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.