Obstructive Sleep Apnea a risk factor for diabetes
By Live Dr - Sun Jul 03, 1:00 pm
Obstructive sleep apnea (OSA) is a disorder characterized by repetitive episodes of partial or complete collapse of the upper airway during sleep leading to apnea and hypopnea. In severely affected patients more than 30 apneas occur per hour and are associated with oxygen desaturations, increased respiratory effort, and arousals from sleep (Kohler and Stradling, 2010). Symptomatic OSA is highly prevalent and occurs in about 4% of middle-aged men and in 2% of middle-aged women (Young et al., 1993). However, minimally symptomatic or asymptomatic OSA is estimated to occur in about one out of five adults (Young et al., 2002). As obesity is a major risk factor for OSA, the prevalence of OSA is expected to increase as the average body weight of the population rises. Sleep apnea may lead to a number of acute consequences, of which daytime sleepiness is the most noticeable for affected patients. Sleepiness causes impairment of quality of life and increases the risk of accidents, including when driving or operating machinery (Barbe et al., 1998; George et al., 2002). OSA is also proposed to be associated with a substantial cardiovascular morbidity (Marin et al., 2005) and has been proven to be an independent risk factor for hypertension (Haentjens et al., 2007; Kohler et al., 2008).
The treatment of choice for OSA is continuous positive airway pressure (CPAP) therapy (Jenkinson et al., 1999; Giles et al., 2006). The CPAP device generates a positive pressure in the upper airways via a breathing mask, preventing airway collapse, apneas, and sleep fragmentation, thus providing a more restful sleep without intermittent hypoxia and recurrent arousals from sleep.
Excess weight and visceral obesity are the predominant risk factors for insulin resistance and type 2 diabetes (Mokdad et al., 2001; Kopelman, 2000). In insulin resistance, body cells become increasingly resistant to the effects of insulin and this condition precedes the evolution of type 2 diabetes where the pancreas cannot produce sufficient insulin to maintain normoglycemia. Due to the higher prevalence of diabetes in patients with OSA as compared with the normal population (Meslier et al., 2003), it has been postulated that OSA may be a causal factor in the pathogenesis of diabetes.
Mechanisms underpinning the association between OSA and diabetes may include intermittent hypoxia and consecutive increased oxidative stress as well as arousals associated with sympathetic nervous system activation and sleep fragmentation (Punjabi et al., 2003).
Obstructive apneas are often associated with oxygen desaturations resulting in intermittent hypoxia. As the effects of intermittent hypoxia are difficult to segregate from the effects of arousals, sympathetic activation, and sleep fragmentation, a limited number of studies used simulated intermittent hypoxia to clarify basic mechanisms in animal models by cycling delivery of oxygen, nitrogen, and air in closed chambers. In non-obese mice, intermittent hypoxia for 9 hours (60 cycles/hour with a FiO2 nadir of 5-6%) was shown to increase insulin resistance assessed by the hyperinsulinemic euglycemic clamp technique (Iiyori et al., 2007). This increase in insulin resistance also persisted when the autonomous nervous system was chemically blocked and thus the effect of intermittent hypoxia seemed to be independent from sympathetic nervous system activity. This might be due to intermittent hypoxia causing an increase in counter regulatory glucocorticoid levels. In obese mice, exposure to 12 weeks of intermittent hypoxia produced a sustained increase in insulin resistance (Polotsky et al., 2003). In the latter study, deficient leptin levels were identified as a factor linking intermittent hypoxia and insulin resistance as replacement or up-regulation of leptin protected the animals against the development of insulin resistance.
Another mechanism linking intermittent hypoxia with insulin resistance may be via increased oxidative stress, which itself has been implicated as a contributor to the onset of diabetes (Rains and Jain, 2011). The exact mechanisms by which oxidative stress may cause insulin resistance are unknown (Dandona et al., 2004; Maddux et al., 2001). In an animal model of long-term intermittent hypoxia (8 weeks) simulating oxygenation patterns of OSA in mice, several NADPH oxidase proteins were activated promoting oxidative injury and proinflammatory gene expression (Zhan et al., 2005). In another animal model study, simulated cycles of hypoxia and re-oxygenation accounted for a state of oxidative stress and significant increase of reactive oxygen species in mice (Xu et al., 2004).
There is also evidence that simulated intermittent hypoxia (6 hours per day for 4 days) in healthy humans leads to an increased level of oxidative stress by increased production of reactive oxygen species (Pialoux et al., 2009); however, data of simulated intermittent hypoxia in humans and its effect on glucose metabolism is scant. An experiment in 14 healthy volunteers revealed that exposure to hypoxia for 30 minutes (oxygen saturation 75%) caused glucose intolerance (Oltmanns et al., 2004). In the latter study, neurohormonal stress response was also evaluated and an increase in plasma epinephrine concentration was noted under hypoxic conditions. The effect of acute intermittent hypoxia on glucose metabolism was investigated in only one study; 13 healthy volunteers were exposed to 5 hours of intermittent hypoxia or normoxia during wakefulness (Louis and Punjabi, 2009). The authors reported a decrease in insulin sensitivity with intermittent hypoxia and a shift in sympathovagal balance towards an increase in sympathetic nervous system activity.