Abstract
Intermittent hypoxemia (IH), a pathophysiologic consequence of obstructive sleep apnea (OSA), adversely affects insulin sensitivity, insulin secretion, and glucose tolerance. Nifedipine, an L-type calcium channel blocker frequently used for treatment of hypertension, can also impair insulin sensitivity and secretion. However, the cumulative and interactive repercussions of IH and nifedipine on glucose homeostasis have not been previously investigated. Adult male C57BL6/J mice were exposed to either nifedipine or vehicle concurrently with IH or intermittent air (IA) over five days. IH exposure entailed cycling fractional inspired oxygen levels between 0.21 and 0.055 at a rate of 60 events per hour. Nifedipine (20 mg/kg/day) or vehicle was administered via subcutaneous osmotic pumps resulting in four groups of mice: IA-vehicle (control), IA–nifedipine, and IH-vehicle, IH–nifedipine. Compared to IA (control), IH increased fasting glucose (Mean Δ:33.0 mg/dl; p<0.001) and insulin (mean Δ: 0.53 ng/ml; p<0.001) with nifedipine having no independent effect. Furthermore, glucose tolerance was worse with nifedipine alone, and IH further exacerbated the impairment in glucose disposal (p=0.013 for interaction). Nifedipine also decreased glucose-stimulated insulin secretion and the insulinogenic index, with addition of IH attenuating those measures further. There were no discernible alterations in insulin biosynthesis/processing, insulin content, or islet morphology. These findings underscore the detrimental impact of IH on insulin sensitivity and glucose tolerance, while highlighting that nifedipine exacerbates these disturbances through impaired β- cell function. Consequently, cautious use of L-type calcium channel blockers is warranted in OSA patients, particularly in those at risk for type 2 diabetes.