Part 3: Targeting chronically elevated sympathetic tone to improve glycemic control and cardiometabolic health in type 2 diabetes patients
Anthony H. Cincotta, PhD is President, Chief Science Officer & Founder of VeroScience . Dr. Cincotta is the founder and is responsible for overseeing all research and development.
He has over 28 successful years in clinical research and development and is recognized as one of the world’s leading authorities on Metabolic Syndrome and Circadian Neuroendocrine Resetting Therapy.
Although generally not recognized by clinicians treating type 2 diabetes (T2D), chronic overactivity of the sympathetic nervous system (SNS) is a common feature of the disease that precipitates a multitude of diverse adverse effects on cellular, tissue, organ, and whole–body level physiology that initiate and maintain metabolic derangements that contribute significantly to type 2 diabetes and its associated pathologies (1-15) (see list below). Several brain centers modulate the central nervous system (CNS) regulation of sympathetic outflow. However, the hypothalamus, in particular the biological clock pacemaker suprachiasmatic nuclei, communication with the pre-autonomic neurons of the paraventricular nuclei (PVN) and ventromedial hypothalamic nuclei (VMH), plays a significant role in sympathetic/parasympathetic activity balance to organ systems of the body (16-23). Persistent perceived immediate or impending stresses to the brain including westernized high fat, high simple sugar diets, psychosocial stress, and altered sleep/wake architecture, alter hypothalamic neurophysiology (presumably in large part via inducing proinflammatory intracellular signaling ) to induce pre-autonomic neurons to chronically activate sympathetic outflow to the viscera and vasculature (reviewed in 25, 26) resulting in cardiometabolic pathophysiological consequences (see list below). Thus, the pathophysiologic cardiometabolic molecular milieu generated in the periphery feeds back centrally to maintain the sympathetic outflow’s chronic activation. A pathological positive feedback loop is thus generated and sustained. Significantly, these environmental stresses reduce brain (hypothalamic) dopaminergic activity (27-31), which usually acts to restrain such sympathetic over-activation (25, 26, 32, 33). In particular, diminution in the circadian peak of hypothalamic dopaminergic activity allows for VMH and PVN potentiation of preganglionic sympathetic outflow from the CNS to the peripheral tissues. Such reduced dopaminergic activity also facilitates a high-fat diet’s diabetogenic impact on hypothalamic glucose sensing (to impede peripheral postprandial insulin action thus) (34). A chronic reduction of brain hypothalamic dopaminergic activity allows for chronic increased sympathetic outflow activation to the periphery to potentiate insulin resistance syndrome (25, 26, 32).
A brief (and incomplete) listing of pathophysiological consequences of chronically elevated SNS activity on cardiometabolic health may be summarized as follows:
- Inhibition of muscle insulin action and glucose uptake (35-40)
- Reduction of blood flow to skeletal muscle thus reducing glucose uptake (38, 39)
- Impairment of hepatic insulin action on glucose balance (resulting in increased hepatic glucose output and decreased post-meal glucose disposal) (24, 35, 41-47)
- Stimulation of hepatic triglyceride synthesis and secretion potentiating hypertriglyceridemia (48-50)
- Stimulation of hepatic inflammation potentiating fatty liver (51-56)
- Stimulation of white adipose basal lipolytic rate leading to increased plasma FFA levels potentiating insulin resistance, beta–cell dysfunction, and fatty liver (50, 57-61)
- Inhibition of insulin action in white adipose leading to increased plasma FFFA levels potentiating insulin resistance, beta–cell dysfunction, and fatty liver (40, 58)
- Stimulation of inflammation in the white (visceral) adipose tissue potentiating insulin resistance (40, 50, 62-64)
- Stimulation of several distinct proinflammatory immunocyte populations potentiating insulin resistance, hypertension, beta–cell dysfunction, and fatty liver (65-76)
- Immuno-suppression against infection and cancer (14, 56, 77-91)
- Stimulation of micro-and macro-vascular inflammation, oxidative stress and endothelial dysfunction and reduction of NO activity thus contributing to arterial stiffness (76, 92, 93)
- Direct and indirect stimulation of cardiomyocyte oxidative stress, inflammation, and apoptosis (94-97)
- Potentiation of cardiac insulin resistance facilitating diabetic cardiomyopathy (95, 98)
- Potentiation of sudden cardiac death (including by cardiac sympathetic nerve sprouting (99)
- Induction and potentiation of congestive heart failure (100-102)
- Over-activation of the renin-angiotensin system (103-106)
- Potentiation of renovascular hypertension (104, 107-109)
- Potentiation of renal inflammation and dysfunction and chronic kidney disease (108, 110-112)
- Chronic stimulation of vasoconstriction leading to elevated blood pressure (105, 113, 114)
Bromocriptine, a potent dopamine D2 receptor agonist, possesses vigorous sympatholytic activity (reviewed in 25, 26). Bromocriptine-QR [Cycloset], a quick–release formulation of micronized bromocriptine, is the only FDA-approved sympatholytic agent for treating type 2 diabetes. Circadian-timed morning administration of Cycloset has been demonstrated to reduce postprandial glucose levels across the three standard meals of the day without raising the plasma insulin level and to improve insulin-stimulated glucose disposal (25). Additionally, in a large placebo–controlled, randomized trial of Cycloset impact on cardiovascular outcomes, the therapy significantly reduced composite adverse cardiovascular events by 40 to 55% within one year (115-118). The timing of dosing of this quick-release formulation of micronized bromocriptine is timed to the onset of waking from daily sleep to mimic the natural daily rise in dopaminergic activity in healthy insulin-sensitive individuals that preclinical neurophysiologic studies indicate functions to facilitate normal metabolism in large part by maintaining an expected sympathetic/parasympathetic balanced output to the periphery (25, 26, 32, 33).
Among individuals with insulin resistance syndrome, elevated resting heart rate (eRHR) (heart rate of >/= 70 beats per minute (BPM)(26)) is a marker of elevated sympathetic tone (4, 7, 8, 119). Both eRHR and high sympathetic tone strongly associate with and predict the future development of insulin resistance, metabolic syndrome, type 2 diabetes, cardiovascular disease, and mortality (2-5, 120-125). Consequently, we investigated the possible effect of Cycloset to reduce eRHR in T2D subjects and tested the relation between its ability to do so and its anti-diabetes effectiveness (26). In this study of 372 T2D subjects whose hyperglycemia was treated with one or two oral anti-diabetes agents (baseline HbA1c = 6.9) and with baseline eRHR (≥ 70 BPM), Cycloset therapy for six months significantly reduced both eRHR (by 3.4 BPM) and systolic blood pressure (by 3.6 mmHg), relative to placebo (a clear sign of attenuation of the overactive sympathetic drive to the periphery). Cycloset was without effect on regular resting heart rate (baseline RHR of < 70 BPM). Among T2D subjects with baseline HbA1c ≥ 7.5 and baseline eRHR ≥ 70 BPM or ≥ 80 BPM, Cycloset significantly reduced eRHR by 6.1 and 9.9 BPM, respectively, relative to placebo. The magnitude of the eRHR reduction was positively correlated to the baseline eRHR (Figure 1). Thus, the greater the baseline eRHR, the greater the reduction in eRHR with Cycloset vs placebo therapy. Furthermore, the greater the eRHR reduction, the greater was the HbA1c reduction following Cycloset vs placebo therapy (Figure 2). For subjects with baseline eRHR of ≥ 80 BPM and HbA1c > 7.5, the between group difference in change from baseline HbA1c of Cycloset vs. placebo was significantly reduced -1.22. These data may be interpreted as – among T2D subjects, the greater the elevation in sympathetic tone, the greater the dysglycemia, and also the more significant the positive Cycloset effect to reduce both elevated sympathetic tone and dysglycemia. The inference is that the Cycloset-induced reduction in eRHR is a marker of reduced over-active sympathetic tone generally to the viscera and vasculature, an outcome substantiated by previous studies (126, reviewed within 26), which in turn facilitates an improvement in dysglycemia as outlined herein.
When taken in composite, these preclinical and clinical findings discussed herein of adverse cardiometabolic consequences of elevated sympathetic tone and dopaminergic control of sympathetic tone highlight the positive impact of central dopaminergic stimulation to reduce elevated sympathetic tone and thereby improve glycemic control in type 2 diabetes subjects.
Figure 1. Bromocriptine-QR versus Placebo Reduces Elevated Resting Heart Rate (Between Group Difference in Change from Baseline) as a Function of Baseline Resting Heart and Baseline Hemoglobin A1c (data from ref. 26).
Data are shown as mean ± standard error of the mean.
Figure 2. Glycemic Control Effect of Bromocriptine-QR versus Placebo (Between Group Difference in Change from Baseline HbA1c) in T2DM Subjects with Suboptimal Glycemic Control (Baseline HbA1c ≥ 7.5) Stratified by Baseline Resting Heart Rate (data from ref. 26). Data shown as mean ± standard error of mean.