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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #115: Diabetes and Sleep Apnea Part 5

Mar 6, 2018
 

OSA and beta-cell function

While the impact of OSA in IR has been studied extensively, the impact of OSA on β-cell function has received little attention, despite being an essential part of the pathogenesis of T2DM and prediabetes. A small number of animal studies showed that intermittent hypoxia increases β-cell death, and results in β-cell dysfunction, although the intermittent hypoxia used in this study is far greater than that which occurs in humans with OSA [78]. One study in humans examined 118 patients without diabetes using the modified frequent sampling intravenous glucose tolerance test and found that the disposition index, a measure of β-cell function, was also reduced in patients with moderate to severe sleep-disordered breathing [65]. Similarly, a more recent study in patients with T2DM showed that patients with OSA had lower insulin secretion reserve than those without OSA [79], but there was no adjustment for adiposit differences between groups.

Mechanisms underpinning the relationship between OSA and dysglycemia

Despite the strong association between OSA and dysglycemia, the underlying mechanisms are not clear. There are, however, several possible mechanisms that link OSA to dysglycemia, IR, and β-cell dysfunction, such as changes in sleep architecture, sympathetic overactivation, increased inflammatory cytokines, hormonal changes, increased oxidative stress, and the development of nonalcoholic fatty liver disease (NAFLD) (Figure 22.2).

Intermittent hypoxia is an important component of OSA and may contribute to much of its pathologic consequences. Intermittent hypoxia for as little as 5 hours in healthy volunteers can reduce insulin sensitivity without compensatory increase in insulin secretion, suggesting an impact on β-cell function as well [80]. Intermittent hypoxia is associated with increased hypoxia-inducible factor-1 (HIF-1) which occurs either secondary to hypoxia itself [81] or to oxidative stress [82]. HIF-1 upregulates sterol regulatory element-binding protein (SREBP)-1 [83], which is associated with increased lipid biosynthesis and insulin resistance [84]. HIF is also involved in systemic inflammation [85]. Interestingly, in mice with partial deficiency of HIF-1, intermittent hypoxia does not result in IR [3,83].

In addition to intermittent hypoxia, OSA is associated with changes in sleep architecture such as reduction in slow wave sleep and sleep quality resulting in excessive daytime sleepiness.These changes in sleep architecture and quality have been associated with a reduction in insulin sensitivity and dysglycemia [86].

OSA is associated with many hormonal changes that can affect glucose metabolism. These include activation of the hypothalamic pituitary adrenal (HPA) axis and suppression of the GH axis and IGF-1; some of which can be reversed with CPAP treatment [87,88]. Gherlin has been shown to be higher in patients with OSA, which is reduced by CPAP treatment [89]. Catecholamines are also elevated in patients with OSA and are lowered by CPAP [90].

OSA is also associated with changes in adipokines. Adiponectin levels correlate negatively with the OSA severity independent of age, BMI, and visceral fat volume [91]. Several other studies showed lower adiponectin levels in OSA patients, although short CPAP treatment did not seem to reverse this trend [92,93]. Inversely to adiponectin, leptin levels were shown to be higher in obese subjects with OSA compared to age and BMI-matched obese subjects without OSA (p<0.05) [50]. There are several studies that similarly showed increased leptin levels in patients with OSA [49].

Sympathetic overactivation plays an important role in the regulation of glucose and fat metabolism and the development of T2DM [94]. OSA is associated with increased sympathetic activity [92]. It is likely that both the recurrent hypoxia [95] and recurrent arousals [96] contribute to the activation of the sympathetic sstem. OSA is also associated with elevated inflammatory cytokines such as IL-6, TNF-α, and NF-κB [92].

OSA may also be a risk factor for the developing of histologically proven nonalcoholic fatty liver disease (NAFLD) and for progressing to NASH [66,97]. Nocturnal desaturations were found to be associated with hepatic inflammation, hepatocyte ballooning, and liver fibrosis [66]. Another study also found that subjects with histologic NASH had significantly lower desaturation, lower mean nocturnal oxygen saturation, and higher AHI compared with non-NASH controls [97]. A randomized controlled trial showed that four weeks of CPAP had no impact on liver enzymes in patients with moderate to severe OSA [98]; it must be noted, however, that liver enzymes are not a sensitive measure of NAFLD/NASH.

Recurrent hypoxia and mitochondrial dysfunction in OSA result in the formation of reactive oxygen species (ROS) which leads to cellular and DNA damage and oxidative stress [99]. Many studies support OSA as a cause of oxidative stress [92]. Repetitive episodes of re-oxygenation following hypoxia, as seen in OSA, simulate ischemia–reperfusion injury which results in the generation of ROS [100]. ROS levels have been shown to be 2–3 times higher in patients with OSA compared to healthy controls [99]. In addition, multiple studies have shown increased oxidized lipids, DNA, and carbohydrates in patients with OSA and animals exposed to intermittent hypoxia [99]. All the aforementioned mechanisms can impact on IR and/or β-cell function resulting in impaired glucose metabolism and eventually T2DM.

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