Metabolic

Mind-dopamine-clock interactions regulate cardiometabolic well being by T2D

Author: Anthony H. Cincotta, PhD

Editor’s Note: This is the third in a recurring series of articles about Dr. Cincotta’s work on the dopamine clock in the brain and type 2 diabetes. Click here to visit again Part 1 and Part 2.

Part 3: Targeting a chronically elevated sympathetic tone to improve blood sugar control and cardiometabolic health in type 2 diabetes patients

Anthony H. Cincotta, PhD, is President, Chief Science Officer, and Founder of VeroScience. Dr. Cincotta is the founder and responsible for overseeing all research and development.
He’s over 28 successful years in clinical research and development and is considered one of the world’s leading agencies for metabolic syndrome and Circadian NeuroendÖCrine reset therapy.

Even though general Not accepted from attending physicians Type 2 diabetes (T2D), chronic overactivity of the sympathetic nervous system (SNS) is a common feature of tThe disease The was cancelled a variety of diverse disadvantageous Effects on cellular, Tissue, organ and whole– –body level physiology The initiatede and maintain Metabolic disorders that contributes to it significant to Type 2 diabetes and its associated pathologies (1-15) (see list below). Several brain centers modulate the regulation of the sympathetic outflow through the central nervous system (CNS). H.however, the hypothalamus, particularly the suprachiasmatic nuclei of the biological clock pacemaker, Communication with the pre-autonomous neurons of the paraventricle Cores (VAT) and ventromedial hypothalamic nuclei (VMH), plays a significant Role in sympathetic / parasympathetic activity Balance to the body’s organ systems (16-23). Persistent pImmediate or threatened stresses on the brain, including Western high-fat, high-fat diets, psychosocial stresses, and altered sleep / wake architecture, alter hypothalamic neurophysiology (probably largely by inducing proinflammatory intracellular signal transmission [24]) to induce pre-autonomous neurons chronic Activate the sympathetic outflow to the bowels and vessels (checked in 25, 26) leading to cardiometabolic pathologyphysiological consequences (see list below). Thus, the pathophysiological cardiometabolic molecular environment Feedback generated in the periphery centrally to maintain the chronic activation of the sympathetic outflow. A is pathological positive feedback loop so generated and sustained. SignificantThis pollution Reduce the dopaminergic activity of the brain (hypothalamic) (27-31), Which believeAlly acts too Reluctancen so personable Over-activation (25, 26, 32, 33). Specifically, Diminution in the circadian peak of hypothalamic dopaminergic activity enables the VMH and PVN potentiation of the preganglionic sympathetic drainage from the CNS to the peripheral tissues. Such decreased dopaminergic activity also facilitates the diabetogenic effects of a high-fat diett for hypothalamic glucose acquisition (up to thus impede the peripheral postprandial insulin action) (34). A chronic Reduction of the brain hypothalamic Dopaminergic Activity allows chronic increased sympathetic drainage activation to the periphery Potentiate insulin resistance syndrome (25, 26, 32).

A short one (and incomplete) List of the pathophysiological consequences of a chronically increased SNS activity on cardiometabolic health can be summarized as follows::

  1. Inhibition of muscles Insulin action and glucose uptake (35-40)
  2. Reduction of blood flow to skeletal muscle, which reduces glucose absorption (38, 39)
  3. Impairment of the liver’s ability to control the glucose balance of insulin (which leads to increased and decreased release of glucose in the liver after eating Glucose disposal) (24, 35, 41-47)
  4. Stimulation of hepatic triglyceride synthesis and secretion Potentiation of hypertriglyceridemia (48-50)
  5. Stimulation of inflammation of the liver Potentiation of fatty liver (51-56)
  6. Stimulation of the basal lipolytic rate of white fat, resulting in increased plasma FFA levels Potentiation of insulin resistance, beta– –Cell dysfunction and fatty liver (50, 57-61)
  7. Inhibiting the action of insulin in white fat, resulting in increased plasma FFFA levels Potentiation of insulin resistance, beta– –Cell dysfunction and fatty liver (40, 58)
  8. Stimulates inflammation in white (visceral) adipose tissue Potentiation of insulin resistance (40, 50, 62-64)
  9. Stimulation of several different proinflammatory immunocytes Populations Potentiation of insulin resistance, Hypertension, beta– –Cell dysfunction and fatty liver (65-76)
  10. Immunosuppression against infections and cancer (14, 56, 77-91)
  11. Stimulation of Micro and macrovascular Inflammation, oxidative stress and endothelial dysfunction as well as reduction in NO activity so contribute to arterial stiffness (76, 92, 93)
  12. Direct and indirectly Cardiac stimulationomyocyte oxidative stressinflammation, and apoptosis (94-97)
  13. Potentiation of cardiac insulin resistance to alleviate diabetic cardiomyopathy (95, 98)
  14. Potentiation of sudden cardiac death (also through germination of the sympathetic heart nerve) (99)
  15. Induction and potentiation of heart failure (100-102)
  16. Overactivation of the renin-angiotensin system (103-106)
  17. Exponentiation of renovascular hypertension (104, 107-109)
  18. Potentiation of kidney inflammation and dysfunction as well as chronic kidney diseases (108, 110-112)
  19. Chronic stimulation of vasoconstriction, which leads to increased blood pressure (105, 113, 114)

Bromocriptine, a potent dopamine D2 receptor agonist, owns strong sympatholytic activity (checked in 25, 26). Bromocriptine QR [Cycloset], a quick one– –Release formulation of micronized Bromocriptine, is the only FDA approved sympatholytic for treating Type 2 diabetes. Circadian timed morning management of Cycloset has been shown to lower postprandial glucose levels around the world three Standard meals of the day without increasing the plasma insulin level and improving the insulin-stimulated glucose dispositionl (25). Additionally igreat placebo– –In a controlled, randomized study of the effects of Cycloset on cardiovascular outcomes, the therapy significantly reduced combined adverse cardiovascular events by 40 to 55% within one year (115-118). The timing of the dosage of this quick release formulation of micronized Bromocriptine is designed for the onset of wake up of Every day Sledgep imitate the natural Every day Increase in dopaminergic activity in healthy insulin-sensitive individuals The show preclinical neurophysiological studies Functions too facilitate normal metabolism for the most part by Maintaining an expected sympathetic / parasympathetic balanced output to the periphery (25, 26, 32, 33).

Under individuals With Insulin resistance Syndrome, increased heart rate at rest (eRHR) (Heart Rate of> / = 70 Beats per minute (BPM)(26)) is a marker for an elevated sympathetic tone (4, 7, 8, 119). Both eRHR and high sympathetic tone strong connect with the future and predict it Development of insulin resistance, metabolic syndrome, type 2 diabetes, Cardiovascular disease, and mortality (2-5, 120-125). Consequently, We investigated the possible effect of Cyclort too reduce eRHR in T2D subjects and tested the relationship between its ability to do so and its effectiveness against diabetes (26). in the these Study of 372 T2D subjects, whose hyperGlycemia was treated with one or two oral anti-diabetes agentss (Baseline HbA1c = 6.9) and with baseline eRHR ( 70 BPM), cycloset therapy for six Months reduced both significantly eRHR (around 3.4 BPM) and systolic blood pressure (around 3.6 mmHg), relative to placebo (a clear sign of the attenuation of the overactive sympathetic drive to the periphery). Cycloset was without effect regular Resting heart rate (Basic RHR from <70 BPM). Among T2D subjects with baseline HbA1c 7.5 and baseline eRHR 70 BPM or 80 BPM, Cycloset significantly reduced eRHR around 6.1 and 9.9 BPM, respectively, relative to placebo. The extent of the eRHR reduction was positively correlated to the basis eRHR (Number 1). T.House, tThe larger the base eRHR, the greater the reduction in eRHR with Cycloses vs placebo Therapy. FurthermoreThe greater the eRHR reduction, the greater the HbA1c reduction after Cycloset vs. Placebo therapy (Number 2). For subjects with eRHR at the start of the study from 80 BPM and HbA1c> 7.5, the difference between the groups in the change from baseline HbA1c of Cycloset vs.. Was placebo significantly reduced -1.22. These data can be interpreted as follows: In T2D patients, the higher the sympathetic tone, the greater the dysglycemia, and also the more significant the positive Cycloset effect to reduce both increased sympathetic tone and dysglycemia. The conclusion is that the cycloset-induced reduction in eRHR is a marker for reduction overactive sympathetic Tone generally on the viscera and vasculature, a finding that has been proven by previous studies (126, checked Within the 26th), which in turn facilitates an improvement in the dysglycemia described here.

If taken together, this preclinical and clinical findings discussed herein of disadvantageous The cardiometabolic consequences of increased sympathetic tone and dopaminergic control of sympathetic tone underscore the positive effects of central dopaminergic stimulation to reduce the increased sympathetic tone and thereby improve blood sugar control in type 2 diabetes patients.

illustration 1. Bromocriptine QR compared to placebo reduces the increased resting heart rate (between group differences in change from baseline) as a function of baseline resting heart and baseline hemoglobin A1c (Data of ref. 26).

Data are displayed as mean value ± standard error of the mean.

Figure 2. Glycemic control effect of bromocriptine QR compared to placebo (between group differences in the change from baseline HbA1c) in T2DM subjects with suboptimal blood sugar control (baseline HbA1c ≥ 7.5), stratified according to baseline resting heart rate (data from Ref. 26)). Data displayed as mean value ± standard error of the mean.

1-126 References (PDF)

Part 1: A new paradigm for understanding and treating metabolic syndrome: targeted changes in the biological clock system in the T2D

Part 2:: A New Paradigm for Understanding and Treating Metabolic Syndrome, Part 2

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