Rationale: Cross-sectional association has been reported between sleep-disordered breathing (SDB) and insulin resistance, but no prospective studies have been performed to determine whether SDB is causal in the development of diabetes. Objectives: The purpose of our study was to investigate the prevalence and incidence of type II diabetes in subjects with SDB and whether an independent relationship exists between them. Methods: A cross-sectional and longitudinal analysis was performed in 1,387 participants of the Wisconsin Sleep Cohort. Full polysomnography was used to characterize SDB. Diabetes was defined in two ways: (1 ) physician-diagnosis alone or (2 ) for those with glucose measurements, either fasting glucose у 126 mg/dl or physician diagnosis. Measurements and Main Results:There was a greater prevalence of diabetes in subjects with increasing levels of SDB. A total of 14.7% of subjects with an apnea-hypopnea index (AHI) of 15 or more had a diagnosis of diabetes compared with 2.8% of subjects with an AHI of less than 5. The odds ratio for having a physician diagnoses of diabetes mellitus with an AHI of 15 or greater versus an AHI of less than 5 was 2.30 (95% confidence interval, 1.28-4.11; p ϭ 0.005) after adjustment for age, sex, and body habitus. The odds ratio for developing diabetes mellitus within 4 yr with an AHI of 15 or more compared with an AHI of less than 5 was 1.62 (95% confidence interval, 0.67-3.65; p ϭ 0.24) when adjusting for age, sex, and body habitus. Conclusions: Diabetes is more prevalent in SDB and this relationship is independent of other risk factors. However, it is not clear that SDB is causal in the development of diabetes.Keywords: diabetes; incidence; prevalence; sleep apnea Sleep-disordered breathing (SDB) and diabetes mellitus (DM) are prevalent diseases that share several risk factors, including advanced age and obesity (1, 2). Diabetes was the sixth leading cause of death listed on U.S. death certificates in 2003 and is associated with a higher incidence of cardiovascular, cerebrovascular, and renal disease (3, 4). There is also mounting evidence that SDB may be an independent risk factor for cardiovascular and cerebrovascular disease (5). Interest in a potential independent link between the two diseases continues to grow.Several studies have explored this relationship with conflicting results. Four recent studies demonstrated an inverse relationship between apnea-hypopnea index (AHI) and insulin sensitiv- ity (6-9). The relationship was independent of body mass index (BMI) and age in all three studies. Another study found a relationship between fasting insulin levels and increasing AHI in patients with BMI of 29 or greater, but not in those with lower BMIs (10). Finally, Stoohs and colleagues found the relationship between worsening insulin sensitivity and SDB in a group of 50 "healthy, normotensive individuals" was completely accounted for by increased BMI (11). The primary objective of these studies was to explore the relationship between insulin sensitivity, or surroga...
An important determinant of [H(+)] in the environment of the central chemoreceptors is cerebral blood flow. Accordingly we hypothesized that a reduction of brain perfusion or a reduced cerebrovascular reactivity to CO(2) would lead to hyperventilation and an increased ventilatory responsiveness to CO(2). We used oral indomethacin to reduce the cerebrovascular reactivity to CO(2) and tested the steady-state hypercapnic ventilatory response to CO(2) in nine normal awake human subjects under normoxia and hyperoxia (50% O(2)). Ninety minutes after indomethacin ingestion, cerebral blood flow velocity (CBFV) in the middle cerebral artery decreased to 77 +/- 5% of the initial value and the average slope of CBFV response to hypercapnia was reduced to 31% of control in normoxia (1.92 versus 0.59 cm(-1) s(-1) mmHg(-1), P < 0.05) and 37% of control in hyperoxia (1.58 versus 0.59 cm(-1) s(-1) mmHg(-1), P < 0.05). Concomitantly, indomethacin administration also caused 40-60% increases in the slope of the mean ventilatory response to CO(2) in both normoxia (1.27 +/- 0.31 versus 1.76 +/- 0.37 l min(-1) mmHg(-1), P < 0.05) and hyperoxia (1.08 +/- 0.22 versus 1.79 +/- 0.37 l min(-1) mmHg(-1), P < 0.05). These correlative findings are consistent with the conclusion that cerebrovascular responsiveness to CO(2) is an important determinant of eupnoeic ventilation and of hypercapnic ventilatory responsiveness in humans, primarily via its effects at the level of the central chemoreceptors.
Vasodilator responses to chemical stimuli in the cerebral circulation and the forearm are impaired in many patients with obstructive sleep apnea. Some of these impairments can be improved with continuous positive airway pressure.
We measured ventilation, arterial O2 saturation, end‐tidal CO2 (PET,CO2), blood pressure (intra‐arterial catheter or photoelectric plethysmograph), and flow velocity in the middle cerebral artery (CFV) (pulsed Doppler ultrasound) in 17 healthy awake subjects while they performed 20 s breath holds under control conditions and during ganglionic blockade (intravenous trimethaphan, 4.4 ± 1.1 mg min−1 (mean ±s.d.)). Under control conditions, breath holding caused increases in PET,CO2 (7 ± 1 mmHg) and in mean arterial pressure (MAP) (15 ± 2 mmHg). A transient hyperventilation (PET,CO2−7 ± 1 mmHg vs. baseline) occurred post‐apnoea. CFV increased during apnoeas (by 42 ± 3 %) and decreased below baseline (by 20 ± 2 %) during post‐apnoea hyperventilation. In the post‐apnoea recovery period, CFV returned to baseline in 45 ± 4 s. The post‐apnoea decrease in CFV did not occur when hyperventilation was prevented. During ganglionic blockade, which abolished the increase in MAP, apnoea‐induced increases in CFV were partially attenuated (by 26 ± 2 %). Increases in PET,CO2 and decreases in oxyhaemoglobin saturation (Sa,O2) (by 2 ± 1 %) during breath holds were identical in the intact and blocked conditions. Ganglionic blockade had no effect on the slope of the CFV response to hypocapnia but it reduced the CFV response to hypercapnia (by 17 ± 5 %). We attribute this effect to abolition of the hypercapnia‐induced increase in MAP. Peak increases in CFV during 20 s Mueller manoeuvres (40 ± 3 %) were the same as control breath holds, despite a 15 mmHg initial, transient decrease in MAP. Hyperoxia also had no effect on the apnoea‐induced increase in CFV (40 ± 4 %). We conclude that apnoea‐induced fluctuations in CFV were caused primarily by increases and decreases in arterial partial pressure of CO2 (Pa,CO2) and that sympathetic nervous system activity was not required for either the initiation or the maintenance of the cerebrovascular response to hyper‐ and hypocapnia. Increased MAP or other unknown influences of autonomic activation on the cerebral circulation played a smaller but significant role in the apnoea‐induced increase in CFV; however, negative intrathoracic pressure and the small amount of oxyhaemoglobin desaturation caused by 20 s apnoea did not affect CFV.
Our previous work showed a diminished cerebral blood flow (CBF) response to changes in Pa(CO(2)) in congestive heart failure patients with central sleep apnea compared with those without apnea. Since the regulation of CBF serves to minimize oscillations in H(+) and Pco(2) at the site of the central chemoreceptors, it may play an important role in maintaining breathing stability. We hypothesized that an attenuated cerebrovascular reactivity to changes in Pa(CO(2)) would narrow the difference between the eupneic Pa(CO(2)) and the apneic threshold Pa(CO(2)) (DeltaPa(CO(2))), known as the CO(2) reserve, thereby making the subjects more susceptible to apnea. Accordingly, in seven normal subjects, we used indomethacin (Indo; 100 mg by mouth) sufficient to reduce the CBF response to CO(2) by approximately 25% below control. The CO(2) reserve was estimated during non-rapid eye movement (NREM) sleep. The apnea threshold was determined, both with and without Indo, in NREM sleep, in a random order using a ventilator in pressure support mode to gradually reduce Pa(CO(2)) until apnea occurred. results: Indo significantly reduced the CO(2) reserve required to produce apnea from 6.3 +/- 0.5 to 4.4 +/- 0.7 mmHg (P = 0.01) and increased the slope of the ventilation decrease in response to hypocapnic inhibition below eupnea (control vs. Indo: 1.06 +/- 0.10 vs. 1.61 +/- 0.27 l x min(-1) x mmHg(-1), P < 0.05). We conclude that reductions in the normal cerebral vascular response to hypocapnia will increase the susceptibility to apneas and breathing instability during sleep.
Obstructive sleep apnea (OSA) is a recognized cause of secondary hypertension. OSA episodes produce surges in systolic and diastolic pressure that keep mean blood pressure levels elevated at night. In many patients, blood pressure remains elevated during the daytime, when breathing is normal. Contributors to this diurnal pattern of hypertension include sympathetic nervous system overactivity and alterations in vascular function and structure caused by oxidant stress and inflammation. Treatment of OSA with nasal continuous positive airway pressure (CPAP) abolishes apneas, thereby preventing intermittent arterial pressure surges and restoring the nocturnal "dipping" pattern. CPAP treatment also has modest beneficial effects on daytime blood pressure. Because even small decreases in arterial pressure can contribute to reducing cardiovascular risk, screening for OSA is an essential element of evaluating patients with hypertension.
We measured ventilation, arterial O2 saturation, end-tidal CO2 (PET,CO2), blood pressure (intra-arterial catheter or photoelectric plethysmograph), and flow velocity in the middle cerebral artery (CFV) (pulsed Doppler ultrasound) in 17 healthy awake subjects while they performed 20 s breath holds under control conditions and during ganglionic blockade (intravenous trimethaphan, 4.4 +/- 1.1 mg min-1 (mean +/- S.D.)). Under control conditions, breath holding caused increases in PET,CO2 (7 +/- 1 mmHg) and in mean arterial pressure (MAP) (15 +/- 2 mmHg). A transient hyperventilation (PET,CO2 -7 +/- 1 mmHg vs. baseline) occurred post-apnoea. CFV increased during apnoeas (by 42 +/- 3 %) and decreased below baseline (by 20 +/- 2 %) during post-apnoea hyperventilation. In the post-apnoea recovery period, CFV returned to baseline in 45 +/- 4 s. The post-apnoea decrease in CFV did not occur when hyperventilation was prevented. During ganglionic blockade, which abolished the increase in MAP, apnoea-induced increases in CFV were partially attenuated (by 26 +/- 2 %). Increases in PET,CO2 and decreases in oxyhaemoglobin saturation (Sa,O2) (by 2 +/- 1 %) during breath holds were identical in the intact and blocked conditions. Ganglionic blockade had no effect on the slope of the CFV response to hypocapnia but it reduced the CFV response to hypercapnia (by 17 +/- 5 %). We attribute this effect to abolition of the hypercapnia-induced increase in MAP. Peak increases in CFV during 20 s Mueller manoeuvres (40 +/- 3 %) were the same as control breath holds, despite a 15 mmHg initial, transient decrease in MAP. Hyperoxia also had no effect on the apnoea-induced increase in CFV (40 +/- 4 %). We conclude that apnoea-induced fluctuations in CFV were caused primarily by increases and decreases in arterial partial pressure of CO2 (Pa,CO2) and that sympathetic nervous system activity was not required for either the initiation or the maintenance of the cerebrovascular response to hyper- and hypocapnia. Increased MAP or other unknown influences of autonomic activation on the cerebral circulation played a smaller but significant role in the apnoea-induced increase in CFV; however, negative intrathoracic pressure and the small amount of oxyhaemoglobin desaturation caused by 20 s apnoea did not affect CFV.
Arousals from NREM sleep transiently reduce CBFV, whereas arousals from REM sleep transiently increase CBFV, despite qualitatively and quantitatively similar increases in MAP, HR, and VE in the two sleep states.
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