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.

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.

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.