Obstructive Sleep Apnea, Metabolic Syndrome and Diabetes

Introduction

Obstructive sleep apnea (OSA) is a clinical condition characterized by recurrent episodes of obstructions of the upper airway leading to increased negative intrathoracic pressure, sleep fragmentation and intermittent hypoxia during sleep. Current prevalence of OSA pointed that one third of the sleep studies showed some degree of OSA.1 Among adults 30–70 years of age, approximately 13% of men and 6% of women have moderate to severe forms of OSA.2 Current estimates represent an increase of millions of additional afflicted persons mainly explained by the ongoing obesity epidemic. If OSA is already common in the general population, the prevalence of OSA in patients with the Metabolic Syndrome and patients with diabetes is even more impressive: in patients with the Metabolic Syndrome, a previous report found that 60% of them presented moderate to severe OSA.3 Of note, the vast majority of them were not aware about the OSA diagnosis.3 In patients with diabetes, the prevalence of OSA range from 29% to 63% depending of the criteria adopted for OSA.4-5 This prevalence is even higher (over 86%) in patients with diabetes who are obese.6 A major challenge to the field has been to understand whether OSA is a mere epiphenomenon or an additional burden that exacerbates the metabolic dysfunction predisposing people to metabolic syndrome and diabetes. Significant advances were done in the last decades and are summarized here.

Metabolic dysfunction in OSA

Glucose metabolism. An independent association between OSA, insulin resistance and type 2 diabetes has been demonstrated by several cross-sectional studies and large population-based studies.7-11 Particularly, data from the Sleep Heart Health Study found that patients with moderate to severe OSA have lower insulin sensitivity and a higher prevalence of impaired fasting glucose and glucose intolerance.7 More recently, the association between OSA and insulin resistance was explored in lean individuals.9 The authors found that lean patients with OSA had 27% lower insulin sensitivity and 37% less than lean-matched controls.9 These results reinforce the concept that the relationship between OSA and insulin resistance is independent of obesity. Persistent insulin resistance may predispose to an increased incidence of diabetes. Indeed, Botros and colleagues found that OSA increases the risk of developing diabetes, independent of other risk factors.10

There are several potential mechanisms by which OSA contributes to insulin resistance and impaired insulin secretion including hepatic insulin resistance due to the activation of hepatic lipid biosynthesis and sympathetic and hypothalamic-pituitary-adrenal axis activations, among others.12

Lipid metabolism. Consistent evidence from animal models of OSA have shown that chronic intermittent hypoxia (a hallmark of OSA) induces in both lean and obese mice fasting dyslipidemia due to activation of the transcription factor sterol regulatory element-binding protein-1 (SREBP-1) and an important downstream enzyme of triglyceride and phospholipid biosynthesis, stearoyl-CoA desaturase-1.13-15 Moreover, chronic intermittent hypoxia also impaired inhibits clearance of triglyceride-rich lipoproteins inactivating adipose lipoprotein lipase.16-17 Despite this evidence, there is no consistent data in humans suggesting that OSA is a risk factor for dyslipidemia. Indeed, conflicting results have been observed in cross-sectional and interventional studies.18 Taking into account components of the metabolic syndrome, some reports found increased levels of triglycerides3,11,19-21 and reduced levels of high density lipoproteins (HDL)19-21 while others did not.22-23 Of note, the majority of the studies were not specifically designed to evaluate the lipid profile. Therefore, more evidence is still needed.

Blood pressure and OSA

High blood pressure is another component of the Metabolic Syndrome. The relationship between OSA and high blood pressure is supported by a large body of evidence in humans and animals.24-26 Increased blood pressure in OSA is multifactorial in origin and may depend on sympathetic overactivity, systemic inflammation, oxidative stress, endogenous vasoactive factors and endothelial dysfunction.27

Impact of OSA treatment on metabolic syndrome components and diabetes

So far, there is no definitive evidence regarding the impact of OSA treatment on metabolic syndrome and diabetes. Such studies have the potential to provide stronger evidence for a causal association between OSA and the metabolic syndrome and diabetes. The vast majority of the studies explored the impact of continuous positive airway pressure (CPAP) on individual components of the metabolic syndrome. There is evidence suggesting that CPAP can reverse insulin resistance in patients with OSA.28-31 However, the results are not consistent.32-33 Methodological limitations such as short duration of CPAP, small sample size, lack of controlling for physical activity/diet and population characteristics may explain the lack of response to CPAP. Recent meta-analyses suggest a favorable effect of CPAP on insulin resistance in non-diabetic patients.34-35 This result was mainly observed in patients who used CPAP more than 4h/night. In patients with type 2 diabetes, there is evidence suggesting that CPAP improves glycemic control.36-37

The impact of CPAP on lipid profiles is a topic of considerable debate. No consistent results have been observed so far. While some studies showed a positive effects of CPAP treatment on lipids (including post prandial lipemia),38-41 others were not able to detect any significant effect.42-43

Taking into account the metabolic syndrome as a "whole", the results are conflicting: Dorkova and colleagues demonstrated in a non-randomized study that in patients who used CPAP for ≥4 h/night for eight weeks, CPAP therapy reduced several components of the metabolic syndrome including blood pressure, triglycerides and glucose levels, compared to patients with low adherence to CPAP (<4 h/night).44 More recently, a sub-analysis45 from a previous report46 tested the effects of 12 weeks of CPAP in patients with OSA using a randomized control design. Compared to sham-CPAP, the authors found no significant reversal of the Metabolic Syndrome diagnosis after treatment. Further randomized studies with longer follow-up will be necessary to address the impact of OSA on metabolic syndrome.

Perspectives

OSA, metabolic syndrome and diabetes are common medical disorders that have important clinical, epidemiological, and public health implications. The current literature suggests that OSA promotes metabolic dysfunction, increases the incidence of diabetes and impaired glucose control. Therefore, OSA seems to be more than an epiphenomenon in the metabolic syndrome and in diabetes.47 However, OSA is commonly under diagnosed, and we suggest there may be a role for OSA screening in patients with the metabolic syndrome and diabetes. Finally, large randomized clinical studies will be necessary to define the impact of OSA treatment on metabolic and cardiovascular outcome.


References

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Clinical Topics: Diabetes and Cardiometabolic Disease, Sleep Apnea

Keywords: Sleep Apnea, Obstructive, Blood Pressure, Metabolic Syndrome X


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