title: Intermittent hypoxia-induced glucose intolerance is abolished by α-adrenergic blockade or adrenal medullectomy.
abstract: Obstructive sleep apnea causes intermittent hypoxia (IH) during sleep and is associated with dysregulation of glucose metabolism. We developed a novel model of clinically realistic IH in mice to test the hypothesis that IH causes hyperglycemia, glucose intolerance, and insulin resistance via activation of the sympathetic nervous system. Mice were exposed to acute hypoxia of graded severity (21, 14, 10, and 7% O2) or to IH of graded frequency [oxygen desaturation index (ODI) of 0, 15, 30, or 60, SpO2 nadir 80%] for 30 min to measure levels of glucose fatty acids, glycerol, insulin, and lactate. Glucose tolerance tests and insulin tolerance tests were then performed under each hypoxia condition. Next, we examined these outcomes in mice that were administered phentolamine (α-adrenergic blockade) or propranolol (β-adrenergic blockade) or that underwent adrenal medullectomy before IH exposure. In all experiments, mice were maintained in a thermoneutral environment. Sustained and IH induced hyperglycemia, glucose intolerance, and insulin resistance in a dose-dependent fashion. Only severe hypoxia (7% O2) increased lactate, and only frequent IH (ODI 60) increased plasma fatty acids. Phentolamine or adrenal medullectomy both prevented IH-induced hyperglycemia and glucose intolerance. IH inhibited glucose-stimulated insulin secretion, and phentolamine prevented the inhibition. Propranolol had no effect on glucose metabolism but abolished IH-induced lipolysis. IH-induced insulin resistance was not affected by any intervention. Acutely hypoxia causes hyperglycemia, glucose intolerance, and insulin resistance in a dose-dependent manner. During IH, circulating catecholamines act upon α-adrenoreceptors to cause hyperglycemia and glucose intolerance.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland jjun2@jhmi.edu.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Jun
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep 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, Critical Care, and Sleep Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ronald
authors.initials: R
authors.lastname: Devera
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep 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, Critical Care, and Sleep 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, Critical Care, and Sleep 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, Critical Care, and Sleep Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
mesh_terms: D000313:Adrenal Medulla / Q000502:physiology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D018149:Glucose Intolerance / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010101:Oxygen Consumption / Q000502:physiology; D020181:Sleep Apnea, Obstructive / Q000378:metabolism / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects
chemical_list: D000317:Adrenergic alpha-Antagonists
keywords: sympathetic; thermoneutral