Carotid body denervation prevents fasting hyperglycemia during chronic intermittent hypoxia

Abstract

Obstructive sleep apnea causes chronic intermittent hypoxia (IH) and is associated with impaired glucose metabolism, but mechanisms are unknown. Carotid bodies orchestrate physiological responses to hypoxemia by activating the sympathetic nervous system. Therefore, we hypothesized that carotid body denervation would abolish glucose intolerance and insulin resistance induced by chronic IH. Male C57BL/6J mice underwent carotid sinus nerve dissection (CSND) or sham surgery and then were exposed to IH or intermittent air (IA) for 4 or 6 wk. Hypoxia was administered by decreasing a fraction of inspired oxygen from 20.9% to 6.5% once per minute, during the 12-h light phase (9 a.m.-9 p.m.). As expected, denervated mice exhibited blunted hypoxic ventilatory responses. In sham-operated mice, IH increased fasting blood glucose, baseline hepatic glucose output (HGO), and expression of a rate-liming hepatic enzyme of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK), whereas the whole body glucose flux during hyperinsulinemic euglycemic clamp was not changed. IH did not affect glucose tolerance after adjustment for fasting hyperglycemia in the intraperitoneal glucose tolerance test. CSND prevented IH-induced fasting hyperglycemia and increases in baseline HGO and liver PEPCK expression. CSND trended to augment the insulin-stimulated glucose flux and enhanced liver Akt phosphorylation at both hypoxic and normoxic conditions. IH increased serum epinephrine levels and liver sympathetic innervation, and both increases were abolished by CSND. We conclude that chronic IH induces fasting hyperglycemia increasing baseline HGO via the CSN sympathetic output from carotid body chemoreceptors, but does not significantly impair whole body insulin sensitivity.

Increased Cardiometabolic Risk and Worsening Hypoxemia at High Altitude

“…terial chemoreceptors. In humans and animals, various forms of hypoxia-induced glucose intolerance may be significantly attenuated by sympathetic blockade or by chemoreceptor denervation (Peltonen et al, 2012;Jun et al, 2014;Shin et al, 2014). Chronic activation of the sympathetic nervous system may be a pathway toward the development of metabolic syndrome (Brotman et al, 2002).…”

Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells in an Insulin-Dependent and Independent Manner

“…By contrast, Polak et al [12] isolated hepatocytes from mice after 14 days of IH and revealed increased total glucose output as compared to cells from control mice, which was attributed to increased gluconeogenesis. Shin et al [13] also reported increased baseline hepatic glucose output and liver PEPCK transcription in lean mice after 6-week IH exposure. Potentially, the lower PEPCK transcription that we observed from hepatocytes in response to IH does not resemble outcomes from these in vivo experiments because of other systemic effects of IH on catecholamines and hormones, or because of differences in experimental technique.…”

“…First, this was by design an in vitro study of the isolated metabolic responses of liver cells to IH. In vivo, systemic effects of IH may modify direct hepatic metabolic responses to IH, including autonomic signaling [13], and changes to substrate delivery [32]. Second, as with any in vitro study, there are limitations to the model of IH.…”

“…Several studies evaluated liver glucose output and insulin signal transduction in response to IH [11][12][13][14], but did not achieve consistent conclusions. In terms of how IH influences hepatic glucose metabolism and insulin sensitivity, the major proposed mechanism is the systemic activation of sympathetic nervous system in response to IH [11,13,15]. Less attention has been directed towards direct effects of IH on liver cells per se.…”

Comparison of the association with sleep apnoea of obesityversusinsulin resistance

“…We decided to only enrol men to minimise potential confounding effects of sex differences in anthropometric and polysomnographic characteristics in OSA [9], and we were able to demonstrate an independent association of insulin resistance with OSA severity without need for a control group. While the pathophysiological nature of this relationship remains uncertain, there is evidence that carotid body-mediated sympathetic activation in the setting of chronic intermittent hypoxia may contribute to metabolic abnormalities [10].…”