Sympathetic inhibition attenuates hypoxia induced insulin resistance in healthy adult humans
Date
2012
Authors
Peltonen, Garrett Lee, author
Bell, Christopher, advisor
Miller, Benjamin F., committee member
Hamilton, Karyn L., committee member
Gentile, Christopher L., committee member
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Abstract
Acute and chronic exposure to hypoxia is known to decrease insulin sensitivity in healthy humans and animals, while simultaneously increasing the activity of the sympathetic nervous system (SNS). Likewise, obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) are clinical conditions characterized by hypoxia, elevated SNS activity, and a high prevalence of insulin resistance. In contrast to hypoxic exposure and hypoxic related diseases, hyperoxia (FIO2 = 1.00) has been shown to improve insulin sensitivity while concomitantly decreasing SNS activity. Consistent with this, continuous positive airway pressure (CPAP), a common OSA treatment, has proven effective in abolishing nocturnal bouts of intermittent hypoxia, enhancing insulin sensitivity and diminishing SNS activity. Although the underlying mechanism of hypoxia induced insulin resistance remains unclear, it appears that elevated SNS activity may be a mediating factor. Therefore, we hypothesized that inhibition of the SNS would attenuate hypoxia induced insulin resistance. METHODS: 10 males (23±1 years, body mass index 24.2±0.8 kg/m2 (mean±SE)) reported to our laboratory on 4 separate mornings, separated by a minimum of 7 days, after a 12-hour fast and 48-hour abstention from exercise. Insulin sensitivity was determined via the hyperinsulinemic euglycemic clamp technique under each of the following conditions: normoxia (FIO2=0.21), hypoxia (FIO2=0.11), normoxia and SNS inhibition (48-hour transdermal clonidine administration (Catapres-TTS; 0.2mg/day)), and hypoxia SNS inhibition. RESULTS: Oxyhemoglobin saturation was decreased (P<0.01) during hypoxia (63±2%) compared to normoxia (96±0%) and there was no significant effect of SNS inhibition on oxyhemoglobin saturation in either normoxia or hypoxia (P>0.25). Norepinephrine was elevated in hypoxia (137±13%; P=0.02), as determined by area under curve and expressed relative to normoxia. SNS inhibition prevented the hypoxia induced increase in norepinephrine (94±14%; P=0.43). The glucose infusion rate (adjusted for fat free mass and circulating insulin), required to maintain blood glucose at 90 mg/dl (5 mmol/L) during administration of insulin, was decreased during hypoxia (128±30 nmol/kg fat free mass/pmol/L/min; P=0.03) compared to normoxia (225±23) and remained unchanged during normoxia and SNS inhibition (219±19; P=0.86), and hypoxia and SNS inhibition (169±23; P=0.23). CONCLUSION: Inhibition of the SNS attenuates hypoxia induced insulin resistance.
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Subject
clonidine
glucose
hyperinsulinemic euglycemic clamp
hypoxic
noradrenaline
norepinephrine