Obstructive Sleep Apnea, Metabolic Syndrome and Diabetes
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.
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.
- Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased Prevalence of Sleep-Disordered Breathing in Adults. Am J Epidemiol 2013;177:1006-1014.
- Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230-5.
- Drager LF, Lopes HF, Maki-Nunes C, et al. The impact of obstructive sleep apnea on metabolic and inflammatory markers in consecutive patients with metabolic syndrome. PLoS One 2010;5:e12065.
- Einhorn D, Stewart DA, Erman MK, Gordon N, Philis-Tsimikas A, Casal E. Prevalence of sleep apnea in a population of adults with type 2 diabetes mellitus. Endocr Pract 2007;13:355-62.
- Laaban JP, Daenen S, Léger D, Pascal S, Bayon V, Slama G, Elgrably F. Prevalence and predictive factors of sleep apnoea syndrome in type 2 diabetic patients. Diabetes Metab 2009;35:372-7.
- Foster GD, Sanders MH, Millman R, et al.; Sleep AHEAD Research Group. Obstructive sleep apnea among obese patients with type 2 diabetes. Diabetes Care 2009;32:1017-9.
- Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE; Sleep Heart Health Study Investigators. Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol 2004;160:521-30.
- Reichmuth KJ, Austin D, Skatrud JB, Young T. Association of sleep apnea and type II diabetes: a population-based study. Am J Respir Crit Care Med 2005;172:1590-5.
- Pamidi S, Wroblewski K, Broussard J, Day A, Hanlon EC, Abraham V, Tasali E. Obstructive sleep apnea in young lean men: impact on insulin sensitivity and secretion. Diabetes Care 2012;35:2384-9.
- Botros N, Concato J, Mohsenin V, Selim B, Doctor K, Yaggi HK. Obstructive sleep apnea as a risk factor for type 2 diabetes. Am J Med 2009;122:1122-7.
- Togeiro SM, Carneiro G, Ribeiro Filho FF, et al. Consequences of Obstructive Sleep Apnea on Metabolic Profile: A Population-Based Survey. Obesity (Silver Spring) 2013;21:847-51.
- Drager LF, Jun JC, Polotsky VY. Metabolic consequences of intermittent hypoxia: relevance to obstructive sleep apnea. Best Pract Res Clin Endocrinol Metab 2010;24:843-51.
- Li J, Thorne LN, Punjabi NM, et al. Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res 2005;97:698-706.
- Li J, Grigoryev DN, Ye SQ, et al. Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. J Appl Physiol 2005;99:1643-8.
- Savransky V, Jun J, Li J, et al. Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase. Circ Res 2008;103:1173-80.
- Drager LF, Li J, Shin MK, et al. Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea. Eur Heart J 2012;33:783-90.
- Drager LF, Yao Q, Shin MK, et al. Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4. Am J Respir Crit Care Med 2013;188:240-8.
- Drager LF, Jun J, Polotsky VY. Obstructive sleep apnea and dyslipidemia: implications for atherosclerosis. Curr Opin Endocrinol Diabetes Obes 2010;17:161-5. Erratum in: Curr Opin Endocrinol Diabetes Obes. 2010;17:394.
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- Newman AB, Nieto FJ, Guidry U, Lind BK, Redline S, Pickering TG, Quan SF; Sleep Heart Health Study Research Group. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol 2001;154:50-9.
- Tan KC, Chow WS, Lam JC, Lam B, Wong WK, Tam S, Ip MS. HDL dysfunction in obstructive sleep apnea. Atherosclerosis 2006;184:377-82.
- Tokuda F, Sando Y, Matsui H, Koike H, Yokoyama T. Serum levels of adipocytokines, adiponectin and leptin, in patients with obstructive sleep apnea syndrome. Intern Med 2008;47:1843-9.
- Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378-84.
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- Pedrosa RP, Krieger EM, Lorenzi-Filho G, Drager LF. Recent advances of the impact of obstructive sleep apnea on systemic hypertension. Arq Bras Cardiol 2011;97:e40-7.
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- Harsch IA, Schahin SP, Radespiel-Tröger M, Weintz O, Jahreiss H, Fuchs FS, Wiest GH, Hahn EG, Lohmann T, Konturek PC, Ficker JH. Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2004;169:156-62.
- Schahin SP, Nechanitzky T, Dittel C, Fuchs FS, Hahn EG, Konturek PC, Ficker JH, Harsch IA. Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome. Med Sci Monit 2008;14:CR117-21.
- Tasali E, Chapotot F, Leproult R, Whitmore H, Ehrmann DA. Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 2011;96:365-74.
- Davies RJ, Turner R, Crosby J, Stradling JR. Plasma insulin and lipid levels in untreated obstructive sleep apnoea and snoring; their comparison with matched controls and response to treatment. J Sleep Res 1994;3:180-5.
- West SD, Nicoll DJ, Wallace TM, Matthews DR, Stradling JR. Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax 2007;62:969-74.
- Yang D, Liu Z, Yang H, Luo Q. Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis. Sleep Breath 2013;17:33-8.
- Iftikhar IH, Khan MF, Das A, Magalang UJ. Meta-analysis: continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes. Ann Am Thorac Soc 2013;10:115-20.
- Dawson A, Abel SL, Loving RT, Dailey G, Shadan FF, Cronin JW, Kripke DF, Kline LE. CPAP therapy of obstructive sleep apnea in type 2 diabetics improves glycemic control during sleep. J Clin Sleep Med 2008;4:538-42.
- Babu AR, Herdegen J, Fogelfeld L, Shott S, Mazzone T. Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea. Arch Intern Med 2005;165:447-52.
- Steiropoulos P, Tsara V, Nena E, Fitili C, Kataropoulou M, Froudarakis M, Christaki P, Bouros D. Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome. Chest 2007;132:843-51.
- Cuhadaroğlu C, Utkusavaş A, Oztürk L, Salman S, Ece T. Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea. Lung 2009;187:75-81.
- Robinson GV, Pepperell JC, Segal HC, Davies RJ, Stradling JR. Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials. Thorax 2004;59:777-82.
- Phillips CL, Yee BJ, Marshall NS, Liu PY, Sullivan DR, Grunstein RR. Continuous positive airway pressure reduces postprandial lipidemia in obstructive sleep apnea: a randomized, placebo-controlled crossover trial. Am J Respir Crit Care Med 2011;184:355-61.
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- Coughlin SR, Mawdsley L, Mugarza JA, Wilding JP, Calverley PM. Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J 2007;29:720-7.
- Dorkova Z, Petrasova D, Molcanyiova A, Popovnakova M, Tkacova R. Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome. Chest 2008;134:686-92.
- Hoyos CM, Sullivan DR, Liu PY. Effect of CPAP on the metabolic syndrome: a randomised sham-controlled study. Thorax 2013;68:588-9.
- Hoyos CM, Killick R, Yee BJ, Phillips CL, Grunstein RR, Liu PY. Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study. Thorax 2012;67:1081-9.
- Drager LF, Togeiro SM, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome. J Am Coll Cardiol 2013;62:569-76.
Keywords: Sleep Apnea, Obstructive, Blood Pressure, Metabolic Syndrome X
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