Chronically elevated sympathetic nervous system tone: A significant, common, and poorly realised contributor to cardiometabolic disease in type 2 diabetes

A prodigious volume of published clinical and basic science studies has delineated the significant impact of chronically elevated sympathetic nervous system (SNS) tone to promote hyperglycemia1, 2 <S1–S28> and potentiate cardiovascular disease (CVD) risk <S9, S20, S22, S29–S46> in cardiometabolic diseases such as the metabolic syndrome (insulin resistance) and type 2 diabetes (T2D). However, few practicing clinicians are aware of the major impact of chronically elevated SNS tone in exacerbating cardiovascular risk in these common metabolic disorders. Over 40 years ago, clinical investigators from our group conducted one of the earliest clinical studies demonstrating the adverse influence of acute systemic SNS stimulation on whole-body insulin sensitivity in healthy adults assessed via the euglycemic-hyperinsulinemic clamp technique3 <S47>. In these healthy volunteers, a 2-h intravenous infusion of epinephrine to elevate the plasma epinephrine level to levels observed during stress induced marked peripheral and hepatic insulin resistance. The implications were clear that chronically elevated SNS tone could exert serious adverse metabolic consequences if left unabated. While the substantive role of chronically elevated SNS tone (adrenergic and noradrenergic activity) in the genesis and maintenance of hypertension has been well recognised for decades (reviewed in Parati and Esler's work4; <S48–S56>), the other cardiometabolic aspects of this neuropathology have been less well appreciated in clinical practice. However, since our early study3 <S47>, multiple biomedical investigations have identified important roles for chronically elevated SNS tone in the induction of dysmetabolism including potentiation of: (i) daylong elevated free fatty acid levels, (ii) daylong plasma hypertriglyceridemia—especially elevated triglyceride-rich lipoprotein (TRL) levels, (iii) glucose intolerance, (iv) increased hepatic glucose production (particularly during the postprandial state), (v) metabolic and immune tissue inflammatory cytokine production, (vi) vascular vasoconstriction limiting glucose and insulin access to muscle tissue <S57–S59>and (vii) insulin resistance, thus facilitating postprandial hyperglycemia5-8 <S1–S28, S33, S35, S60–S81>, reviewed in <S82>. Furthermore, there is a peculiar relation between insulin and SNS interactions that is critical to the understanding of the contribution of chronically elevated SNS tone to cardiometabolic disease as follows. In healthy, insulin-sensitive subjects, postprandial hyperinsulinemia transiently stimulates CNS activation of muscle sympathetic nerve activity but also blunts SNS vascular vasoconstriction <S83> thus blocking adverse SNS vasoconstrictive effects on insulin-mediated glucose disposal. However, in insulin-resistant states such as obesity and T2D, insulin stimulation of CNS SNS outflow is activated more chronically and the insulin effect to curtail chronic SNS vasoconstriction and its other cardiometabolic dysfunctions such as increased hepatic glucose and triglyceride synthesis and secretion, adipose lipolysis, and sterile inflammation is largely diminished <S9, S11, S19, S57–S59, S84–S86>. As a consequence, a positive feedback loop is created between insulin resistance and chronically elevated SNS tone thus sustaining the insulin resistance syndrome. Furthermore, physiologic hyperinsulinemia for as little as 48 h in healthy insulin-sensitive, normal-glucose-tolerant individuals begets moderate-to-severe insulin resistance. Available evidence suggests that most insulin resistant subjects have some degree of elevated SNS tone when appropriately assessed as muscle sympathetic nerve overactivity, sustained resting heart rate elevation, decreased heart rate variability, or increased plasma norepinephrine turnover rate <S1, S11>. In fact, where it has been studied, chronically elevated SNS tone typically precedes the onset of insulin resistance <S3–S6>. Moreover, the association of SNS overactivity with insulin resistance syndrome has been noted across several different population ethnicities and geographic locations globally <S87–S91>. Clinical conditions that often associate with chronically elevated SNS tone when its level is appropriately measured include (a) history of hypertension plus elevated plasma triglyceride level (>150 mg/dL) <S86, S92–S94> and/or (b) sustained elevated resting heart rate <S95>. With respect to cardiovascular disease, the effect of chronically elevated SNS tone to potentiate the development of hypertension generally is well appreciated <S48–S56>. However, the effect of elevated SNS tone to drive systemic inflammation in metabolic tissues (liver, adipose, muscle, kidney) and the immune system (bone marrow, lymphoid system, spleen, circulating and tissue-residing immunocytes) <S22, S23, S33, S35, S60–S81>, although well delineated, is poorly recognised and represents a key element in CVD progression (reviewed in Cincotta et al.'s work9) <S75–S79, S82, S96–S129>. Such chronically elevated systemic SNS tone, not only induces oxidative stress leading to proinflammatory cytokine/chemokine production in metabolic tissues and immunocytes, but also drives homing of pro-inflammatory immunocytes to the cardiovascular wall (reviewed in <S82>). In the cardiovascular wall, these pro-inflammatory immunocytes initiate: (a) endothelial dysfunction, (b) vascular insulin resistance, (c) deposition of vascular TRL and low-density lipoprotein lipids, (d) excess extracellular matrix deposition by embedded immunocytes (monocytes and macrophages), smooth muscle cells, and endothelial cells, (e) macrophage foam cell formation, and (f) chemokine-driven recruitment of pro-inflammatory peripheral blood mononuclear cells (reviewed in Cincotta et al.'s work9) <S9, S20, S22, S23, S29–S46, S60–S81>. The effects of chronically elevated SNS tone on glucose and lipid metabolism, vascular pathology, and immune-targeted proinflammatory status combine to make chronically increased sympathetic tone a significant driver of CVD (reviewed in <S82>). Whole-body autonomic balance is complex and involves interaction between centres within the central nervous system (CNS) and CNS feedback from multiple peripheral organs (e.g., kidney, liver, adipose, immune system). In this regard, a variety of sympatholytic approaches that function either at specific CNS pre- or post-ganglionic efferent neurons to specific organs or peripherally at certain visceral sites, such as I1 imidizoline receptor agonists, noradrenergic alpha-2 receptor agonists, short chain free fatty acid receptors 3 (FFAR3) antagonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and renal sympathetic afferent denervation have all been associated with improvements in certain aspects of cardiometabolic disease <S130–S138>. However, in mechanistic contradistinction to the above sympatholytic interventions that target specific segments (e.g., organs) of SNS efferent influence, the dopaminergic neuronal-clock circuitry within the CNS that modulates pre-autonomic control centers of the autonomic nervous system is an important regulator of systemic efferent and afferent autonomic tone throughout the daily (day/night) cycle <S25, S139–S154> thus contributing to the coordination of whole body autonomic balance governing metabolic and cardiovascular physiology. In brief, the circadian peak of CNS dopaminergic activity acts as a brake (tonic inhibition) on SNS autonomic over-dominance. Induced loss or blockade of CNS dopaminergic activity at any one of several CNS target neuronal systems allows for chronically increased CNS SNS outflow and resultantly can potentiate cardiometabolic disease mechanisms <S25, S33, S35, S66–S81, S139–S148, S155–S171>. Environmental (western lifestyle) insults that reduce CNS dopaminergic activity, such as high fat/simple sugar diets, altered sleep/wake cycles, depression/anxiety, all contribute to the induction of chronically elevated SNS tone <S143, S172–S191>. Importantly, in the setting of chronically elevated SNS tone (including in hypertension), dopaminergic pharmacological stimulation attenuates the SNS overactivity9-14 <S25, S139–S148, S192–S210>. Circadian-timed administration of Cycloset (bromocriptine-QR, a unique formulation of micronised bromocriptine), a potent sympatholytic, dopamine receptor agonist is an FDA-approved therapy for T2D. The scientific basis and clinical profile for this therapy have been reviewed in detail elsewhere <S211>. Very briefly, early morning Cycloset administration (1.6–4.8 mg/day) provides a short (~2 h) pulse of increased bromocriptine bioavailability in an effort to re-establish the normal circadian peak of CNS dopaminergic activity, attenuation of which has been found to be present in insulin-resistant states and operative, via CNS modulation of the neuroendocrine axis (including sustained SNS overactivation to metabolic, vascular, and immune tissues), in the development of glucose intolerance and reduced maximally insulin-stimulated glucose disposal in preclinical and clinical studies <S211, S212>. Such circadian-timed administration of Cycloset improves postprandial hyperglycemia across the meals of the day and cardiovascular outcomes in T2D subjects, <S211> (see also below). The therapy has a well-established good safety profile in the T2D population with only transient (14-day median) mild to moderate gastrointestinal disturbance during the therapy's 6-week initiation phase occurring in less than 8% of the population during this period <S213, S214>. In a large (N = 3070), controlled trial of overall adverse event outcomes as the primary endpoint with such circadian-timed morning dosing of this unique Cycloset formulation, no significant increase in CNS adverse events deriving from “overshooting” of CNS sympatholytic activity or dopaminergic agonism or otherwise was observed. Of note, adverse event reporting of hypertension was reduced 52% (p = 0.01) in Cycloset versus placebo subjects <S215>. Numerical increases in CNS adverse events among Cycloset subjects included transient orthostatic hypotension upon therapy initiation (0.3% for Cycloset and 0.2% for placebo), syncope (1.6% for Cycloset and 0.7% for placebo), somnolence (4.3% for Cycloset and 1.3% for placebo), and hypoesthesia (1.4% for Cycloset and 1.1% for placebo) <S216>. With regard to this therapy, we conducted a mechanistic study to examine the impact of circadian-timed Cycloset on postprandial glucose metabolism, markers of SNS tone, and immune drivers of cardiovascular inflammation and damage in T2D subjects whose glycemia was inadequately controlled by GLP-1 RA therapy <S82, S217>. Cycloset significantly improved endothelial dysfunction in association with reduced circulating norepinephrine and norepinephrine metabolite levels, postprandial hyperglycemia, plasma markers of systemic oxidative stress and inflammation, hypertension, and mRNA expression of a plethora of key cardiovascular-directed proinflammatory pathway proteins in peripheral blood mononuclear cells <S82, S217>. In total, these findings provide mechanistic support for the observed effect of Cycloset to reduce CVD events in T2D subjects by 42% within a single year in a broadly inclusive population of T2D subjects from the Cycloset Safety Trial15-18 <S213, S214, S218, S219>. Moreover, consistent with the therapy's CNS sympatholytic dopaminergic effect, a post hoc analysis of this study demonstrated that this large (42%) reduction in CVD event rate was further enhanced to a 62% reduction in a subpopulation of hypertensive T2D subjects19 <S220>, that have a heightened CVD risk20 <S29, S30, S221>. Addressing the dual neuropathology of CNS hypodopaminergic tone and elevated SNS outflow impact on CVD <S33, S35, S66–S81, S155–S171> has the potential to alleviate multiple downstream cardiometabolic pathophysiological (metabolic, hemodynamic, and immune) disturbances that combine to promote CVD in T2D patients21 <S211>. A final note is warranted here regarding SNS overactivity in cardiometabolic diseases such as T2D and the use of complementary acting agents to effectively address the T2D condition. Glucagon like peptide-1 receptor agonists (GLP-1 RAs) and SGLT2 inhibitors are established early therapies for T2D. They improve glycemic control primarily by acting to stimulate post-meal pancreatic beta cell glucose mediated insulin secretion or attenuation of inordinate renal glucose reabsorption, respectively. <S222, S223> Moreover, certain therapeutics within these two classes have demonstrated an impact to reduce CVD outcomes in prospective, randomised, placebo-controlled, FDA-registration trials by 12 up to 26% over a 2–5 year treatment period. <S224, S225> Yet, while these therapies are effective anti-diabetes agents with some CVD risk reduction, a significant fraction of these patients remain in need of further glycemic control either concurrently or eventually and still carry a large residual CVD risk22 <S226>. As such, targeting the complex pathophysiology of T2D by exploiting the complementary mechanisms of action of these agents with those of the potent sympatholytic, dopamine agonist actions of Cycloset that act to reduce (a) daylong postprandial hyperglycemia without stimulating an increase in plasma insulin and (b) CVD event rate in the prospective, randomised, placebo-controlled, FDA-registration Cycloset Safety Trial by 42%–52% in a single year <S213, S214, S218, S219> early in the disease progression may prove to be a reasonable future treatment approach in T2D patients in need of such therapy. We wish to thank Ms. Lorrie Albarado for her expert assistance in preparing the manuscript for publication. There is no funding associated with writing this commentary. The author declares no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70347. 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