Glucoregulatory Consequences and Cardiorespiratory Parameters in Rats Exposed to Chronic–Intermittent Hypoxia: Effects of the Duration of Exposure and Losartan

Abstract

Background: Obstructive sleep apnea (OSA) is associated with glucose intolerance. Both chronic sleep disruption and recurrent blood oxygen desaturations (chronic–intermittent hypoxia, CIH) may cause, or exacerbate, metabolic derangements. Methods: To assess the impact of CIH alone, without accompanying upper airway obstructions, on the counter-regulatory response to glucose load and cardiorespiratory parameters, we exposed adult male Sprague-Dawley rats to CIH or sham room air exchanges for 10 h/day for 7, 21, or 35 days and then, 1 day after conclusion of CIH exposure, conducted intravenous glucose-tolerance tests (ivgtt) under urethane anesthesia. Additional rats underwent 35 days of CIH followed by 35 days of regular housing, or had 35 day-long CIH exposure combined with daily administration of the type 1 angiotensin II receptor antagonist, losartan (15 mg/kg, p.o.), and then were also subjected to ivgtt. Results: Compared with the corresponding control groups, CIH rats had progressively reduced glucose-stimulated insulin release and impaired glucose clearance, only mildly elevated heart rate and/or arterial blood pressure and slightly reduced respiratory rate. The differences in insulin release between the CIH and sham-treated rats disappeared in the rats normally housed for 35 days after 35 days of CIH/sham exposure. The losartan-treated rats had improved insulin sensitivity, with no evidence of suppressed insulin release in the CIH group. Conclusion: In adult rats, the glucose-stimulated insulin release is gradually suppressed with the duration of exposure to CIH, but the effect is reversible. Elimination of the detrimental effect of CIH on insulin release by losartan suggests that CIH disrupts glucoregulation through angiotensin/catecholaminergic pathways. Accordingly, treatment with continuous positive airway pressure may ameliorate pre-diabetic conditions in OSA patients, in part, by reducing sympathoexcitatory effects of recurrent nocturnal hypoxia.

The effect of adrenal medullectomy on metabolic responses to chronic intermittent hypoxia

“…The pathogenesis of β cell dysfunction during IH has been attributed to oxidative stress, apoptosis of β cells and up-regulation of the renin-angiotensin system (Wang et al , 2013;Xu et al , 2009;Yokoe et al , 2008;Fenik et al , 2012). Our data suggest that the impairment of insulin secretion in IH is caused by the surge in circulating epinephrine.…”

“…We have previously developed a mouse model of chronic IH, which mimics the oxyhemoglobin saturation profile in patients with OSA (Jun et al , 2010;Polotsky et al , 2006;Reinke et al , 2011;Tagaito et al , 2001). Acute and chronic IH induces insulin resistance in mice (Polotsky et al , 2003;Iiyori et al , 2007;Drager et al , 2011;Polak et al , 2013;Lee et al , 2013) and impairs glucose stimulated insulin secretion in mice and rats (Polak et al , 2013;Lee et al , 2013;Fenik et al , 2012). Yokoe et al reported that IH induces replication of pancreatic β-cells (Yokoe et al , 2008), whereas Xu et al reported increases both in β-cell apoptosis and proliferation (Xu et al , 2009).…”

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

“…In addition to an increased NE terminal density and increased α 1 -adrenoceptor expression, CIH could also increase the baseline levels of catecholamines in the brain because, in other studies, CIH exposure resulted in increased plasma levels of catecholamines and increased baseline activity of the sympathetic system (72, 148, 149, 151, 495). However, in Wistar-Kyoto rats, only dopamine levels were increased, whereas NE or 5-HT levels were not, following hypocapnic CIH when measured in tissue homogenates collected from different brain regions (303).…”

Inhibition of Lipolysis Ameliorates Diabetic Phenotype in a Mouse Model of Obstructive Sleep Apnea

“…Blood glucose was determined using a glucometer (Accu-Check Aviva; Roche, Indianapolis, IN) at 0, 10, 20, 30, 60, 90, and 120 minutes after intraperitoneal injection of 1 g/kg glucose (n = 10 per group) or at 0, 10,20,30,40,50,60,90, and 120 minutes after intraperitoneal injection of 0.5 IU/kg insulin (ITT; n = 10 per group).…”

“…Several animal studies have suggested that exposure to intermittent hypoxia (IH) compromised whole-body glucose homeostasis, reducing insulin sensitivity, glucose tolerance, and muscle glucose uptake; at the same time, it elevated fasting blood glucose, augmenting hepatic glucose release, and impairing secretion from pancreatic b cells (6)(7)(8)(9)(10)(11). Similarly, exposure of healthy human volunteers to IH for 5 hours induced insulin resistance and impaired pancreatic b cell function (12).…”