Carotid body denervation prevents fasting hyperglycemia during chronic intermittent hypoxia

Mi Kyung Shin, Qiaoling Yao, Jonathan C. Jun, Shannon Bevans-Fonti, Doo Young Yoo, Woobum Han, Omar Mesarwi, Ria Richardson, Ya Yuan Fu, Pankaj J. Pasricha, Alan R. Schwartz, Machiko Shirahata, Vsevolod Y. Polotsky

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)765-776
Number of pages12
JournalJournal of applied physiology
Volume117
Issue number7
DOIs
StatePublished - Oct 1 2014

Keywords

  • Gluconeogenesis
  • Hepatic glucose output
  • Hypoxic chemoreflex
  • Sleep apnea
  • Type 2 diabetes

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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