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Published ahead of print on February 1, 2007, doi:10.1164/rccm.200610-1527OC
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American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 851-857, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200610-1527OC

Original Article

Intermittent Hypoxia Causes Insulin Resistance in Lean Mice Independent of Autonomic Activity

Nao Iiyori1, Laura C. Alonso2, Jianguo Li3, Mark H. Sanders1, Adolfo Garcia-Ocana2, Robert M. O'Doherty2, Vsevolod Y. Polotsky3 and Christopher P. O'Donnell1

1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and 2 Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and 3 Divisions of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Christopher P. O'Donnell, Ph.D., Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, NW628 MUH 3459 Fifth Avenue, Pittsburgh PA 15213. E-mail: odonnellcp{at}upmc.edu

Rationale and Objectives: Although many clinical physiology and epidemiology studies show an association between obstructive sleep apnea (OSA) and markers of insulin resistance, no causal pathway has been established. The purpose of the current study was to determine if the intermittent hypoxia (IH) stimulus that characterizes OSA causes insulin resistance in the absence of obesity. Furthermore, we assessed the impact of IH on specific metabolic function in liver and muscle. Finally, we examined the potential mechanistic role of the autonomic nervous system (ANS) in mediating insulin resistance in response to IH.

Methods and Results: Hyperinsulinemic euglycemic clamps were conducted and whole-body insulin sensitivity, hepatic glucose output, and muscle-specific glucose utilization assessed in conscious, chronically instrumented adult male C57BL/6J mice exposed to (1) IH (achieving a nadir of FIO2 = 5–6% at 60 cycles/h for 9 h), (2) intermittent air as a control, (3) IH with ANS blockade (hexamethonium), or (4) IA with ANS blockade. IH decreased whole-body insulin sensitivity compared with intermittent air (38.8 ± 2.7 vs. 49.4 ± 1.5 mg/kg/min, p < 0.005) and reduced glucose utilization in oxidative muscle fibers, but did not cause a change in hepatic glucose output. Furthermore, the reduction in whole-body insulin sensitivity during IH was not restored by ANS blockade.

Conclusion: We conclude that IH can cause acute insulin resistance in otherwise lean, healthy animals, and that the response is associated with decreased glucose utilization of oxidative muscle fibers, but that it occurs independently of activation of the ANS.

Key Words: blood glucose • hyperinsulinemic euglycemic clamp • muscle glucose utilization • obstructive sleep apnea


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
Clinical studies suggest that sleep apnea can independently contribute to development of insulin resistance. However, there is no direct evidence of a cause-and-effect relationship or potential mechanisms linking sleep apnea and insulin resistance.

What This Study Adds to the Field
Intermittent hypoxia produces insulin resistance in lean mice. Insulin resistance during intermittent hypoxia was not dependent on the autonomic nervous system.

 



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