Lambert G. J Hypertens. 2010;28(3):543-50.
  33. Sympathetic nervous activation in obesity and the metabolic syndrome–causes, consequences and therapeutic implications. Lambert GW, Straznicky NE, Lambert EA, Dixon JB, Schlaich MP. Pharmacol Ther. 2010;126(2):159-72.
  34. Cardiovascular and renal complications of type 2 diabetes in obesity: role of sympathetic nerve activity and insulin resistance. Masuo K, Rakugi H, Ogihara T, Esler MD, Lambert GW. Curr Diabetes Rev. 2010 Mar;6(2):58-67.
  35. Stress and its role in sympathetic nervous system activation in hypertension and the metabolic syndrome. Lambert EA, Lambert GW. Curr Hypertens Rep. 2011;13(3):244-8.
  36. Increased visceral adipose tissue is associated with increased resting heart rate in patients with manifest vascular disease. Bemelmans RH1, van der Graaf Y, Nathoe HM, Wassink AM, Vernooij JW, Spiering W, Visseren FL; SMART Study Group. Obesity (Silver Spring). 2012;20(4):834-41.
  37. Risk of elevated resting heart rate on the development of type 2 diabetes in patients with clinically manifest vascular diseases. Bemelmans RH, Wassink AM, van der Graaf Y, Nathoe HM, Vernooij JW, Spiering W, Visseren FL; SMART Study Group. Eur J Endocrinol. 2012;166(4):717-25.
  38. Leptin increasing sympathetic nerve outflow in obesity: A cure for obesity or a potential contributor to metabolic syndrome? Simonds SE, Cowley MA, Enriori PJ. J. Adipocyte. 2012;1(3):177-181.
  39. Obesity and adipokines: effects on sympathetic overactivity. Smith MM, Minson CT. J Physiol. 2012;590(8):1787-801.
  40. The risk of resting heart rate on vascular events and mortality in vascular patients. Bemelmans RH, van der Graaf Y, Nathoe HM, Wassink AM, Vernooij JW, Spiering W, Visseren FL; SMARTStudy Group. Int J Cardiol. 2013;168(2):1410-5.
  41. Obesity-related metabolic syndrome: mechanisms of sympathetic overactivity. Canale MP, Manca di Villahermosa S, Martino G, Rovella V, Noce A, De Lorenzo A, Di Daniele N. Int J Endocrinol. 2013;2013:865965.
  42. Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome. Thorp AA, Schlaich MP. J Diabetes Res. 2015;2015:341583.
  43. Excessive sympathetic activation in heart failure with obesity and metabolic syndrome: characteristics and mechanisms. Grassi G, Seravalle G, Quarti-Trevano F, Scopelliti F, Dell’Oro R, Bolla G, Mancia G. Hypertension. 2007;49(3):535-41.
  44. Sympathetic activation in cardiovascular and renal disease. Grassi G, Arenare F, Pieruzzi F, Brambilla G, Mancia G. J Nephrol. 2009;22(2):190-5.
  45. Heart rate, sympathetic cardiovascular influences, and the metabolic syndrome. Grassi G, Arenare F, Quarti-Trevano F, Seravalle G, Mancia G. Prog Cardiovasc Dis. 2009;52(1):31-7.
  46. Sympathetic activation in cardiovascular disease: evidence, clinical impact and therapeutic implications. Grassi G, Seravalle G, Mancia G. Eur J Clin Invest. 2015;45(12):1367-75.
  47. Role of the sympathetic nervous system in hypertension and hypertension-related cardiovascular disease. Seravalle G, Mancia G, Grassi G. High Blood Press Cardiovasc Prev. 2014;21(2):89-105.
  48. The autonomic nervous system and hypertension. Mancia G, Grassi G. Circ Res. 2014;114(11):1804-14.
  49. Sympathetic regulation of vascular function in health and disease. Bruno RM, Ghiadoni L, Seravalle G, Dell’oro R, Taddei S, Grassi G. Front Physiol. 2012;3:284.
  50. Oxidative Stress and Hypertensive Diseases. Loperena R, Harrison DG. Med Clin North Am. 2017;101(1):169-193.
  51. Should the sympathetic nervous system be a target to improve cardiometabolic risk in obesity? Lambert EA, Straznicky NE, Dixon JB, Lambert GW. Am J Physiol Heart Circ Physiol. 2015;309(2):H244-58.
  52. Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension. Dinh QN, Drummond GR, Sobey CG, Chrissobolis S. Biomed Res Int. 2014;2014:406960.
  53. Glycemic control is impaired in the evening in prediabetes through multiple diurnal rhythms. Sonnier T, Rood J, Gimble JM, Peterson CM. J Diabetes Complications. 2014;28(6):836-43.
  54. Cortisol secretion in patients with type 2 diabetes: relationship with chronic complications. Chiodini I, Adda G, Scillitani A, Coletti F, Morelli V, Di Lembo S, Epaminonda P, Masserini B, Beck-Peccoz P, Orsi E, Ambrosi B, Arosio M. Diabetes Care. 2007;30(1):83-8.
  55. Cortisol: the villain in metabolic syndrome? Paredes S, Ribeiro L. Rev Assoc Med Bras (1992). 2014;60(1):84-92.
  56. Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver. Macfarlane DP, Raubenheimer PJ, Preston T, Gray CD, Bastin ME, Marshall I, Iredale JP, Andrew R, Walker BR. Am J Physiol Gastrointest Liver Physiol. 2014;307(7):G760-8.
  57. Age and the metabolic syndrome affect salivary cortisol rhythm: data from a community sample. Ceccato F, Barbot M, Zilio M, Ferasin S, De Lazzari P, Lizzul L, Boscaro M, Scaroni C. Hormones (Athens). 2015;14(3):392-8.
  58. Endocrine stress responses and risk of type 2 diabetes mellitus. Siddiqui A, Madhu SV, Sharma SB, Desai NG. Stress. 2015;18(5):498-506.
  59. Diurnal salivary cortisol, glycemia and insulin resistance: The multi-ethnic study of atherosclerosis. Joseph JJ, Wang X, Spanakis E, Seeman T, Wand G, Needham B, Golden SH. Psychoneuroendocrinology. 2015;62:327-35.
  60. Adrenal adenomas, subclinical hypercortisolism, and cardiovascular outcomes. Di Dalmazi G, Pasquali R. Curr Opin Endocrinol Diabetes Obes. 2015;22(3):163-8.
  61. Neuroendocrine perturbations as a cause of insulin resistance. Björntorp P. Diabetes Metab Res Rev. 1999;15(6):427-41.
  62. Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats. Ezrokhi M, Luo S, Trubitsyna Y, Cincotta AH. Diabetol Metab Syndr. 2014;6:104.
  63. Bromocriptine redirects metabolism and prevents seasonal onset of obese hyperinsulinemic state in Syrian hamsters. Cincotta AH, MacEachern TA, Meier AH. Am J Physiol. 1993;264(2 Pt 1):E285-93.