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

Abstract

Reactive oxygen species Inflammation HyperinsulinaemiaHypercaloric diets, obesity Carotid body overactivation Insulin resistance HypertensionSympathetic nervous system activity ? 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 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. 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 O 2 , CO 2 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. Abstract figure legend Role of the carotid body (CB) in the development of insulin resistance through an increase in sympathetic nervous system activity. Obesity and hypercaloric diets promote hyperinsulinaemia, inflammation and the increase in oxidative stress. The hyperinsulinaemia and/or inflammation and/or reactive oxygen species stimulate the CB and promote its overactivation that contributes to the excessive sympatho-excitation that originates insulin resistance and hypertension.Abbreviations CB, carotid body; CSN, carotid sinus nerve; NEFAs, non-esterified fatty acids; OSA, obstructive sleep apnoea; SNS, sympathetic nervous system.

Translating carotid body function into clinical medicine

“…, ; Prabhakar, ; Conde et al . ). Certainly, in the last decade the idea that the CB plays a major role in the progression and maintenance of hypertension, cardiorespiratory and autonomic alterations in OSA, HF and cardiometabolic diseases has received progressive attention (Fig.…”

“…; Conde et al . ). For instance, intermittent hypoxia (IH), the main characteristic of OSA produces CB oxidative that increases ET‐1, angiotensin II and pro‐inflammatory cytokines levels in the CB (Iturriaga et al .…”

“…1). Nevertheless, a growing body of new evidence has shown that an abnormal enhanced CB chemosensory discharge elicits sympathetic hyperreactivity, which is the common hallmark of resistant hypertension, systolic heart failure (HF), obstructive sleep apnoea (OSA) and cardiometabolic diseases (for reviews, see: Schultz et al 2013;Iturriaga et al 2016Iturriaga et al , 2017Prabhakar, 2016;Conde et al 2017). Certainly, in the last decade the idea that the CB plays a major role in the progression and maintenance of hypertension, cardiorespiratory and autonomic alterations in OSA, HF and cardiometabolic diseases has received progressive attention (Fig.…”

“…The mechanisms underlying the CB chemosensory potentiation elicited by those diseases are not completely known. However, it is likely that alteration of the normal CB chemotransduction process due to oxidative stress is responsible for the carotid chemosensory potentiation in OSA, HF and metabolic models (Peng & Prabhakar, 2003, 2004Ding et al 2009;Del Rio et al 2010;Conde et al 2017). For instance, intermittent hypoxia (IH), the main characteristic of OSA produces CB oxidative that increases ET-1, angiotensin II and pro-inflammatory cytokines levels in the CB (Iturriaga et al 2014).…”

Targeting autonomic imbalance in pathophysiology: is the carotid body the new nirvana?

“…Conde et al . () consider whether the carotid body is responsible for the metabolic disturbances of insulin resistance, dyslipidaemia and raised sympathetic activity. They show that by disconnecting the carotid body's inputs to the brain they are able to reverse the pathophysiology of insulin resistance, hyperglycaemia, dyslipidaemia and hypertension in rats fed a hypercaloric diet.…”