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Published ahead of print on February 1, 2007, doi:10.1164/rccm.200610-1527OC

Am. J. Respir. Crit. Care Med., Volume 175, Number 8, April 2007, 851-857

A more recent version of this article appeared on April 15, 2007
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Submitted on October 23, 2006
Accepted on February 1, 2007

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 Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, 2 Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, 3 Department of Medicine, Divisions of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA

* To whom correspondence should be addressed. 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. Further 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 either: (i) IH (achieving a nadir of FIO2=5-6% at 60 cycles per/hr for 9 hr); (ii)intermittent air (IA) as a control; (iii) IH with ANS blockade (hexamethonium); (iv) IA with ANS blockade. IH decreased whole-body insulin sensitivity compared to IA (38.8 ± 2.7 mg/kg/min versus 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 occurs independent of activation of the ANS.
Key words: blood glucose, hyperinsulinemic euglycemic clamp, muscle glucose utilization, obstructive sleep apnea




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