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Science, Technology and Medicine open access publisher.Publish, read and share novel research. Sympathovagal Imbalance in Type 2 Diabetes — Role of Brainstem Thyrotropin-Releasing HormoneHong Yang1[1] Research & Development, Department of Veterans Affairs, Greater Los Angeles Health Care System and Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles and Los Angeles, California, USA1.
Gautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, Cui Y, Mears D, Lu H, Deng C, Heard T and Wess J. Toshinai K, Mondal MS, Nakazato M, Date Y, Murakami N, Kojima M, Kangawa K and Matsukura S. It took a few cups to figure out the best results using the Ekobrew but once we figured it out we couldn’t be happier.
With the insulin pump you can get your insulin levels as close as possible to the way normal pancreas would produce. Autoimmune problems such as diabetes anemia thyroid malfunction and skin rashes rsult in patches of baldness also referred to as alopecia areata. Phone App Giveaway Application DownLoad Social Networking Htc Yahoo Search Engine Free Download Nokia Samsung Blackberry Opera Photos Specs Comparison Top List iPad Tips Video Hp Taste might seem like an odd way to refer to a disease that involves urine but diabetes mellitus is so-named because the earliest health-care workers in ancient Greece Richard Anderson Albert Khan Ph.D. How magnesium prevents diabetes: Researches have shown that magnesium can prevent diabetes.
Maintaining homeostasis requires that the body continuously monitor its internal conditions. In order to set the system in motion, a stimulus must drive a physiological parameter beyond its normal range (that is, beyond homeostasis).
Humans have a similar temperature regulation feedback system that works by promoting either heat loss or heat gain ([link]b). Blood vessels in the skin begin to dilate allowing more blood from the body core to flow to the surface of the skin allowing the heat to radiate into the environment. The depth of respiration increases, and a person may breathe through an open mouth instead of through the nasal passageways. In contrast, activation of the brain’s heat-gain center by exposure to cold reduces blood flow to the skin, and blood returning from the limbs is diverted into a network of deep veins. Positive feedback intensifies a change in the body’s physiological condition rather than reversing it. Childbirth at full term is an example of a situation in which the maintenance of the existing body state is not desired.
The first contractions of labor (the stimulus) push the baby toward the cervix (the lowest part of the uterus).
Homeostasis is the activity of cells throughout the body to maintain the physiological state within a narrow range that is compatible with life.
After you eat lunch, nerve cells in your stomach respond to the distension (the stimulus) resulting from the food. Which of the following is an example of a normal physiologic process that uses a positive feedback loop? Identify the four components of a negative feedback loop and explain what would happen if secretion of a body chemical controlled by a negative feedback system became too great.
The four components of a negative feedback loop are: stimulus, sensor, control center, and effector.
What regulatory processes would your body use if you were trapped by a blizzard in an unheated, uninsulated cabin in the woods? The autonomic nervous system is a major pathway mediating the brain regulation of metabolism2.1. Brainstem Thyrotropin-Releasing Hormone (TRH)-containing circuits regulate sympathovagal outflow to visceral organs3.1. Introduction Type 2 diabetes (T2D) is the world’s fastest growing disease with high morbidity and mortality rates. Diabetic alteration of cardiac vago-sympathetic modulation assessed with tone-entropy analysis.
Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Energy Expenditure and Body Composition of Chronically Maintained Decerebrate Rats in the Fed and Fasted Condition. Microvascular specializations promoting rapid interstitial solute dispersion in nucleus tractus solitarius. Electrophysiological study of paraventricular nucleus neurons projecting to the dorsomedial medulla and their response to baroreceptor stimulation in rats.
Stimulation of the paraventricular nucleus modulates the activity of gut-sensitive neurons in the vagal complex.
Effects of hypothalamic stimulation on activity of dorsomedial medulla neurons that respond to subdiaphragmatic vagal stimulation. Tolbutamide excites rat glucoreceptive ventromedial hypothalamic neurones by indirect inhibition of ATP-K+ channels. Serotonin released from intestinal enterochromaffin cells mediates luminal non-cholecystokinin-stimulated pancreatic secretion in rats.
Cholinergic neurons in the rat central nervous system demonstrated by in situ hybridization of choline acetyltransferase mRNA. The origin and development of the vagal and spinal innervation of the external muscle of the mouse esophagus. The distribution of neuronal nitric oxide synthase in the nucleus tractus solitarii of the squirrel monkey.
Medullary catecholaminergic neurons projecting to lateral hypothalamic area and expressing Fos after chemical stimulation of the stomach in the rat. Central Neural Regulation of Cardiovascular Function by Angiotensin: A Focus on the Rostral Ventrolateral Medulla.
Three types of putative presympathetic neurons in the rostral ventrolateral medulla studied with rat brainstem-spinal cord preparation. Efferent projections of rat rostroventrolateral medulla C1 catecholamine neurons: Implications for the central control of cardiovascular regulation.
CNS sites involved in sympathetic and parasympathetic control of the pancreas: a viral tracing study. Acute hyperinsulinemia and its reversal by vagotomy after lesions of the ventromedial hypothalamus in anesthetized rats.
Locations and innervation of cell bodies of sympathetic neurons projecting to the gastrointestinal tract in the rat.
Ventromedial hypothalamic lesion-induced vagal hyperactivity stimulates rat pancreatic cell proliferation. Relationships Between the Autonomic Nervous System and the Pancreas Including Regulation of Regeneration and Apoptosis: Recent Developments. Meal-induced insulin secretion in dogs is mediated by both branches of the autonomic nervous system. Cephalic-phase insulin and glucagon release in normal subjects and in patients receiving pancreas transplantation.
Insulin secretion and sensitivity after simultaneous pancreas-kidney transplantation estimated by continuous infusion of glucose with model assessment.
Metabolism of oral glucose in pancreas transplant recipients with normal and impaired glucose tolerance. Pathophysiology of hyperinsulinemia following pancreas transplantation: altered pulsatile versus Basal insulin secretion and the role of specific transplant anatomy in dogs. Muscarinic stimulation of pancreatic insulin and glucagon release is abolished in m3 muscarinic acetylcholine receptor-deficient mice.
A critical role for beta cell M(3) muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo.
Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Brainstem Thyrotropin-Releasing Hormone Regulates Food Intake through Vagal-Dependent Cholinergic Stimulation of Ghrelin Secretion. Summary Description and Clinical Pharmacology Indications and Dosage Warnings and Precautions Side Effects and Adverse Reactions Drug Interactions Overdosage Contraindications Other Rx Info. Health Benefits Of Okra o Lady Fingers: The superior fiber found in okra helps to prevent diabetes and constipation. Stevia enables pregnant women to enjoy the taste of sugar learn how to incorporate this natural diabetes type 2 medication sweetener into your gestational diabetes diet meal.
I don’t think being vegan turns people that way rather I think it just draws many that are already self-righteous.
From body temperature to blood pressure to levels of certain nutrients, each physiological condition has a particular set point. A sensor, also referred to a receptor, is a component of a feedback system that monitors a physiological value.
As the sweat evaporates from the skin surface into the surrounding air, it takes heat with it. A person’s body retains very tight control on water levels without conscious control by the person. A deviation from the normal range results in more change, and the system moves farther away from the normal range.
Enormous changes in the mother’s body are required to expel the baby at the end of pregnancy. The cervix contains stretch-sensitive nerve cells that monitor the degree of stretching (the sensors). Homeostasis is regulated by negative feedback loops and, much less frequently, by positive feedback loops.
If too great a quantity of the chemical were excreted, sensors would activate a control center, which would in turn activate an effector.
This would reduce blood flow to your skin, and shunt blood returning from your limbs away from the digits and into a network of deep veins. The vagal regulation of visceral function is altered by abnormal blood glucose levels in T2D4.2.
The potential to develop effective therapies is severely limited by poor understanding of mechanisms underlying the etiology and progression of T2D. A study on heart rate variability in first-degree relatives of Type 2 diabetes patients and control subjects. Following these principles and his six week intensive plan i lost almost 25 pounds (from 266) in three months without fasting. While there are many strong similarities in the symptoms of both Type I and Type II Diabetes the following symptoms are more pronounced and begin suddenly with Type I whereas they are slower and less predominant with Type II. For example, in the control of blood glucose, specific endocrine cells in the pancreas detect excess glucose (the stimulus) in the bloodstream. If heat loss is severe, the brain triggers an increase in random signals to skeletal muscles, causing them to contract and producing shivering.
And the events of childbirth, once begun, must progress rapidly to a conclusion or the life of the mother and the baby are at risk. These nerve cells send messages to the brain, which in turn causes the pituitary gland at the base of the brain to release the hormone oxytocin into the bloodstream. Less blood circulating means reduced blood pressure and reduced perfusion (penetration of blood) to the brain and other vital organs. Both have the same components of a stimulus, sensor, control center, and effector; however, negative feedback loops work to prevent an excessive response to the stimulus, whereas positive feedback loops intensify the response until an end point is reached.
Your brain’s heat-gain center would also increase your muscle contraction, causing you to shiver. Increasing evidence suggests that the brain plays a key role in regulating metabolism [1, 2]. Scientists believe that therapies that boost GLP-1 levels could help to favorably alter the course of diabetes and its associated side effects.21. I paired the large medium-firm seat cushion with the duro-med relax-a-bac for the perfect solution.
A further fact that demonstrates that xylitol is a 100% natural product is that it is a byproduct of lipitor and developing diabetes the human metabolism Several studies have suggested that a low GI diet can help in the prevention of type-2 diabetes such that replacing sugar with Xylitol may reduce the risk of type-2 diabetes.
I purchased this product to use for a dog that I adopted who had an infected hot spot on his leg. Insulin resistance diabetes test dublin occurs when the normal diabetic dinner recipes pinterest amount of insulin hormone secretd by the pancreas is not able to unlock the cells? MODY (maturity onset diabetes of the young) - single-gene disorder, early onset, strong family history, present as type 2 diabetes, which gene is involved change clinical outcome of disease.


From taking god care of our health, to reducing our body weight to beautifying our skin and hair, these seeds can do a lot for us.Health Benefits of Sabja SeedsLet us start with some potential health benefits of sabja seeds. The control center is the component in a feedback system that compares the value to the normal range.
These pancreatic beta cells respond to the increased level of blood glucose by releasing the hormone insulin into the bloodstream.
Childbirth and the body’s response to blood loss are two examples of positive feedback loops that are normal but are activated only when needed. The extreme muscular work of labor and delivery are the result of a positive feedback system ([link]). Oxytocin causes stronger contractions of the smooth muscles in of the uterus (the effectors), pushing the baby further down the birth canal.
In particular, the exquisitely precise adjustments in the sympathetic and parasympathetic outflow by the brain are critical for maintaining metabolic homeostasis. I eat out at least 15 x a week and I never realized that vegetable oil in restaurants could contain large amounts of trans (hydrogenated) fats.
After I cried my way through more than half I realized this book was not a sermon of meal plan for diabetes person useless information to me. I've been using Dryel sheets for years now and it saves me a LOT of money at the dry cleaners! Here we go:Packed with Nutrition Fresh sabja seeds are loaded with all those essential nutrients, which are required for germination of the plant. For example, the set point for normal human body temperature is approximately 37°C (98.6°F) Physiological parameters, such as body temperature and blood pressure, tend to fluctuate within a normal range a few degrees above and below that point. If the value deviates too much from the set point, then the control center activates an effector.
The insulin signals skeletal muscle fibers, fat cells (adipocytes), and liver cells to take up the excess glucose, removing it from the bloodstream. The brain triggers the thyroid gland in the endocrine system to release thyroid hormone, which increases metabolic activity and heat production in cells throughout the body. The body responds to this potential catastrophe by releasing substances in the injured blood vessel wall that begin the process of blood clotting. Your body would also produce thyroid hormone and epinephrine, chemicals that promote increased metabolism and heat production. Enhanced sympathetic drive and impaired vagal efferent function contribute to multisystemic pathophysiology of T2D, including reduced insulin secretion, gastroparesis, hypertension, and high cardiovascular mortality [3-6].
Adding these seeds to your regular diet can help you get sufficient amounts of carbohydrates, proteins, fats, sugar, dietary fibers, vitamins, minerals, and calories.
Control centers in the brain and other parts of the body monitor and react to deviations from homeostasis using negative feedback.
An effector is the component in a feedback system that causes a change to reverse the situation and return the value to the normal range.
As glucose concentration in the bloodstream drops, the decrease in concentration—the actual negative feedback—is detected by pancreatic alpha cells, and insulin release stops.
The brain also signals the adrenal glands to release epinephrine (adrenaline), a hormone that causes the breakdown of glycogen into glucose, which can be used as an energy source. The cycle of stretching, oxytocin release, and increasingly more forceful contractions stops only when the baby is born.
The aim of this chapter is to emphasize the importance of the brainstem, which contains sympathovagal regulatory nuclei, in the regulation of metabolism, especially in T2D conditions.
Hence, your bodily functions are regularized and you can stay away from a number of ailments.Helps in Digestion Scientists have proved that sabja seeds have excellent carminative effects. The breakdown of glycogen into glucose also results in increased metabolism and heat production. I focus on the role of b ainstem thyrotropin-releasing hormone (TRH) in the physiology of autonomic control of metabolism and the pathophysiology of autonomic dysfunction in T2D. The Liberals won’t even try to rebuild anything because they support 95% of what the CPC is doing. Clotting is contained in a local area based on the tightly controlled availability of clotting proteins.
TRH is a three amino acid neuropeptide originally discovered in the hypothalamic paraventricular nucleus. They serve the purpose of a natural detoxifying agent, which cleanses out our entire gastrointestinal tract efficiently.
The maintenance of homeostasis by negative feedback goes on throughout the body at all times, and an understanding of negative feedback is thus fundamental to an understanding of human physiology. As the stomach becomes toxin-free, the process of digestion turns easier and the scopes of developing various digestive issues like upset stomach, cramps, indigestion, flatulence, etc. Our studies found an impaired brainstem TRH action on the vagal efferent control in a T2D rat model. All you need to do is to soak a handful of the seeds in a glass of milk and drink it every night before going to bed. Understanding brainstem disorders responsible for the sympathovagal imbalance in T2D is fundamental for revealing the mechanism of T2D development. It will make the movements of bowel through your intestines smoother, thereby relieving constipation.Heals Acidity or Stomach BurnSabja seeds are very much soothing for our gastrointestinal tract, especially stomach.
Targeting on restoring a balanced sympathetic-vagal regulatory function of brainstem TRH could be a new direction for the prevention and therapy of T2D.
If you feel an acute burning sensation in your abdomen, you should consume sabja seeds the previous way, i.e. Sympathovagal motor and premotor neurons in the brainstem and the spinal cordThe sympathetic and parasympathetic nerves are the two functionally opposite branches innervating visceral organs to mediate and integrate the central control of body metabolism. They are known to bring the amount of sugar in our bloodstream under control, which eventually stabilizes the blood sugar levels and treats diabetes in an efficient manner.Relieves Respiratory IssuesAs per a new study, sabja seeds are extremely helpful in reducing various respiratory issues. While numerous studies have well established the metabolic regulatory center of the hypothalamus, more and more recent studies revealed the importance of the brainstem in the neuroanatomically distributed control of energy balance [7]. Take 1 tablespoon of pure raw honey, 1 tablespoon of finely grated ginger and 1 tablespoon of fresh sabja seeds in a glass of water.
Studies by Grill et al using the chronically decerebrate rat models demonstrated that the brainstem, also called hindbrain, contains an essential mechanism detecting metabolic need and exhibiting autonomic response to the metabolic challenge [7-9]. The brainstem is sufficient to mediate many aspects of the energetic response to starvation and maintain the normal glucose levels [10].
You will get rid of cold, cough, influenza, bronchial asthma, and so on.Diminishes Stress Sabja seeds are one of the best natural stress busters. As said before, they have wonderful calming effects on our body, which are to some extent similar to aromatherapy. The Dorsal Vagal Complex (DVC) and the nucleus Ambiguus (Amb)The DVC is composed of the dorsal motor nucleus of the vagus (DMV) and the nucleus tractus solitarii (NTS) (Fig.1), which respectively contains somata of parasympathetic efferents projecting to the visceral organs [11-13] and neurons receiving vagal afferent input from the viscera [14]. Therefore, incorporating these seeds in your daily food actually means reduced stress level, increased mental clarity, improved mental strength and uplifted mood.Regulates Body HeatWhen it comes to keeping our body cool during those scorching summer days, sabja seeds can be a true rescuer.
The nearby area postrema (AP) and portions of the NTS, where the blood-brain barrier is incomplete, can be the portal of entry for circulating hormones entering the brain [15].
The Amb contains vagal motor neurons projecting to the thoracic organs as well as the upper gastrointestinal (GI) tract and the pancreas (Fig. Just submerge a handful of fresh sabja seeds in a glass of water and drink it after a hour or so.Weight Loss Benefits of Sabja SeedsAccording to health experts, sabja seeds can help us shed off excess body fat significantly, if included in a weight loss diet. Basically, sabja seeds expand as much as 30 times their actual volume or size, when soaked in water. It makes the texture of the seeds gelatinous and turns the drink into a filling one (with least calorie consumption). Stimulation of the neurons in the paraventricular nucleus of the hypothalamus (PVN) activates DMV neurons projecting to the gut [16,17].
In short, the high fiber content of these seeds can keep us full for a longer time and curb our appetite dramatically.Skin Benefits of Sabja SeedsA healthy skin is nothing but the reflection of a good health.
The ventromedial hypothalamic nucleus (VMH), which contains glucose sensitive neurons, also has direct connections with DMV and NTS [18,19]. So, let’s take a peek into the skin benefits offered by such incredibly healthful sabja seeds:Being a natural detox, sabja seeds can cleanse your internal system and keep several skin issues like acne, pimples, blackheads, whiteheads, etc.
In addition, the DMV receives descending connections from the locus coeruleus (LC), which is the origin of the noradrenergic innervation of the preganglionic autonomic nuclei in the medulla oblongata [20].Vagal afferent fibers arise from neurons in the nodose ganglia and their central and peripheral terminals are located respectively in the NTS and visceral organs. A number of NTS neurons directly, or indirectly via interneurons, connect with vagal motor neurons in the DMV, forming vago-vagal reflex, which may result in increased or decreased vagal efferent activity, and thus is an important component in the brainstem circuits controlling the vagal efferent function, independent of the higher brain [21-23].Acetylcholine is the major transmitter of vagal preganglionic motoneurons in the DMV, which contains intense choline acetyltransferase (ChAT) [24].
By retrograde tracing of subdiaphragmatic vagus, the majority (52%) of labeled DMV cells is ChAT positive [25]. Nitric oxide (NO)-synthesizing neurons are identified in the DMV as vagal motoneurons projecting to the GI tract and also in the NTS [26,27].
The catecholaminergic NTS neurons are tyrosine hydroxylase (TH) positive that relay the signals received by the NTS to other brain structures [28]. The spinal intermediolateral cell column (IML) and the rostral ventrolateral medulla (RVLM)The sympathetic preganglionic motor neurons are located in the IML of the spinal cord. A group of brainstem neurons in the RVLM are sympathetic premotor neurons that project monosynaptically to the IML. Brainstem RVLM is the final common point of convergence of most brain pathways regulating sympathetic tone controlling functions of multisystemic visceral organs [29, 30].
The efferent projections of the catecholamine neurons in the C1 area of the RVLM display important central control of the cardiovascular regulation [31].
Transneuronal labeling studies also showed that the RVLM is a major brain region involved in sympathetic control of the pancreas [32]. Brain regulation of pancreatic endocrine secretion through vagal and sympathetic nervesThe central nervous system requires glucose as an essential source of energy.
To maintain blood glucose levels within a narrow range, the brain regulates pancreatic endocrine secretion through rich innervation of vagal and sympathetic nerves in the islets [33].
In rats, three of the five vagal branches, the posterior gastric, anterior gastric, and the hepatic branches, mediate insulin secretion [34]. The direct sympathetic innervation of the pancreas comes from the sympathetic chains and splanchnic and celiac ganglia [35].
Insulin secretion is stimulated by vagal activation and inhibited by sympathetic-adrenal activation [36].
The integrity of vagus-cholinergic component plays an important role in pancreatic islet proliferation and insulin secretion of the cephalic phase and during the early absorption period, and is necessary to maintain normal glucose tolerance [33, 37-40]. Impairment in glucose tolerance is frequently observed in pancreas-transplanted patients due to denervation of the grafted pancreas.
These patients have a high basal invariant insulin levels but a reduced insulin secretory capacity in response to glucose challenge; cephalic phase insulin release is absent [41-43]. Acetylcholine is the major neurotransmitter of the vagus nervous and M3 receptor represents the major muscarinic receptor that is functional in pancreatic ?-cells [36, 45, 46]. Mutant mice selectively lacking M3 receptor in pancreatic ?-cells display impaired glucose tolerance and greatly reduced insulin release. In contrast, mice selectively overexpressing M3 receptors in ?-cells show a profound increase in glucose tolerance and insulin release. Moreover, the ?-cell M3-overexpressing mice are resistant to diet-induced glucose intolerance and hyperglycemia [47].
These findings indicate that autonomic nerves play a key role in maintaining proper insulin release and glucose homeostasis. The importance of the vagus nerve in food intake regulationFood intake provides body energy. Autonomic innervation, especially cholinergic processes of the vagus control hunger, meal initiation, and food digestion. Vagal-cholinergic (muscarinic) activation regulates gastric ghrelin biosynthesis and secretion [48, 49].
Elevation of plasma ghrelin induced by food deprivation can be blocked by subdiaphragmatic vagotomy and atropine treatment [50]. Circulating ghrelin levels in humans are increased or reduced by cholinergic agonists or antagonists, respectively [51]. Brainstem sympathovagal-controlling circuits respond to metabolic alterationsHypoglycemia is a well established central stimulus that enhances autonomic activities [52-55]. The neuronal activations in the PVN, DVC and other autonomic-regulatory nuclei are initiated when blood glucose levels are immediately below the normal range; the extent of neuronal activation negatively correlates with glucose levels [55]. Microinjection of glucose into the DVC prevents hypoglycemia-induced gastric motility response, indicating a direct influence of glucose concentration on the DVC neurons [56, 57]. Acute glucose deprivation by 2-deoxy-glucose induces Fos expression in NADPH-positive neurons in the NTS and DMV [58] and in catecholamine neurons in the RVLM [59].


Electrophysiological data suggest that some DMV neurons have an enteroceptor function detecting changes in glucose concentration in their environment [60]; however, another study found that glucose had no direct effect on DMV neurons, which appear to be affected by glucose action on NTS neurons [61]. The NTS neurons transmit information of local glucose availability and peripheral glucose metabolic signals received from the vagal afferents toward other brain areas, such as the nearby DMV, via circuits mediating vagal-vagal reflex, and the hypothalamus, including the PVN, via the ascending adrenergic and noradrenergic pathways [61-64]. The response of medullary vagal-regulatory circuits to altered blood glucose levels seems independent of the higher brain structures. In dogs, decerebration and mid-brain or pontine section did not prevent insulin-hypoglycemia-induced gastric acid secretion, which was drastically reduced after destruction of the DMV [65].
Beside the enhanced vagal efferent outflow, which mediates hypoglycemia induced food intake, neuronal activation in the RVLM by glucose deprivation increases sympathetic efferent activity [59], which is important for the liver to produce and release more glucose.
These findings indicate that activating brainstem autonomic regulatory circuits is an important counterregulatory response for changed metabolic status.3.
Brainstem raphe nuclei, including the raphe pallidus (Rpa), raphe obscurus (Rob) and the parapyramidal regions (PPR) are among other major loci capable of TRH synthesis in the brain (Fig.1). Raphe nuclei project TRH-containing fibers to sympathetic and vagal motor neurons located respectively in the brainstem DVC, the RVLM, and the spinal IML, areas densely clustered with TRH-immunoreactive nerve terminals and TRH receptor 1 [66-69] (Figs.1,2). Electron microscopic studies revealed that TRH terminals make direct synaptic contacts with dendrites of neurons in medial NTS and vagal motoneurons throughout the DMV [68].
TRH-containing fibers also innervate sympathetic premotor loci, particularly the RVLM [69, 71, 72]. These TRH-containing brainstem-spinal circuits are important central components of autonomic regulation of visceral organ functions and in particular, the baroreflex pathways [73]. Brainstem TRH regulation of gastric, pancreatic, and cardiovascular functionsStudies in the 1980s by Amir S et al and others found that intracerebroventricular (icv) injection of TRH induces hyperglycemia through pathways involving the adrenal gland in rats, but prevents central and peripheral stimuli-induced hyperglycemia in mice through stimulating insulin release [74-78].
The gastric myenteric plexus innervates smooth muscle and mucosal layers and receives dense and intricate network of vagal efferent axons [83-86]. Electrical stimulation of the rat cervical vagus nerve induces widespread Fos expression in the gastric myenteric plexus in rats [87, 88]. Similarly, intracisternal injection of TRH analog, known to activate vagal preganglionic neurons in the DMV and increase gastric vagal efferent discharges [80, 89,90], activates gastric myenteric neurons in rats [91]. Brainstem microinjection and intrathecal (it) injection studies revealed that pontine locus coeruleus, brainstem RVLM and spinal IML are TRH action sites for activating sympathetic efferent pathways [69, 79, 92, 93], whereas the DMV, the Amb, and the dorsal portion of the RVLM are among those responsible for the resulting stimulation of vagal efferent outflow [69, 94-96].
TRH knockout mice are significantly hyperglycemic with impaired insulin secretion in response to glucose [98]. Physiological and pathophysiological regulation of brainstem TRH gene expressionAutonomic response to external and internal environmental changes is associated with activation of brainstem TRH containing pathways. Brainstem TRH gene expression is upregulated by energy deficiency or increased energy demand, such as starvation, hypothermia, and hypothyroidism [49, 99, 100].The physiological role of brainstem TRH in regulating sympathovagal efferent activities responding to metabolic challenge was first evidenced in the animal model of cold exposure, which is wildly used to induce sympathetic-vagally mediated gastric ulceration [99, 101, 102].
The hypothermia resulting from cold exposure induces Fos expression in the Rpa, Rob, PPR and DVC neurons and enhances brainstem TRH gene expression, especially in the Rpa and Rob [99, 104, 105]. Cold exposure induced gastric ulceration and increased gastric emptying were prevented by icv injection of TRH antiserum or antisense oligodeoxynucleotides of TRH receptor, respectively [109, 110]. Brainstem TRH gene expression is influenced by thyroid hormone levels in a feedback regulatory manner. Thyroidectomy increases TRH mRNA levels in the raphe nuclei and the effect is reversed by thyroid hormone replacement [100]. This finding indicates that abnormal brainstem TRH gene expression and altered TRH regulation of sympathovagal efferent outflow may be involved in the autonomic disorders observed in hypo- or hyperthyroidism. By contrast, RX77368 at 25 ng injected into the lateral ventricle induced a delayed and insignificant orexigenic effect only in the first hour. Brainstem TRH mRNA and TRH receptor1 mRNA increased by 57-58% and 33-35% in 24-48 h fasted rats and returned to the fed levels after a 3 hour re-feeding. Natural food intake in overnight fasted rats was significantly reduced by intracisternal TRH antibody, Y1 antagonist, and peripheral atropine. These data establish a physiological role of brainstem TRH in vagal-ghrelin-mediated stimulation of food intake, which involves interaction with brainstem Y1 receptors [49].
Interaction of TRH with other neurotransmitters and neuropeptides in the DVCThe TRH-synthesizing neurons in brainstem raphe nuclei contain other neuropeptides and neurotransmitters, such as substance P (SP) and serotonin (5-HT).
In the DVC, 5-HT potentiates and SP suppresses the vagal-activating action of TRH [111, 112].
In addition, information of glucose metabolism in the liver is sent to the brainstem via the afferent fibers in the hepatic vagal branch.
Sensors localized in the portal vein pass nutrition signals to the brain through sympathetic-spinal pathways [113, 114]. Of particular noticeable, the vagal-efferent activation by brainstem TRH is inhibited by these signals from proximal gut. We have found that intraduodenal infusion of lipid or intravenous infusion of glucose, CCK, secretin, or PYY inhibits intracisternal TRH-induced gastric acid secretion that is mediated by vagal efferent activation [115-117]. Collectively, research findings show that the TRH containing raphe-DVC pathways and raphe-IML pathways play important physiological roles in maintaining metabolic homeostasis, through balancing sympathovagal outflow that controls multisystemic visceral organs.4.
Sympathovagal imbalance is the linchpin of T2D pathophysiologyRelative to healthy peers, diabetic patients have increased sympathetic and decreased parasympathetic activity that appears to be present at early stages of metabolic impairment, regardless of the presence or absence of autonomic neuropathy [118-121]. T2D patients have higher resting muscle sympathetic nerve activity burst incidence and arterial norepinephrine levels, lower plasma norepinephrine clearance and reduced neuronal reuptake, compared with obese metabolic syndrome patients [122]. The progression from obesity to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition [122].
Moreover, sympathetic overactivity may be a contributing factor to the development of T2D in non-obese men [133].
The vagal regulation of visceral function is altered by abnormal blood glucose levels in T2DConverging evidence suggests that hyper- or hypoglycemia affects GI functions by influencing vagal-cholinergic outflow to the viscera. GI functions stimulated by vagal efferent activation, such as sham feeding-induced pancreatic polypeptide (PP) release and gastric acid secretion, were remarkably reduced in humans during hyperglycemia [134].
In the rat, experimental diabetes lowered gastric acid secretion, which did not decrease further after vagotomy [135]. Hyperglycemia induced by intravenous glucose infusion completely prevented the gastric acid secretion stimulated by intracisternal TRH analog [115]. In contrast to hyperglycemia, insulin-hypoglycemia induces central-vagal stimulus of upper GI functions and has been widely used to test vagus nerve integrity [136-139]. These findings establish the mediating role of the vagus nerve in GI functional alternations induced by altered glucose metabolism. Gastric acid secretion is markedly lower and gastric emptying abnormalities occur in about 30-50% of diabetic patients [141-144]. Although morphological changes in the vagus nerve were identified in diabetic patients [145], many observations indicate that hyperglycemia itself may play a major role in the abnormal GI motility of T2D patients, in addition to the traditionally-attributed irreversible autonomic neuropathy [143, 146].
Acute hyperglycemia causes reversible motility impairment in the GI tract in both healthy subjects and in diabetic patients and animals [147-151].
Delay in gastric emptying is observed within one week after streptozotocin treatment in rats, when there is no autonomic neuropathy developed [152]. Even changes in blood glucose levels within the normal postprandial range significantly impact gastric emptying in both normal subjects and diabetic patients [153]. In fact, after intravenous glucose infusion, both the first and second phases of insulin secretion are impaired in T2D patients [156]. The impaired second phase insulin secretion may result from reduced incretin secretory response and the reduction of absolute incretin effect in T2D [156-158], both can be attributed to impaired vagal efferent activity [159]. The impaired vagal function reduces the proliferation of pancreatic islet ?-cells, resulting in an approximately 60% reduction in ?-cell mass in T2D patients [38, 160]. With increasing duration of T2D, the decrease of postprandial insulin secretion becomes more prominent [161]. The contribution of sympathetic overactivity to the inhibition of insulin secretion in T2D was evidenced in a patient, who underwent a spinal-sympathetic blockage for treating a disorder that was not directly related to diabetes but resulted in a dramatic 50% decrease in her insulin need [162].
Sympathetic hyperactivity contributes to cardiovascular diseases in T2DCardiovascular disease is the leading cause of mortality in patients with T2D. T2D patients have a high incidence of hypertension and nonischemic heart failure, and worse outcomes in acute cardiovascular events compared to non-diabetic controls [163, 164].
A key mechanism underlying cardiovascular disorders is an increase in sympathetic nerve activity [73, 165], in addition to pathological cardiovascular changes due to inflammation and over-activity of the renin-angiotensin system [164, 166-168], which are associated with altered sympathovagal function as well. The cardiac vagal and sympathetic nerve functions are both abnormal in T2D patients, but particularly shown as decreased cardiac vagal baroreflex sensitivity [169].
These autonomic dysregulation contribute to increased blood pressure (BP), cardiac arrhythmias and atrial fibrillation, and the resulting progression to heart failure [4, 118, 170-173].
The attenuated sympathetic response to hypotension may contribute directly to mortality in diabetes and cardiovascular disease [174]. Autonomic dysfunction has become one of the most powerful predictor of risk for cardiac mortality in T2D patients [169, 175]. GK rat is a suitable animal model for studying sympathovagal imbalance in T2DThe GK rat is an extensively studied polygenic model of non-obese T2D that was obtained by selective breeding of individuals with glucose intolerance from a non-diabetic Wistar rat colony [176,177]. GK rats are used to dissect genetic etiology of T2D [178,179], and exhibit well-characterized features typical of human T2D, such as fasting hyperglycemia, impaired insulin-secretory response to glucose, reduced ?-cell mass, chronic inflammation, disruption of hepatic lipid metabolism, hypertension, and insulin resistance [97, 176, 178, 180, 181]. GK rats and human T2D share similar late complications, such as neuropathy, nephropathy, and cardiovascular disorders including heart failure [180, 182-184]. Glucose-stimulated insulin release was reduced by 90% in the first phase and by 75% in the second phase in GK rats [185]. Vagal-dependent increase of islet blood flow, which is required for glucose-induced insulin secretion, is diminished in GK rats [186]. Increased fat content and elevated serum leptin levels in T2D GK rats Higher amounts of visceral fat is a sign of a high ratio of sympathetic vs parasympathetic reactivity [129]. We measured the lean and fat body mass quantities in awake rats by non-invasive magnetic resonance imaging. Compared to Wistar rats with same body weight, GK rats have doubled fat mass and significantly less lean mass.
During rat growth from 285 g to 320 g, the increase in Wistar rats is mainly lean weight while that in GK rats is mainly fat weight. Coinciding with this finding, serum leptin levels elevated in GK rats in normally feed, fast, and refeed status. The well-known gastric acid-stimulatory effect of intracisternal injection of TRH analog was totally absent in T2D GK rats, indicating that TRH action in the DMV to activate vagal efferent outflow is severely damaged in GK rats. Potentiated hyperglycemic and suppressed insulin early-phase responses to TRH analog injected intracisternally, intrathecally into the subarachnoid space at the thoracic 8-11 level, or microinjected into the RVLM in T2D GK rats TRH analog RX77368 (50 ng) injected intracisternally induced markedly greater hyperglycemic and weaker insulin responses in GK rats than in Wistar rats. Bilateral vagotomy blocked RX77368-induced insulin secretion while adrenalectomy abolished its hyperglycemic effect. These results indicate that central-vagal activation-induced insulin secretion is susceptible in T2D GK rats and the dominant sympathetic-adrenal response to brainstem TRH plays a suppressing role on vagal-mediated insulin secretion.
This unbalanced sympathovagal activation by medullary TRH may contribute to the impaired insulin secretion in T2D [82]. Brainstem TRH-triggered cardioacceleration results in death from congestive heart failure in T2D GK rats, showing diminished vagal efferent function in baroreceptor reflex In comparison with Wistar rats, GK rats exhibited basal systolic hypertension (152 ± 2 mmHg) and a significantly potentiated, dose-related hypertensive response to intracisternal injection of TRH analog RX77368 (10-60 ng).
In GK rats only, intracisternal RX77368 (30-60 ng) markedly increased heart rate (+88 bpm) and induced acute cardiac mortality (100%) resulting from congestive heart failure, concurrent with extreme hyperglycemia (>480 mg%), increased plasma H2O2 and 8-isoprostane, and increased heart mRNA levels of NADPH oxidase 4 and vascular cell adhesion molecule-1, which are the oxidative stress and inflammation markers.
GK rats also had elevated basal levels of plasma epinephrine, higher adrenal gene expression of epinephrine-synthesizing enzymes tyrosine hydroxylase and dopamine ?-hydroxylase, and greater responses of plasma catecholamines and the adrenal enzymes to intracisternal TRH analog, compared to Wistar rats.
Pretreatment with the nicotine receptor blocker hexamethonium prevented intracisternal TRH analog induced hypertensive and tachycardic responses, and cardiac mortality in GK rats. The ?-receptor blockage with phentolamine abolished the hypertensive response but enhanced tachycardia (+160 bpm), and reduced mortality by 50%. The angiotensin II type 1 receptor antagonist irbesartan prevented intracisternal RX77368-induced increases in blood pressure, heart rate, and mortality. These findings indicate that sympathetic overactivation triggered by brainstem TRH and the lack of effective vagal counterregulation contribute to the cardiovascular morbidity and mortality in T2D, which involves heightened cardiac inflammation and peripheral oxidative stress responses to the sympathetic drive and a mediating role of renin-angiotensin system [97]. The cardiovascular autonomic imbalance in GK rats further confirms a diminished vagal-activating function of brainstem TRH, which is responsible for the damaged vagal arm function in the baroreceptor reflex.
Summary and perspectives Using the T2D GK rat model, we found a damaged brainstem TRH action on activating the vagal efferent functions, which contributes to reveal the central mechanism of the sympathovagal imbalance in T2D.
Further studies are warranted to investigate in the cellular and molecular levels of the abnormal vagal motor neuronal functions in T2D, such as insulin and TRH signaling in the DVC neurons.



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