Bioelectronic modulation of carotid sinus nerve to treat type 2 diabetes: current knowledge and future perspectives.

Bioelectronic medicine are an emerging class of treatments aiming to modulate body nervous activity to correct pathological conditions and restore health. Recently, it was shown that the high frequency electrical neuromodulation of the carotid sinus nerve (CSN), a small branch of the glossopharyngeal nerve that connects the carotid body (CB) to the brain, restores metabolic function in type 2 diabetes (T2D) animal models highlighting its potential as a new therapeutic modality to treat metabolic diseases in humans. In this manuscript, we review the current knowledge supporting the use of neuromodulation of the CSN to treat T2D and discuss the future perspectives for its clinical application. Firstly, we review in a concise manner the role of CB chemoreceptors and of CSN in the pathogenesis of metabolic diseases. Secondly, we describe the findings supporting the potential therapeutic use of the neuromodulation of CSN to treat T2D, as well as the feasibility and reversibility of this approach. A third section is devoted to point up the advances in the neural decoding of CSN activity, in particular in metabolic disease states, that will allow the development of closed-loop approaches to deliver personalized and adjustable treatments with minimal side effects. And finally, we discuss the findings supporting the assessment of CB activity in metabolic disease patients to screen the individuals that will benefit therapeutically from this bioelectronic approach in the future.

Translating and Testing a Digital Game Promoting Vegetable Consumption in Young Children: Usability Study.

BACKGROUND: Promoting healthy eating in children is key to preventing chronic diseases, and vegetable consumption is notably lower than recommended in this population. Among the interventions tested, gamification has shown promise in promoting familiarization, increasing knowledge, and potentially increasing vegetable intake. OBJECTIVE: This pilot study aimed first to translate the digital game "Veggies4myHeart" into French and to assess its influence on young children's preferences and willingness to taste vegetables when combined with repeated tasting and education. We also aimed to investigate the acceptability and applicability of the game in 2 classrooms. METHODS: During 5 consecutive weekly sessions, children from 2 elementary classes played the digital game consisting of 5 mini games on different vegetables (lettuce, carrot, red cabbage, cucumber, and tomato) in pairs for 10-15 minutes. In addition, they discussed one of the vegetables and tasted the 5 vegetables in each session. Pretest and posttest food preferences and willingness to taste the vegetables were compared. Teachers participated in a semistructured interview. RESULTS: A total of 45 children aged 5 to 6 years tested the French version of the digital game. The children's declared food preferences were already high for carrot, cucumber, and tomato, with scores higher than 4 out of a maximum of 5. The scores did not change significantly after the intervention, except for red cabbage (pretest: mean 2.52, SD 1.49; posttest: mean 3.29, SD 1.67; P=.006) and a composite score (pretest: mean 3.76, SD 1.06; posttest: mean 4.05, SD 1.03; P=.001). Before the intervention, 18 (44%), 30 (73%), 16 (39%), 29 (71%), and 26 (63%) children out of 41 were willing to taste lettuce, carrot, red cabbage, cucumber, and tomato, respectively. After the intervention, no significant statistical differences were observed, with 23 (51%), 36 (80%), 24 (53%), 33 (73%), and 29 (64%) children out of 45 willing to taste lettuce, carrot, red cabbage, cucumber, and tomato, respectively. Teachers supported this tool combined with repeated tasting and education and highlighted facilitators and barriers that should be anticipated to improve implementation in schools. CONCLUSIONS: In this study, we translated an existing digital game applicable and acceptable to both children and teachers. A larger study is warranted to confirm the effectiveness of interventions using the digital game to promote vegetable preference, willingness to taste, and intake.

Increased Abdominal Perimeter Differently Affects Respiratory Function in Men and Women.

Obesity is a worldwide epidemic being the main cause of cardiovascular, metabolic disturbances and chronic pulmonary diseases. The increase in body weight may affect the respiratory system due to fat deposition and systemic inflammation. Herein, we evaluated the sex differences in the impact of obesity and high abdominal circumference on basal ventilation. Thirty-five subjects, 23 women and 12 men with a median age of 61 and 67, respectively, were studied and classified as overweight and obese according to body mass index (BMI) and were also divided by the abdominal circumference. Basal ventilation, namely, respiratory frequency, tidal volume, and minute ventilation, was evaluated. In normal and overweight women, basal ventilation did not change, but obese women exhibited a decrease in tidal volume. In men, overweight and obese subjects did not exhibit altered basal ventilation. In contrast, when subjects were subdivided based on the abdominal perimeter, a higher circumference did not change the respiratory frequency but induced a decrease in tidal volume and minute ventilation in women, while in men these two parameters increased. In conclusion, higher abdominal circumference rather than BMI is associated with alterations in basal ventilation in women and men.

Linking dietary intake, circadian biomarkers, and clock genes on obesity: A study protocol.

Background: The prevalence of obesity continues to rise, and although this is a complex disease, the screening is made simply with the value of the Body Mass Index. This index only considers weight and height, being limited in portraying the multiple existing obesity phenotypes. The characterization of the chronotype and circadian system as an innovative phenotype of a patient's form of obesity is gaining increasing importance for the development of novel and pinpointed nutritional interventions. Objective: The present study is a prospective observational controlled study conducted in Portugal, aiming to characterize the chronotype and determine its relation to the phenotype and dietary patterns of patients with obesity and healthy participants. Methods: Adults with obesity (study group) and healthy adults (control group), aged between 18 and 75, will be enrolled in this study. Data will be collected to characterize the chronotype, dietary intake, and sleep quality through validated questionnaires. Body composition will also be assessed, and blood samples will be collected to quantify circadian and metabolic biomarkers. Discussion: This study is expected to contribute to a better understanding of the impact of obesity and dietary intake on circadian biomarkers and, therefore, increase scientific evidence to help future therapeutic interventions based on chronobiology, with a particular focus on nutritional interventions.

mHealth Applications to Monitor Lifestyle Behaviors and Circadian Rhythm in Clinical Settings: Current Perspective and Future Directions.

Metabolic diseases are a global rising health burden, mainly due to the deleterious interaction of current lifestyles with the underlying biology of these diseases. Daily habits and behaviors, such as diet, sleep, and physical exercise impact the whole-body circadian system through the synchronization of the peripheral body clocks that contribute to metabolic homeostasis. The disruption of this system may promote the development of metabolic diseases, including obesity and diabetes, emphasizing the importance of assessing and monitoring variables that affect circadian rhythms. Advances in technology are generating innovative resources and tools for health care management and patient monitoring, particularly important for chronic conditions. The use of mobile health technologies, known as mHealth, is increasing and these approaches are contributing to aiding both patients and healthcare professionals in disease management and education. The mHealth solutions allow continuous monitoring of patients, sharing relevant information and data with physicians and other healthcare professionals and accessing education resources to support informed decisions. Thus, if properly used, these tools empower patients and help them to adopt healthier lifestyles. This article aims to give an overview of the influence of circadian rhythms disruption and lifestyle habits in the progression of metabolic diseases while also reviewing some of the mobile applications available to monitor lifestyle behaviors and individual chronobiology. Herein is also described the design and development of the NutriClock system, an mHealth solution developed by our team to monitor these variables.

Metabolic Effects of an Oral Glucose Tolerance Test Compared to the Mixed Meal Tolerance Tests: A Narrative Review.

The oral glucose tolerance test (OGTT) is recommended for assessing abnormalities in glucose homeostasis. Recognised as the gold standard test for diagnosing diabetes, the OGTT provides useful information about glucose tolerance. However, it does not replicate the process of absorption and digestion of complex foods, such as that which occurs with a mixed meal tolerance test (MMTT), an alternative that is still not well explored in the diagnosis of metabolic alterations. The MMTT could be an asset in detecting glucose homeostasis disorders, including diabetes since it has more similarities to the common dietary pattern, allowing early detection of subtle changes in metabolic homeostasis in response to combined nutrients. This alternative has the advantage of being more tolerable and pleasant to patients since it induces a more gradual increase in blood glucose, thus reducing the risk of rebound hypoglycemia and other related complications. The present article reviewed the clinical data available regarding the possibility of screening or diagnosing altered glucose homeostasis, including type 2 diabetes mellitus, with the MMTT.

Nutrition education strategies to promote vegetable consumption in preschool children: the Veggies4myHeart project.

OBJECTIVE: To test the efficacy of three nutrition education strategies on the intake of different vegetables in preschool children. DESIGN: This is an experimental study conducted in four Portuguese preschools. The intervention consisted of 20-min educational sessions, once a week, for 5 weeks, with one of the following randomised educational strategies: Portuguese Food Wheel Guide (control), digital game, storybook, storybook and reward (stickers). All groups had repeated exposure to vegetables in all sessions. A pre- and post-test were conducted to determine vegetable intake, and a 6-month follow-up was realised. SETTING: Preschools of Leiria district, Portugal. PARTICIPANTS: A sample of 162 children aged 3 to 6 years. All eligible children attending the preschools were invited to participate. RESULTS: All interventions tested were effective in increasing vegetable consumption both in the short and medium term, without statistically significant differences, compared to the control group. Stickers were more effective in the short term than in the medium term. CONCLUSIONS: The nutritional education strategies associated with repeated exposure tested in this study were effective in promoting vegetable consumption in preschool children. The use of stickers may be a valid strategy to promote the consumption of vegetables less recognised by children.

Blood Pressure Regulation by the Carotid Sinus Nerve: Clinical Implications for Carotid Body Neuromodulation.

Chronic carotid sinus nerve (CSN) electrical modulation through kilohertz frequency alternating current improves metabolic control in rat models of type 2 diabetes, underpinning the potential of bioelectronic modulation of the CSN as a therapeutic modality for metabolic diseases in humans. The CSN carries sensory information from the carotid bodies, peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia. In addition, the CSN also delivers information from carotid sinus baroreceptors-mechanoreceptor sensory neurons directly involved in the control of blood pressure-to the central nervous system. The interaction between these powerful reflex systems-chemoreflex and baroreflex-whose sensory receptors are in anatomical proximity, may be regarded as a drawback to the development of selective bioelectronic tools to modulate the CSN. Herein we aimed to disclose CSN influence on cardiovascular regulation, particularly under hypoxic conditions, and we tested the hypothesis that neuromodulation of the CSN, either by electrical stimuli or surgical means, does not significantly impact blood pressure. Experiments were performed in Wistar rats aged 10-12 weeks. No significant effects of acute hypoxia were observed in systolic or diastolic blood pressure or heart rate although there was a significant activation of the cardiac sympathetic nervous system. We conclude that chemoreceptor activation by hypoxia leads to an expected increase in sympathetic activity accompanied by compensatory regional mechanisms that assure blood flow to regional beds and maintenance of hemodynamic homeostasis. Upon surgical denervation or electrical block of the CSN, the increase in cardiac sympathetic nervous system activity in response to hypoxia was lost, and there were no significant changes in blood pressure in comparison to control animals. We conclude that the responses to hypoxia and vasomotor control short-term regulation of blood pressure are dissociated in terms of hypoxic response but integrated to generate an effector response to a given change in arterial pressure.

Phytopharmacological Strategies in the Management of Type 2 Diabetes Mellitus.

Type 2 Diabetes Mellitus (T2DM) is a chronic disease which corresponds to 90% of the worldwide cases of diabetes, mainly due to epigenetic factors such as unhealthy lifestyles. First line therapeutic approaches are based on lifestyle changes, most of the time complemented with medication mostly associated with several side effects and high costs. As a result, the scientific community is constantly working for the discovery and development of natural therapeutic strategies that provide lower financial impact and minimize side effects. This review focus on these nature-based therapeutic strategies for prevention and control of T2DM, with a special emphasis on natural compounds that present pharmacological activity as dipeptidyl peptidase-4 (DPP4), alpha-amylase, alpha-glucosidase, lipase, and protein tyrosine phosphatase 1B (PTP1B) inhibitors.

Carotid body chemosensitivity: early biomarker of dysmetabolism in humans.

OBJECTIVE: The carotid bodies (CBs) are peripheral chemoreceptor organs classically described as being O2 sensors, which are increasingly emerging as core players in metabolic control. Herein we evaluated CB activity in prediabetes patients and determined its correlation with dysmetabolism clinical features. DESIGN AND METHODS: Prediabetes patients were recruited at the Cardiology Service, Hospital Santa Marta, Centro Hospitalar Lisboa Central, EPE (CHLC-EPE). The study was approved by CHLC-EPE and NOVA Medical School Ethics Committee. Thirty-three prediabetic and 14 age-matched, non-prediabetic, volunteers had their peripheral chemosensitivity evaluated by the Dejours test. Serum biomarkers of metabolic disease, insulin sensitivity (HOMA-IR), blood pressure, carotid intima-media thickness (cIMT) and glucose tolerance were assessed. RESULTS: CB chemosensitivity was significantly increased in prediabetic group (P < 0.01). Fasting blood, glucose intolerance, fasting insulin and HOMA-IR were significantly higher in prediabetes patients. Insulin resistance correlated both with peripheral chemosensitivity, assessed by the Dejours test (P < 0.05) and with abdominal circumference (P < 0.01). HbA1c correlated with HOMA-IR (P < 0.05) and left cIMT (P < 0.05) in prediabetes patients. CONCLUSIONS: We conclude that CB is overactive in prediabetes subjects and that peripheral chemosensitivity correlates with fasting insulin and insulin resistance representing a novel non-invasive functional biomarker to forecast early metabolic disease.

Evaluating the Impact of Different Hypercaloric Diets on Weight Gain, Insulin Resistance, Glucose Intolerance, and its Comorbidities in Rats.

Animal experimentation has a long history in the study of metabolic syndrome-related disorders. However, no consensus exists on the best models to study these syndromes. Knowing that different diets can precipitate different metabolic disease phenotypes, herein we characterized several hypercaloric rat models of obesity and type 2 diabetes, comparing each with a genetic model, with the aim of identifying the most appropriate model of metabolic disease. The effect of hypercaloric diets (high fat (HF), high sucrose (HSu), high fat plus high sucrose (HFHSu) and high fat plus streptozotocin (HF+STZ) during different exposure times (HF 3 weeks, HF 19 weeks, HSu 4 weeks, HSu 16 weeks, HFHSu 25 weeks, HF3 weeks + STZ) were compared with the Zucker fatty rat. Each model was evaluated for weight gain, fat mass, fasting plasma glucose, insulin and C-peptide, insulin sensitivity, glucose tolerance, lipid profile and liver lipid deposition, blood pressure, and autonomic nervous system function. All animal models presented with insulin resistance and dyslipidemia except the HF+STZ and HSu 4 weeks, which argues against the use of these models as metabolic syndrome models. Of the remaining animal models, a higher weight gain was exhibited by the Zucker fatty rat and wild type rats submitted to a HF diet for 19 weeks. We conclude that the latter model presents a phenotype most consistent with that observed in humans with metabolic disease, exhibiting the majority of the phenotypic features and comorbidities associated with type 2 diabetes in humans.

Bioelectronic modulation of carotid sinus nerve activity in the rat: a potential therapeutic approach for type 2 diabetes.

AIMS/HYPOTHESIS: A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents. METHODS: Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT. RESULTS: KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks. CONCLUSIONS/INTERPRETATION: KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.

Carotid body: a metabolic sensor implicated in insulin resistance.

The carotid body is now looked at as a multipurpose sensor for blood gases, blood pH, and several hormones. The matter of glucose sensing by the carotid body has been debated for several years in the literature, and these days there is a consensus that carotid body activity is modified by metabolic factors that contribute to glucose homeostasis. However, the sensing ability for glucose is still being pondered: are the carotid bodies low glucose sensors or, in contrast, are they overresponsive in high-glucose conditions? Herein, we debate the glucose and insulin sensing capabilities of the carotid body as key early events in the overactivation of the carotid body, which is increasingly recognized as an important feature of metabolic diseases. Additionally, we dedicate a final section to discuss new outside-the-box therapies designed to decrease carotid body activity that may be used for treating metabolic diseases.

High fat diet blunts the effects of leptin on ventilation and on carotid body activity.

KEY POINTS: Leptin plays a role in the control of breathing, acting mainly on central nervous system; however, leptin receptors have been recently shown to be expressed in the carotid body (CB), and this finding suggests a physiological role for leptin in the regulation of CB function. Leptin increases minute ventilation in both basal and hypoxic conditions in rats. It increases the frequency of carotid sinus nerve discharge in basal conditions, as well as the release of adenosine from the CB. However, in a metabolic syndrome animal model, the effects of leptin in ventilatory control, carotid sinus nerve activity and adenosine release by the CB are blunted. Although leptin may be involved in triggering CB overactivation in initial stages of obesity and dysmetabolism, resistance to leptin signalling and blunting of responses develops in metabolic syndrome animal models. ABSTRACT: Leptin plays a role in the control of breathing, acting mainly on central nervous system structures. Leptin receptors are expressed in the carotid body (CB) and this finding has been associated with a putative physiological role of leptin in the regulation of CB function. Since, the CBs are implicated in energy metabolism, here we tested the effects of different concentrations of leptin administration on ventilatory parameters and on carotid sinus nerve (CSN) activity in control and high-fat (HF) diet fed rats, in order to clarify the role of leptin in ventilation control in metabolic disease states. We also investigated the expression of leptin receptors and the neurotransmitters involved in leptin signalling in the CBs. We found that in non-disease conditions, leptin increases minute ventilation in both basal and hypoxic conditions. However, in the HF model, the effect of leptin in ventilatory control is blunted. We also observed that HF rats display an increased frequency of CSN discharge in basal conditions that is not altered by leptin, in contrast to what is observed in control animals. Leptin did not modify intracellular Ca2+ in CB chemoreceptor cells, but it produced an increase in the release of adenosine from the whole CB. We conclude that CBs represent an important target for leptin signalling, not only to coordinate peripheral ventilatory chemoreflexive drive, but probably also to modulate metabolic variables. We also concluded that leptin signalling is mediated by adenosine release and that HF diets blunt leptin responses in the CB, compromising ventilatory adaptation.

Insulin resistance: a new consequence of altered carotid body chemoreflex?

Metabolic diseases affect millions of individuals across the world and represent a group of chronic diseases of very high prevalence and relatively low therapeutic success, making them suitable candidates for pathophysiological studies. The sympathetic nervous system (SNS) contributes to the regulation of energy balance and energy expenditure both in physiological and pathological states. For instance, drugs that stimulate sympathetic activity decrease food intake, increase resting metabolic rate and increase the thermogenic response to food, while pharmacological blockade of the SNS has opposite effects. Likewise, dysmetabolic features such as insulin resistance, dyslipidaemia and obesity are characterized by a basal overactivation of the SNS. Recently, a new line of research linking the SNS to metabolic diseases has emerged with the report that the carotid bodies (CBs) are involved in the development of insulin resistance. The CBs are arterial chemoreceptors that classically sense changes in arterial blood O2 , CO2 and pH levels and whose activity is known to be increased in rodent models of insulin resistance. We have shown that selective bilateral resection of the nerve of the CB, the carotid sinus nerve (CSN), totally prevents diet-induced insulin resistance, hyperglycaemia, dyslipidaemia, hypertension and sympathoadrenal overactivity. These results imply that the beneficial effects of CSN resection on insulin action and glucoregulation are modulated by target-related efferent sympathetic nerves through a reflex that is initiated in the CBs. It also highlights modulation of CB activity as a putative future therapeutic intervention for metabolic diseases.

Functional abolition of carotid body activity restores insulin action and glucose homeostasis in rats: key roles for visceral adipose tissue and the liver.

AIMS/HYPOTHESIS: We recently described that carotid body (CB) over-activation is involved in the aetiology of insulin resistance and arterial hypertension in animal models of the metabolic syndrome. Additionally, we have demonstrated that CB activity is increased in animal models of insulin resistance, and that carotid sinus nerve (CSN) resection prevents the development of insulin resistance and arterial hypertension induced by high-energy diets. Here, we tested whether the functional abolition of CB by CSN transection would reverse pre-established insulin resistance, dyslipidaemia, obesity, autonomic dysfunction and hypertension in animal models of the metabolic syndrome. The effect of CSN resection on insulin signalling pathways and tissue-specific glucose uptake was evaluated in skeletal muscle, adipose tissue and liver. METHODS: Experiments were performed in male Wistar rats submitted to two high-energy diets: a high-fat diet, representing a model of insulin resistance, hypertension and obesity, and a high-sucrose diet, representing a lean model of insulin resistance and hypertension. Half of each group was submitted to chronic bilateral resection of the CSN. Age-matched control rats were also used. RESULTS: CSN resection normalised systemic sympathetic nervous system activity and reversed weight gain induced by high-energy diets. It also normalised plasma glucose and insulin levels, insulin sensitivity lipid profile, arterial pressure and endothelial function by improving glucose uptake by the liver and perienteric adipose tissue. CONCLUSIONS/INTERPRETATION: We concluded that functional abolition of CB activity restores insulin sensitivity and glucose homeostasis by positively affecting insulin signalling pathways in visceral adipose tissue and liver.

Disclosing caffeine action on insulin sensitivity: effects on rat skeletal muscle.

Caffeine, a non-selective adenosine antagonist, has distinct effects on insulin sensitivity when applied acutely or chronically. Herein, we investigated the involvement of adenosine receptors on insulin resistance induced by single-dose caffeine administration. Additionally, the mechanism behind adenosine receptor-mediated caffeine effects in skeletal muscle was assessed. The effect of the administration of caffeine, 8-cycle-1,3-dipropylxanthine (DPCPX, A1 antagonist), 2-(2-Furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (SCH58261, A2A antagonist) and 8-(4-{[(4-cyanophenyl)carbamoylmethyl]-oxy}phenyl)-1,3-di(n-propyl)xanthine (MRS1754, A2B antagonist) on whole-body insulin sensitivity was tested. Skeletal muscle Glut4,5'-AMP activated protein kinase (AMPK) and adenosine receptor protein expression were also assessed. The effect of A1 and A2B adenosine agonists on skeletal muscle glucose uptake was evaluated in vitro. Sodium nitroprussiate (SNP, 10nM), a nitric oxide (NO) donor, was used to evaluate the effect of NO on insulin resistance induced by adenosine antagonists. Acute caffeine decreased insulin sensitivity in a concentration dependent manner (Emax=55.54±5.37%, IC50=11.61nM), an effect that was mediated by A1 and A2B adenosine receptors. Additionally, acute caffeine administration significantly decreased Glut4, but not AMPK expression, in skeletal muscle. We found that A1, but not A2B agonists increased glucose uptake in skeletal muscle. SNP partially reversed DPCPX and MRS1754 induced-insulin resistance. Our results suggest that insulin resistance induced by acute caffeine administration is mediated by A1 and A2B adenosine receptors. Both Glut4 and NO seem to be downstream effectors involved in insulin resistance induced by acute caffeine.

Carotid body, insulin, and metabolic diseases: unraveling the links.

The carotid bodies (CB) are peripheral chemoreceptors that sense changes in arterial blood O2, CO2, and pH levels. Hypoxia, hypercapnia, and acidosis activate the CB, which respond by increasing the action potential frequency in their sensory nerve, the carotid sinus nerve (CSN). CSN activity is integrated in the brain stem to induce a panoply of cardiorespiratory reflexes aimed, primarily, to normalize the altered blood gases, via hyperventilation, and to regulate blood pressure and cardiac performance, via sympathetic nervous system (SNS) activation. Besides its role in the cardiorespiratory control the CB has been proposed as a metabolic sensor implicated in the control of energy homeostasis and, more recently, in the regulation of whole body insulin sensitivity. Hypercaloric diets cause CB overactivation in rats, which seems to be at the origin of the development of insulin resistance and hypertension, core features of metabolic syndrome and type 2 diabetes. Consistent with this notion, CB sensory denervation prevents metabolic and hemodynamic alterations in hypercaloric feed animal. Obstructive sleep apnea (OSA) is another chronic disorder characterized by increased CB activity and intimately related with several metabolic and cardiovascular abnormalities. In this manuscript we review in a concise manner the putative pathways linking CB chemoreceptors deregulation with the pathogenesis of insulin resistance and arterial hypertension. Also, the link between chronic intermittent hypoxia (CIH) and insulin resistance is discussed. Then, a final section is devoted to debate strategies to reduce CB activity and its use for prevention and therapeutics of metabolic diseases with an emphasis on new exciting research in the modulation of bioelectronic signals, likely to be central in the future.

Carotid body denervation prevents the development of insulin resistance and hypertension induced by hypercaloric diets.

Increased sympathetic activity is a well-known pathophysiological mechanism in insulin resistance (IR) and hypertension (HT). The carotid bodies (CB) are peripheral chemoreceptors that classically respond to hypoxia by increasing chemosensory activity in the carotid sinus nerve (CSN), causing hyperventilation and activation of the sympathoadrenal system. Besides its role in the control of ventilation, the CB has been proposed as a glucose sensor implicated in the control of energy homeostasis. However, to date no studies have anticipated its role in the development of IR. Herein, we propose that CB overstimulation is involved in the etiology of IR and HT, core metabolic and hemodynamic disturbances of highly prevalent diseases like the metabolic syndrome, type 2 diabetes, and obstructive sleep apnoea. We demonstrate that CB activity is increased in IR animal models and that CSN resection prevents CB overactivation and diet-induced IR and HT. Moreover, we show that insulin triggers CB, highlighting a new role for hyperinsulinemia as a stimulus for CB overactivation. We propose that CB is implicated in the pathogenesis of metabolic and hemodynamic disturbances through sympathoadrenal overactivation and may represent a novel therapeutic target in these diseases.

Effects of CPAP on nitrate and norepinephrine levels in severe and mild-moderate sleep apnea.

BACKGROUND: Reduced plasma nitrate (NO(x)) levels and increased urinary norepinephrine (U-NE) levels have been described in severe obstructive sleep apnea (OSA), and are reverted by continuous positive airway pressure (CPAP). The effect of CPAP on these biomarkers in mild-moderate OSA is not well understood. The aim of this study was to compare NO(x) and U-NE levels and blood pressure (BP) between male patients with mild-moderate and severe OSA and determine the impact of 1 month of CPAP therapy on these parameters. METHODS: We undertook a prospective study of 67 consecutive OSA patients (36 mild-moderate, 31 severe). Measurements of plasma NO(x) at 11 pm, 4 am and 7 am, 24-h U-NE and ambulatory BP were obtained at baseline and after 1 month of CPAP. RESULTS: At baseline, NO(x) levels showed a significant decrease during the night in both groups (p < 0.001). U-NE level and BP were significantly higher in the severe OSA group. After 1 month of CPAP, there was a significant increase in NO(x) levels and a reduction in U-NE level and BP only in patients with severe OSA. CONCLUSIONS: One month of CPAP results in significant improvements in NO(x) levels, 24-h U-NE level and BP in patients with severe OSA, but not in patients with mild-moderate OSA. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01769807.