title: 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Shin
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Jun
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Shannon
authors.initials: S
authors.lastname: Bevans-Fonti
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Doo-Young
authors.initials: DY
authors.lastname: Yoo
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Woobum
authors.initials: W
authors.lastname: Han
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Omar
authors.initials: O
authors.lastname: Mesarwi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Ria
authors.initials: R
authors.lastname: Richardson
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Ya-Yuan
authors.initials: YY
authors.lastname: Fu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Pankaj J
authors.initials: PJ
authors.lastname: Pasricha
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Alan R
authors.initials: AR
authors.lastname: Schwartz
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Machiko
authors.initials: M
authors.lastname: Shirahata
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; vpolots1@jhmi.edu.
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002344:Carotid Body / Q000378:metabolism*; D003714:Denervation; D004195:Disease Models, Animal; D018149:Glucose Intolerance / Q000378:metabolism; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020181:Sleep Apnea, Obstructive / Q000378:metabolism / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology
chemical_list: D001786:Blood Glucose; D051057:Proto-Oncogene Proteins c-akt
keywords: gluconeogenesis; hepatic glucose output; hypoxic chemoreflex; sleep apnea; type 2 diabetes
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