Abstract
Obstructive sleep apnea (OSA) is associated with insulin resistance (IR) and glucose intolerance. Elevated endothelin-1 (ET-1) levels have been observed in OSA patients and in mice exposed to intermittent hypoxia (IH). We examined whether pharmacological blockade of type A and type B ET-1 receptors (ETA and ETB) would ameliorate glucose intolerance and IR in mice exposed to IH. Subcutaneously implanted pumps delivered BQ-123 (ETA antagonist; 200 nmol/kg/day), BQ-788 (ETB antagonist; 200 nmol/kg/day) or vehicle (saline or propyleneglycol [PG]) for 14 days in C57BL6/J mice (10/group). During treatment, mice were exposed to IH (decreasing the FiO2 from 20.9% to 6%, 60/h) or intermittent air (IA). After IH or IA exposure, insulin (0.5 IU/kg) or glucose (1 mg/kg) was injected intraperitoneally and plasma glucose determined after injection and area under glucose curve (AUC) was calculated. Fourteen-day IH increased fasting glucose levels (122 ± 7 vs. 157 ± 8 mg/dL, PG: 118 ± 6 vs. 139 ± 8; both p < 0.05) and impaired glucose tolerance (AUCglucose: 19,249 ± 1105 vs. 29,124 ± 1444, PG AUCglucose: 18,066 ± 947 vs. 25,135 ± 797; both p < 0.05) in vehicle-treated animals. IH-induced impairments in glucose tolerance were partially ameliorated with BQ-788 treatment (AUCglucose: 21,969 ± 662; p < 0.05). Fourteen-day IH also induced IR (AUCglucose: 7185 ± 401 vs. 8699 ± 401; p < 0.05). Treatment with BQ-788 decreased IR under IA (AUCglucose: 5281 ± 401, p < 0.05) and reduced worsening of IR with IH (AUCglucose: 7302 ± 401, p < 0.05). There was no effect of BQ-123 on IH-induced impairments in glucose tolerance or IR. Our results suggest that ET-1 plays a role in IH-induced impairments in glucose homeostasis.
Highlights
Obstructive sleep apnea (OSA) is a common condition characterized by repeated episodes of complete or partial upper airway collapse during sleep, resulting in repetitive drops in hemoglobin oxygen saturation and sleep fragmentation
A causal role for ET-1 is further corroborated by studies documenting improved glucose homeostasis and insulin sensitivity after ET-1 receptor blockade in insulin-resistant rodents, healthy volunteers and insulinresistant subjects [47, 50,51,52]. These findings indicate that chronically elevated ET-1 levels could play a fundamental role in the development of insulin resistance (IR) and glucose intolerance; it remains unclear whether ET-1 is involved in the development of metabolic impairments associated with intermittent hypoxia (IH) and OSA and whether pharmacological treatment with ET-1 receptor antagonists would provide metabolic benefit in these subjects
We investigated whether pharmacological inhibition of ET-1 signaling with the selective ET-1 type A (ETA) or ETB receptor antagonists, BQ-123 or BQ-788, respectively, would ameliorate the detrimental impact of IH on glucose homeostasis
Summary
Obstructive sleep apnea (OSA) is a common condition characterized by repeated episodes of complete or partial upper airway collapse during sleep, resulting in repetitive drops in hemoglobin oxygen saturation and sleep fragmentation. Research in the past decade suggests a role for OSA in the pathogenesis of insulin resistance (IR), glucose intolerance, metabolic syndrome and type 2 diabetes independent of age, obesity or fat distribution [12,13,14]. Mechanisms linking OSA with impaired glucose homeostasis are not fully understood, several lines of evidence suggest that intermittent hypoxia (IH) plays a key role in inducing metabolic impairments. Elevated ET-1 levels play a key role in abnormal carotid body functioning, leading to augmented sympathetic activation and development of systemic hypertension found in OSA [32, 33], while continuous positive airway pressure therapy effectively lowered blood pressure as well as ET-1 levels [27]
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