Introduction Type 2 diabetes mellitus (T2DM) is a heterogeneous disease characterized by hyperinsulinemia, absolute or relative insulin deficiency due to β-cell secretory dysfunction, insulin resistance, glucose intolerance, and fasting hyperglycemia.1 With a projected prevalence of 1.3 billion people with T2DM in 2050, it is one of the leading causes of morbidity and mortality worldwide.2 Understanding the pathogenesis of T2DM is essential for the development of new therapeutic approaches and for improving the health status of afflicted individuals. Augmentation of autonomic nervous system activity via the carotid bodies is a proposed mechanism for the initiation and progression of insulin resistance.3,4,5 Increased sympathetic outflow results in a cascade of effects, including lipolysis, vasoconstriction, increased gluconeogenesis, impaired glucose uptake, and reduced insulin release.5 Insulin, a sympathoexcitatory hormone, activates the sympathetic nervous system through pathways that are not fully understood. While previous research focused on the central nervous system as a source of sympathetic nervous system activation, recent studies support a role for peripheral sensors as well, including the carotid bodies.6,7,8,4,9 Chronic exposure to high levels of insulin could result in long-term facilitation of the carotid bodies (CB), similar to changes observed in the CB during chronic intermittent hypoxia.10,11 The carotid bodies are small organs located above the bifurcation of the common carotid arteries that contain specialized chemosensory type I glomus cells. In addition to their ability to cause hyperventilation in response to hypoxia, the so-called acute hypoxic ventilatory response or HVR, the carotid bodies detect glucose, insulin, lactate, leptin, and GLP1, indicative of their role in metabolic homeostasis.12,13,14,4,15 Hypertrophy of the carotid bodies is observed in T2DM,16,17 an observation also made in animals and humans exposed to chronic or intermittent hypoxia (e.g. in children with congenital heart disease).10,18 These changes are associated with an increased glomus cell excitability, hypersensitivity, and long-lasting carotid body afferent activity that persists even after termination of the underlying causes of CB hypertrophy.19 Interestingly, hyperbaric oxygen therapy, silencing the carotid bodies, improves glucose homeostasis in T2DM patients.20,21 The carotid bodies contain insulin receptors and the sympathoexcitatory effect of insulin on the carotid bodies has been demonstrated before.4 In vivo experiments demonstrated a dose-dependent insulin-induced increase in ventilation while maintaining euglycemia, which was abolished by carotid sinus nerve denervation.4 During euglycemia, increasing insulin levels in human volunteers increased muscle sympathetic nerve activity and ventilation.22,23 100
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