Blockade of endothelin-1 receptor type B ameliorates glucose intolerance and insulin resistance in a mouse model of obstructive sleep apnea
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.