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

Abstract

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.

Abbreviations

CB

carotid body

CSN

carotid sinus nerve

NEFAs

non‐esterified fatty acids

OSA

obstructive sleep apnoea

SNS

sympathetic nervous system

Epidemiology of metabolic diseases

In the last decades we have witnessed a dramatic increase in the prevalence of arterial hypertension, insulin resistance, obesity and dyslipidaemia, central features of metabolic diseases such as the metabolic syndrome, type 2 diabetes mellitus and obstructive sleep apnoea (OSA). Recent data estimated the prevalence of metabolic syndrome in nearly 35% of all adults and of 50% in those aged 60 years or older in the United States (Ford, 2005; Aguilar et al. 2015). Also, type 2 diabetes affects over 8.8% of the world population and it is expected that, in 2040, 642 million people will be diabetic worldwide (International Diabetes Federation, 2015). This represents an alarming health problem, with severe economic and social repercussions, therefore it is imperative to elucidate the biological mechanisms underlying it as well as to identify prevention and treatment strategies.

Sympathetic nervous system contribution to metabolic diseases

The pathophysiological mechanisms underlying the generation of insulin resistance and insulin resistance‐related illnesses are complex and extend beyond sedentary lifestyle, hypercaloric diets and genetic predisposition. In the last decades, visceral obesity has been considered the common pathophysiological pathway responsible for metabolic changes present in the metabolic syndrome, type 2 diabetes and OSA (Ferranini et al. 2007; Katagiri et al. 2007; Lambert et al. 2010). Indeed, several epidemiological studies have shown that visceral obesity has a strong association with insulin resistance and hypertension (Ferranini et al. 1997; Katagiri et al. 2007), being the mechanism of disease based on the release of non‐esterified fatty acids (NEFAs) and bioactive mediators, known as adipokines, by adipocytes (Katagiri et al. 2007; Yanai et al. 2008). The augmentation in circulating NEFAs leads to the decrease in glucose uptake by the skeletal muscle (Boden & Chen, 1995) and also contributes to a decrease in insulin production (Kashyap et al. 2003). In liver, NEFAs cause an increase in glucose production (Boden et al. 2001), elevated hepatic very low density lipoprotein–triacylglycerol output (Byrne et al. 1991) and decreased insulin clearance by the liver (Wiesenthal et al. 1999). Together these metabolic changes lead to insulin resistance and compensatory hyperinsulinaemia, glucose intolerance and hyperlipidaemia. The adipokines expressed by the adipocytes, which include cytokines, growth factors, leptin, resistin, adiponectin, adipsin and components of the renin–angiotensin system, may act in organs of metabolic relevance such as brain, liver, muscle and the immune system, contributing to the modulation of haemostasis, blood pressure, inflammation, atherosclerosis, glucose and lipid metabolism (Kwon & Pessin, 2013). However, the picture is not as clear as it initially seemed: according to some studies insulin resistance is associated with sleep apnoea and with increased cardiovascular risk, independently of obesity (West et al. 2006). Also, hypertension appears to be independent of the amount of fat mass in OSA patients (Pepper et al. 2000). In fact, obesity has been challenged as a major player in the pathophysiology of disrupted glucose homeostasis by the peripheral nervous system. Increasing evidence points towards the sympathetic nerves as having a pivotal role in the generation of organ‐specific insulin resistance, insulin resistance‐related illnesses and also obesity (see Fig. 1) (Lambert GW et al. 2010; Lambert EA et al. 2015; Thorp & Schlaich, 2015). The sympathetic nervous system (SNS) is key in both circulatory and metabolic control. In high energy expenditure situations, sympathetic activation leads to the release of noradrenaline in the nerve endings and stimulation of adrenergic receptors. The responses are organ specific and depend on the adrenoreceptor isoforms expressed in the tissues (for a review, see Lambert et al. 2010). Acute sympathoexcitation (Fig. 2) leads to activation of hepatic sympathetic nerves which stimulate glycogenolysis in the fed state and gluconeogenesis in fasting conditions. In the pancreas, sympathetic stimulation leads to increased glucagon release into the portal vein and to a moderate inhibition of insulin secretion. Activation of sympathetic fibres that innervate adipose tissue leads to lipolysis and release of NEFAs into the circulation. In response to sympathetic stimulation of the kidney, renin is released and, at higher firing rates, sodium retention and local vasoconstriction also occur. In the adrenal glands, sympathetic stimulation causes release of adrenaline into the bloodstream. These effects, if sustained in the long term, may contribute to the development of insulin resistance since they adversely affect metabolic control. Prolonged deregulation of hepatic glucose output and increased glucagon secretion by the pancreas contribute to increase plasma glucose levels. Increased lipolysis and NEFA release into the circulation affect insulin signalling transduction pathways and contribute to decrease insulin action (Boden, 2011). Enduring sympathetic discharges cause pronounced neural‐mediated vasoconstriction and rarefaction in peripheral arterioles, associated with a marked decrease in blood flow and impaired nutrient uptake in skeletal muscle (Lambadiari et al. 2015) and adipose tissue (Ardilouze et al. 2012).

Figure 1. Insulin resistance.

Insulin resistance is a core pathological feature of several metabolic and cardiovascular disturbances, being a principal characteristic of type 2 diabetes and also a risk factor for the development of cardiovascular diseases such as hypertension and atherosclerosis.

Figure 2. Acute activation of the sympathetic nervous system results in the release of noradrenaline (norepinephrine) and the subsequent stimulation of regionally specific adrenergic receptors, causing significant changes in glucose disposal by several organs.

Acute sympathoexcitation leads to increased gluconeogenesis (mediated by α1 adrenergic receptors) and glycogenolysis (mediated by β2 adrenergic receptors) by the liver to provide energetic substrate for the brain. In the pancreas, acute sympathetic activation promotes glucagon release and impairs insulin secretion. In adipose tissue, sympathetic activation triggers β3‐mediated lipolysis and elevates non‐esterified fatty acids (NEFAs) in the circulation. Also, constriction of adipose arterioles causes decreased glucose uptake and decreased triglyceride synthesis. In the skeletal muscle, sympathetic activation triggers glycogenolysis mediated by β2 receptors and glucose uptake is directly related to arteriole tone: in case α1 receptors are activated arteriole constriction decreases glucose uptake mediated by glucose transporters (GLUT). In the kidney, sympathetic activation causes renin release and, at higher neuronal firing rates, sodium (Na⁺) retention. Sympathetic stimulation of the adrenal glands leads to the release of adrenaline (epinephrine) into circulation mediated by muscarinic receptors. Acute increase in sympathetic nervous activity causes α1 receptor‐mediated vasoconstriction and arteriole rarefaction.

Despite increasing knowledge in this area of research, the precise mechanism and the evolutive pathochrony linking sympathetic overactivation, increased insulin secretion and peripheral insulin resistance is complex. Several theories have been postulated to link features of the metabolic syndrome with changes in sympathetic activation. Landsberg and Reaven's work supports the idea that overeating and obesity lead first to peripheral insulin resistance followed by compensatory hyperinsulinaemia and subsequent sympathetic activation (Landsberg & Young, 1978; Reaven, 2004). Alternatively, other groups have postulated that sympathetic overactivation is the trigger that initiates insulin resistance by compromising glucose disposal and lipid kinetics (Laakso et al. 1990; Jamerson et al. 1993). The latter paradigm postulates that hyperinsulinaemia is a compensatory mechanism for decreased glucose uptake at the skeletal muscle caused by sympathetic overactivation (Julius et al. 1992) and is supported by evidence derived from prospective trials, demonstrating that increased sympathetic activation precedes and predicts obesity and insulin resistance development (Masuo et al. 1997; Flaa et al. 2008).

Data in the literature also agree that insulin resistance states are characterized by sympathetic predominance in a resting/basal state and reduced sympathetic responsiveness after physiological sympathetic stimuli. In fact, sympathetic nervous system responses to carbohydrate ingestion are blunted in insulin‐resistant states (Straznicky et al. 2015), and β‐adrenoreceptor‐mediated lipolysis and lipid oxidation in adipose tissue are severely impaired in obesity (Guo et al. 2014). Decreased responsiveness to the sympathetic nervous system could be caused by polymorphisms in genes that are involved in catecholamine signal transduction and have effects on fat cell lipolysis (Arner, 2001).

Interestingly, sympathetic activation has also been associated with triggering of the hypothalamic–pituitary axis and to increased inflammatory cytokine production (Björntorp, 1995). Cortisol is associated with glucose intolerance and may be one of the pathophysiological mechanisms involved in insulin resistance modulated by sympathetic overdrive, although the presence of hypercortisolism in insulin‐resistant individuals is not ubiquitous. Chronic overactivation of the sympathetic nervous system also induces a proinflammatory state mediated by IL‐6 production by adipose tissue, which results in an acute phase response by the liver, indicating that the increased levels of inflammatory markers seen in insulin‐resistant states may also, at least in part, be mediated by the sympathetic nervous system. Pro‐inflammatory cytokines also cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction (de Luca & Olefsky, 2008). Noticeably, maintenance of all or part of the aforementioned adaptor responses induced by chronic activation of the sympathetic nervous system culminates in impaired insulin action.

Hyperinsulinaemia contributes to sympathetic overactivation

Among the several factors that have been proposed to be responsible for the increased sympathetic nerve activity in metabolic abnormalities is hyperinsulinaemia (Reaven, 1988; Landsberg, 2005; Lambert GW et al. 2010; Lambert EA et al. 2015). Increased insulin levels contribute to aggravate pathological features of metabolic disturbances by enhancing atherogenesis, increasing blood pressure and endothelial dysfunction, increasing adipose tissue mass and systemic inflammation and contributing to obesity and the development of type 2 diabetes (Reaven, 1988; Arcaro et al. 2002; Landsberg, 2005; Pedersen et al. 2015).

Several lines of evidence suggest that the excitatory effects of insulin on the SNS are mediated by the central nervous system (for a review see Dampney, 2011). In fact, animal studies have shown that the administration of insulin in the arcuate nucleus and paraventricular nucleus produced an increase in spinal sympathetic outflow, mediated by dorsal hypothalamus and rostral ventrolateral medulla (Cassaglia et al. 2011, Dampney, 2011). In agreement with these results, the injection of anti‐insulin affibody at the arcuate nucleus prevents the sympathetic excitation induced by insulin (Luckett et al. 2013). These data suggested that sympatho‐excitation induced by insulin is mediated by the arcuate nucleus, and therefore by the central nervous system. However, in euglycaemic conditions, intracarotid administration of insulin in anaesthetized dogs produced an increase in blood pressure and sympathetic activity higher than systemic insulin administration strongly suggesting the presence of a peripheral insulin sensor that mediates sympathetic activity (Pereda et al. 1962). Additionally, combined with higher sympatho‐excitation observed in insulin‐resistant states, the fact that insulin transport through the blood–brain barrier is decreased (Kaiyala et al. 2000) or unchanged (Israel et al. 1993), both in animal models of diet‐induced obesity and in insulin‐resistant patients (Kern et al. 2006; Heni et al. 2014), corroborates the hypothesis of the existence of an insulin‐sensitive sympatho‐modulator in the periphery.

The carotid body: a sympatho‐modulator in the peripheral nervous system

The CBs are peripheral chemoreceptors that classically sense changes in arterial blood O₂, CO₂ and pH levels. Hypoxia (O₂ deprivation), hypercapnia (CO₂ retention) and acidosis (pH drop) activate the CB. The response is an increase in the action potential frequency of the CB sensory nerve, the carotid sinus nerve (CSN). CSN activity is integrated in the brain stem to induce a set of respiratory reflexes aimed, primarily, to normalize the altered blood gases via hyperventilation (Gonzalez et al. 1994) and to regulate blood pressure and cardiac performance via sympathetic nervous system activation (Marshall, 1994).

In the last decades, several reports have linked sympathetic overactivation present in essential hypertension, OSA and chronic heart failure with an increase in CB activity. The first work that demonstrated that CB chemoreceptors are involved in the progression of chronic intermittent hypoxia‐induced hypertension dates from 1992 (Fletcher et al. 1992). In that pioneer animal study, the authors showed that bilateral CB denervation prevented the development of hypertension in rats exposed to chronic intermittent hypoxia for 35 days (Fletcher et al. 1992), which mimics OSA in humans. Moreover, subsequent work from other authors demonstrated that chronic intermittent hypoxia leads to an overactivation of the CB, manifested by its increased hypoxic sensory response (Peng & Prabhakar, 2004; Rey et al. 2004). Furthermore, an enhanced chemoreceptor reflex was described in both hypertensive animals and humans that may contribute to the excess sympathetic activity present in essential hypertension (Przybylski et al. 1982; Trzebski et al. 1982; Fukuda et al. 1987; Somers et al. 1988). More recently, a role for the CB in the pathogenesis of essential hypertension was observed in spontaneously hypertensive rats since animals submitted to bilateral CSN denervation exhibited a delay in the development and maintenance of hypertension, a reduction in sympathetic vasomotor tone and a decreased renal sympathetic activity (Abdala et al. 2012; McBryde et al. 2013). Also, the authors demonstrated that unilateral CSN resection was ineffective in decreasing arterial pressure and that bilateral CSN resection was more effective in reducing arterial pressure than the renal denervation (McBryde et al. 2013). These preclinical results were confirmed in humans, where it was shown that the functional abolishment of CB activity with 100% O₂ induced a reduction in both arterial pressure and sympathetic activity in human hypertensive patients (Siński et al. 2012).

In contrast with the data obtained in spontaneously hypertensive rats, recent data from Fudim et al. (2015) showed that the unilateral resection of CB tumours in patients with hypertension was effective in decreasing blood pressure (Fudim et al. 2015). However, over the long term, the effect on pulse pressure and systolic blood pressure was small and without statistical significance (Fudim et al. 2015). The latter results are in agreement with the work of Paton et al. (Paton, 2015) where he showed that CB unilateral ablation decreases short‐term arterial pressure although the effect was attenuated 12 months after ablation suggesting a compensation of the remaining carotid body.

The CB chemoreceptors have also been described to be involved in chronic heart failure in humans and animal models, being associated with the sympathetic activation observed in this syndrome (Sun et al. 1999; Ponikowski et al. 2001). In both rat and rabbit models of chronic heart failure CB ablation, performed by cryogenic destruction, has been shown to reduce the hyperventilation and oscillatory breathing, as well as the tonic sympathetic outflow, resulting in an improvement in cardiac function and prolonged survival (Del Rio et al. 2013; Marcus et al. 2014). These preclinical results are supported by recent data obtained in patients (Niewiński et al. 2013, 2014) showing that unilateral CB removal in a patient with chronic heart failure resulted in a decrease in peripheral chemosensitivity, which was accompanied by improvements in autonomic function, cardiac function, exercise capacity and reduced resting ventilation (Niewiński et al. 2013). Also, in 2014, another study with six chronic heart failure patients showed that bilateral CB removal produced a reduction in ventilatory and blood pressure responses to hypoxia, suggesting a decrease in sympathetic tone (Niewiński et al. 2014). Moreover, CB removal in heart failure patients did not modify the heart chronotropic response, suggesting other peripheral chemoreceptors, may be involved in this response to hypoxia (Niewiński et al. 2014). As a whole, data reflect that CB dysfunction is implicated in the pathophysiology of various human cardiovascular diseases through the modulation of the SNS. Additionally, in the last couple of years, a new line of research has emerged from our laboratory, linking the CB‐mediated sympathetic nerve activation to metabolic diseases (Ribeiro et al. 2013; Conde et al. 2014).

What causes carotid body deregulation in metabolic diseases?

The fact that peripheral insulin administration elicited a higher increase in sympathetic activity than systemic administration (Pereda et al. 1962), together with the evidence that CB overactivation characterizes essential hypertension, OSA, chronic heart failure as well other sympathetically mediated diseases lead us to hypothesize that the CB is a peripheral insulin sensor. According to this new paradigm, CB overstimulation by inadequate insulin levels contributes to the genesis of peripheral insulin resistance and hypertension present in metabolic diseases via SNS activation (Fig. 3).

Figure 3. Schematic representation of the stimuli that activate the carotid body to induce an increase in sympathetic activity that promotes insulin resistance and glucose deregulation and hypertension.

Hyperinsulinaemia, inflammation and reactive oxygen species induce carotid body overactivation leading to an increase in sympathetic nervous system activity that promotes insulin resistance and hypertension.

We have recently described that insulin receptors are present in the whole CB and that they become phosphorylated in response to insulin (Ribeiro et al. 2013). These results are in agreement with the findings of Gallego‐Martin et al. (2014) where it was observed that whole CBs incubated with insulin accumulate more 2‐deoxyglucose than the diaphragm muscle. Also, we have shown that insulin, in physiological concentrations, is capable of eliciting a neurosecretory response in chemoreceptor cells, measured by the increase in intracellular Ca²⁺ concentrations and by the release of dopamine and ATP from whole CBs (Ribeiro et al. 2013). These results obtained in vitro were confirmed by testing the in vivo effect of insulin on ventilation. In euglycaemic conditions, insulin increased ventilation in anaesthetized animals in a dose‐dependent manner, an effect fully mediated by the CB since it was absent in animals that had their CSN resected (Ribeiro et al. 2013). This effect of insulin on ventilation was not new, as Bin‐Jaliah et al. (2004) observed that insulin infusion in hypoglycaemic conditions increased minute ventilation and the rate of O₂ consumption (${\dot{V}}_{{\mathrm{O}}_2}$), an effect that was also totally mediated by the CB since CSN denervation blunted it. Comparing both experimental protocols, and since we have tested the effect of insulin on ventilation in euglycaemic conditions instead of hypoglycaemic conditions as in Bin‐Jaliah et al. (2004), we trust that the effect of insulin on ventilation is mediated by insulin per se and not by low plasma glucose. Therefore, insulin has the ability to activate the CBs and this organ may be the peripheral insulin sensor that mediates sympatho‐excitation.

Apart from insulin, other humoral and local factors have been described as activating the CB, such as leptin, inflammatory cytokines and reactive oxygen species (ROS) (see Fig. 3). It has been suggested that leptin may contribute to peripheral ventilatory control, as the administration of the hormone can reverse hypoxia and hypercapnia in animal models with no functional leptin gene (Tankersley et al. 1998; O'Donnel et al. 1999). The results suggest that the ventilatory effects of leptin are mediated by the CB chemoreceptors and, in fact, the CBs express the leptin‐B receptor (Porzionato et al. 2011). Yet, we have recently shown that the acute stimulatory effect of leptin on ventilation is not CB controlled (Olea et al. 2015).

Other local mediators that are known to activate the CB are ROS (Peng et al. 2009; Del Rio et al. 2010). It has been described that ROS production and regional oxidative stress play a role in the CB chemosensory potentiation and in the progression of hypertension in rats exposed to chronic intermittent hypoxia (Peng et al. 2009; Del Rio et al. 2010); however, we are not aware of any effect of oxidative stress mediators in CB‐dependent glucose metabolism. Additionally, it is well established that the CB senses inflammatory mediators. The expression of receptors for interleukins IL‐1, IL‐6 and IL‐10, as well as for tumour necrosis factor receptor (TNFα), has been shown in the human CB (Mkrtchian et al. 2012). In the cat, Fernandez et al. (2008) demonstrated the co‐localization of TNFα receptors and tyrosine hydroxylase in CB chemoreceptor cells and its functionality. When the authors administered TNFα, this pro‐inflammatory cytokine was incapable of modifying basal CSN chemosensory discharge ex vivo, but reduced the hypoxia‐induced enhanced frequency of chemosensory discharge in a dose‐dependent manner (Fernandez et al. 2008). This inhibitory effect of TNFα observed in the cat is in contrast with the findings of Lam et al. (2008, 2012) in the rat, where the authors showed in dissociated CB chemoreceptor cells that TNFα enhances the [Ca²⁺]_i response to acute hypoxia, this increase being significantly larger in cells from the CB of rats exposed to chronic hypoxia or to chronic intermittent hypoxia. Yet, TNFα is not the only cytokine that acts on the CB. Rat CB chemoreceptor cells showed a strong expression of interleukin‐1 (IL‐1) receptor type I (Wang et al. 2002) and interleukin‐6 (IL‐6) receptor α (Wang et al. 2006). In rat CB chemoreceptor cells IL‐1β significantly decreased the outward potassium current and triggered a transient rise in [Ca²⁺]_i (Shu et al. 2007). Moreover, IL‐1β stimulated CSN discharges. In the same way application of exogenous IL‐6 induced an increase in [Ca²⁺]_i and the release of catecholamines from rat CB chemoreceptor cells (Fan et al. 2009). Knowing that both subclinical inflammation and oxidative stress are correlated with insulin resistance (de Rooij et al. 2009) and both mediators stimulate the CB, it is possible that these molecules also play a role in the modulation of CB‐mediated insulin resistance.

The carotid bodies control whole body glucose homeostasis

Animals submitted to hypercaloric diets exhibit CB overactivation: they present an increase in spontaneous ventilation, an increase in the respiratory responses to ischaemic hypoxia, an increase in hypoxia‐evoked release of dopamine from the CB and an increase in the CB expression of tyrosine hydroxylase (Ribeiro et al. 2013). This chronic overactivation of the carotid bodies is tied to enhanced sympatho‐excitation, acknowledged by increased circulating and adrenal medulla catecholamines, that culminates in the development of insulin resistance through the mechanisms mentioned above (Ribeiro et al. 2013; Conde et al. 2014). Moreover, we have shown that bilateral CSN resection prevents the development of these features (Ribeiro et al. 2013) confirming the CB as a key player in controlling peripheral insulin sensitivity (Fig. 3). Our hypothesis of involvement of the CB in the genesis of metabolic disturbances was also supported by the findings of Shin et al. (2014). They observed that mice exposed for 4‐6 weeks to chronic intermittent hypoxia exhibited increased fasting blood glucose, increased hepatic glucose output and insulin resistance. The authors have shown that CSN denervation prevented the chronic intermittent hypoxia‐induced hyperglycaemia and the increase in baseline glucose hepatic output, an effect that was associated with the abolishment of sympathetic overactivation induced by the CB (Shin et al. 2014). The latter results in chronic intermittent hypoxia animals (Shin et al. 2014), as well as our data in hypercaloric animal models (Ribeiro et al. 2013; Conde et al. 2014), are in accordance with the findings by Limberg et al. (2014) where hyperoxic silencing of carotid chemoreceptors reduced muscle sympathetic nerve activity in hyperinsulinaemic conditions, suggesting that the CB mediates insulin‐dependent sympatho‐excitation in humans. Confirming this role, as well as the involvement of the CB in metabolic disease pathogenesis, we have recently shown that the suppression of CB activity with hyperbaric oxygen therapy (100% O₂ at 2.5 absolute atmospheres, 70 min, 20 sessions) ameliorates fasting glycaemia and post‐prandial glucose tolerance in type 2 diabetes patients (Vera‐Cruz et al. 2015). Additionally, other works performed in healthy humans, exposed to hyperoxia, have also shown the involvement of CB in the counterregulatory response to hyperinsulinaemia‐induced hypoglycaemia, since a decrease in the release of counterregulatory hormones was observed (Wehrwein et al. 2010). Also, blood pressure responses to hyperinsulinaemia‐induced hypoglycaemia are reduced in hyperoxic conditions in healthy humans, suggesting that the sympathetic control of blood pressure is attenuated (Wehrwein et al. 2012). Recently, the same authors provided corroborative results that show that the effect of hyperoxia on the hypoglycaemia counterregulatory response is mediated by the CBs (Wehrwein et al. 2015). However, in patients who had had bilateral CB resection due to glomus cell tumours, the counterregulatory response to insulin‐induced hypoglycaemia was not modified, suggesting that physiological adaptations may occur over time and/or that the response to hypoglycaemic conditions in humans do not rely specifically on CB glucose sensing (Wehrwein et al. 2015). The long‐term adaptation that may occur after CB resection may explain why these results contrast with the data obtained by Koyama et al. (2000) in dogs, where 16 days after CB resection a decrease in the counterregulatory response during insulin‐induced hypoglycaemia was observed. Nonetheless, all these findings highlight a role for the CB in metabolic control, not only in pathological, but also in physiological conditions.

In conclusion, we propose that insulin‐triggered CB activation is a key step in the development of the excessive sympatho‐excitation that characterizes metabolic diseases, creating a vicious cycle that originates insulin resistance and hypertension. Therefore, the modulation of CB activity emerges as a possible therapeutic strategy for the treatment of metabolic diseases.

Additional information

Competing interests

None declared.

Funding

J.F.S. and M.J.R. are supported by PhD Grants from the Portuguese Foundation for Science and Technology (FCT), PD/BD/105890/2014 and SFR/BD/88983/2012, respectively.

Biography

Silvia Conde’s research focuses on understanding the physiology of the autonomic nervous system, in particular the carotid body, and in the application of its findings to pathological states allowing the identification of molecular targets for therapy. Silvia received her degree in biochemistry from the Faculty of Sciences, University of Lisbon. She pursued her PhD in 2007 from both NOVA University of Lisbon and from the University of Valladolid. She is Principal Investigator at CEDOC – Chronic Disease Research Center and tenured assistant professor at NOVA Medical School. In 2009 she was awarded a L'Oréal Medal of Honour for Women in Science.