REVIEW
Treating Obstructive Sleep Apnea With Continuous Positive Airway Pressure Benefits Type 2 Diabetes Management Weiguang Zhong, MD, PhD,*Þ Yongming Gorge Tang, PhD,Þþ Xiaoning Zhao, PhD,Þþ Frisca Yan Go, MD,*Þ Ronald M. Harper, PhD,§ and Hongxiang Hui, MD, PhDÞ|| Abstract: Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are both common major public health concerns. Epidemiological and clinical evidence postulates that OSA may be a causal factor in the pathogenesis of T2DM. This review examines recent empirical developments in theory, research, and practice regarding T2DM and OSA. We first examined the data from 10 studies that covered 281 patients with T2DM who used continuous positive airway pressure therapy, followed by research that describes how hypoxia/reoxygenation in OSA may be key triggers that initiate or contribute to the status of insulin resistance and inflammation. We then propose mechanisms that may relate diabetes with OSA. The issues that should be addressed in the future are outlined. We suggest that intervention with continuous positive airway pressure may improve diabetic symptoms and should be encouraged for patients with diabetes. Key Words: obstructive sleep apnea, continuous positive airway pressure, type 2 diabetes, insulin resistance, inflammation (Pancreas 2014;43: 325Y330)
T
ype 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by high blood glucose level in the context of insulin resistance (IR) and relative insulin deficiency. Longterm complications from high blood glucose level can include heart disease, stroke, diabetic retinopathy, kidney failure, and poor peripheral circulation, leading to amputation. Diabetes management, maintaining blood glucose levels at a normal or near-normal level at 70 to 130 mg/dL or 3.9 to 7.2 mmol/L, is usually achieved by increasing exercise, dietary modification, and use of medications such as metformin or insulin. However, the success in maintaining glycemic control is significantly associated with age, race/ethnicity, duration of diabetes, type and number
From the *UCLA Sleep Disorders Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; †International Center for Metabolic Diseases, School of Biotechnology, Beijiao Hospital, Southern Medical University, Guangzhou, People’s Republic of China; ‡Cedars-Sinai Medical Center, Los Angeles, CA; §Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; and ||Department of Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA. Received for publication March 14, 2013; accepted September 27, 2013. Reprints: Hongxiang Hui, MD, PhD, Life Science Bldg, 8 FL, Southern Medical University, Guangzhou, People’s Republic of China (e (TNF->), interleukin 6 (IL-6), monocyte chemoattractant protein 1, and others. These proinflammatory molecules are active participants in the development of IR and the increased risk of cardiovascular disease associated with obesity.29 Animal and cell culture studies have demonstrated preferential activation of inflammatory pathways by intermittent hypoxia, which is an integral feature of OSA. In diabetes with OSA, repetitive hypoxia and reoxygenation converge to exacerbate the inflammation in diabetes.30
Proinflammatory Cytokines Elevated levels of both TNF-> and IL-6 have been reported in diabetes. Both TNF-> and IL-6 are increased in patients with OSA compared with the BMI-matched controls,31Y33 and AHI is related to these cytokines independent of obesity.34,35 In addition, multiple studies have reported a decrease of TNF->36,37 and IL-6 levels after CPAP treatment.
Nuclear Factor-JB Activation Nuclear factor-JB (NF-JB) is a heterodimer protein composed of different combinations of members of the Rel family * 2014 Lippincott Williams & Wilkins
CPAP Benefits Type 2 Diabetes Management
of transcription factors. The Rel/NF-JB family of transcription factors is involved mainly in induced stress, immune system, and inflammatory responses. The expression of NF-JB transcript and protein is increased in the mitochondria and contributes to enhanced oxidative stress in type 2 diabetes, and the treatment with the blockers of NF-JB attenuates mitochondrial oxidative stress and protects against cardiac dysfunction through modulation of cardiac NF-JB activity.38 Cultured cell lines exposed to intermittent hypoxia show selective activation of NF-JB.39 Both human OSA and mice exposed to intermittent hypoxia showed increased activation of NF-JB and increased nitric oxide syntheses.40 Nuclear factorJBYbinding activity in circulating neutrophils and monocytes isolated from OSA subjects is elevated compared with that of the control subjects and was reversed by CPAP treatment in some subjects with severe OSA.41,42
C-Reactive Protein C-reactive protein (CRP) is released from the liver as a response to inflammatory processes in the body when fighting an infection or producing inflammation to an irritant in the body. Studies comparing otherwise healthy obese men with and without OSA report that OSA is accompanied by increased C-reactive protein levels after controlling for BMI in both adults31,34,43 and children.44 Continuous positive airway pressure therapy is able to reduce levels of CRP among patients with OSA.39,45,46,89 On the other hand, negative results are also reported in several studies,47Y50 suggesting that the issue is controversial.
Adipokines as Mediators of Metabolic Dysfunction in OSA Leptin is an important adipokine that regulates appetite and energy expenditure. Several recent studies demonstrated higher leptin levels in subjects with OSA compared with the BMImatched control subjects, suggesting a relative leptin-resistant state in OSA.51Y53 Spiegel et al54 reported that restricted sleep of 4 hours per night for 2 nights resulted in an increase of 28% of ghrelin levels and an 18% reduction in leptin levels compared with 10 hours of sleep per night for 2 nights. However, others also reported that the association between these 2 is not significant after adjusting for obesity.55,56 Adiponectin is another adipocyte-derived molecule with antiinflammatory and insulin-sensitizing properties in vitro, and hypoadiponectinemia has been suggested to play an important role in the development of diabetes mellitus or metabolic syndrome.41 However, several studies relating adiponectin to OSA have been negative, showing no significant independent relationship between these 2,57,58 whereas 1 study showed a trend of decreased adiponectin levels with OSA severity independent of IR and BMI.42 Ghrelin, a hunger-stimulating hormone produced in the stomach, is a 28-amino acid peptide and affects appetite regulation. Higher levels of ghrelin are associated with obesity and are lowered after weight loss.55 Higher ghrelin levels also accompany short or restricted sleep, such as in patients with OSA, and those levels can be reduced after 2 days of CPAP therapy.59
Relational Mechanisms Intermittent hypoxia and arousals activate the sympathetic nervous system, which is followed by the release of contrainsulin hormones, such as adrenaline and nonadrenaline. Moreover, IL-6, NF-JB, oxidative stress, and adipokines leptin, resistin, and adiponectin are more frequently expressed. Finally, OSA-induced disturbances of the physiologic sleep profile itself may cause impaired glucose tolerance.60 www.pancreasjournal.com
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Hypoxia/Reoxygenation in OSA Induces Stress Responses, Oxidative Stress, and Production of Reactive Oxygen Species Repetitive episodes of hypoxia/reoxygenation during transient cessation of breathing in OSA promote systemic oxidative stress and inflammation.61 In mice, repetitive cycles of intermittent hypoxemia followed by reoxygenation (8 weeks) activate several nicotinamide adenine dinucleotide phosphate oxidases and trigger the formation of reactive oxygen species, eliciting the release of inflammatory cytokines such as TNF-> and IL-6 and CRP. In a cross-sectional study of 128 subjects, Yamauchi and Kimura62 investigated the relationship between the severity of OSA and oxidative stress and found that increased OSA severity is associated with enhanced oxidative stress. Several molecular markers related to these changes have been reported in patients with OSA and include increased circulating free radicals, increased lipid peroxidation, decreased antioxidant capacity, elevation of tumor necrosis factor and interleukins, increased levels of the proinflammatory nuclear transcription factor JB, decreased circulating nitric oxide, and elevation of vascular adhesion molecules and vascular endothelial growth factor.63 The repetitive hypoxia/reoxygenation in OSA induces inflammatory cytokines, and reactive oxygen species contributes to the development of IR, A-cell dysfunction, and impaired glucose tolerance and leads ultimately to the diabetic disease state.64 In addition, these observations suggest that the alleviation of oxidative stress might be a useful strategy in the treatment of patients with diabetes associated with sleep apnea.
OSA Increased Level of Catecholamines Arousals are transient cortical activations during sleep that may occur because of interrupted ventilation in OSA. Mice exposed for 35 days to intermittent hypoxia showed increased levels of catecholamines and elevated blood pressure. Increased sympathetic nervous system activity has been linked to IR. A restricted sleep time of 4 hours per night leads to considerably increased sympathetic activity and a nearly 40% slower rate
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of glucose clearance when compared with 8 hours of sleep. Fragmented sleep achieved by auditory and mechanical stimuli (approximately 30 events per hour) leads to decreased IS and to an increase in morning serum cortisol levels, likely a consequence of increased nocturnal sympathetic activity. Hypoxia and hypercapnia caused by sleep-disordered breathing provoke sympathetic nervous activity, releasing epinephrine, norepinephrine, and cortisol. Sympathetic hyperactivity and increased catecholamine impair glucose homeostasis and induce IR by increasing glycogenolysis and gluconeogenesis.
OSA Induces Pancreatic A-Cell Damage Low oxygen levels during periods of obstruction also seem to play an important role in the pathophysiologic status of the pancreas. Hypoxia and reoxygenation regulate the activity of pancreatic cells through hypoxia-inducible factor 1>65,66 and trigger a cascade of events, including autonomic activation, alterations in neuroendocrine function, and release of potent proinflammatory mediators such as TNF-> and IL-6,5 ultimately resulting in damage of pancreatic A-cells and inducing IR and T2DM.52,67
OSA Changes Appetite and Balance of Energy Expenditure Reduced sleep duration either increases energy intake and/or reduces energy expenditure. Lack of sleep decreases plasma leptin levels, increases plasma ghrelin and cortisol levels, alters glucose homeostasis, and activates the orexin system, all of which affects appetite.68,69 Lack of sleep can also lead to weight gain and obesity by increasing the time available for eating and by making it more difficult to maintain a healthy lifestyle (Fig. 1).70 In summary, the potential mechanisms underlying the link between OSA, IR, and glucose intolerance include activation of the sympathetic nervous system and hypothalamic-pituitary axis, changes in the inflammatory pathways, and hypoxic injury to tissues (pancreas, hypothalamic and endothelia cells).
FIGURE 1. Obstructive sleep apnea deteriorates or induces type 2 diabetes. IGTT indicates intravenous glucose tolerance test.
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Future Directions Relatively little systematic work has been done to substantiate that OSA induces diabetes or to determine that diabetes causes OSA at a pathophysiologic or molecular level. Although most studies support the suggestion that CPAP treatment benefits diabetes management,71 some studies suggest that it is not the case. Continuous positive airway pressure has also failed to improve IR,47Y49,55 leptin levels,64,68 TNF->, or IL-6 in several studies. There is clearly a need for future, largescale, randomized, well-controlled CPAP studies with better compliance to therapy and long-term follow-up to fully investigate the effects of CPAP treatment on glucose control. Some people may find wearing a CPAP mask uncomfortable or constricting; for those patients, bilevel positive airway pressure or other OSA treatments such as an oral appliance may be an option. For patients with central sleep apnea, adaptive servoventilation, a device that uses a different algorithm to adjust bilevel pressures, is a more effective treatment than CPAP to eliminate complex central sleep apnea and improve glucose metabolism in patients with OSA with T2DM. In summary, substantial evidence is emerging that suggests benefits between OSA intervention and diabetes management, and further attempts to use such interventions will lead to novel and effective strategies to control glycemia in diabetes. ACKNOWLEDGMENTS We greatly thank Ms Ying Peng for her help in figure preparation.
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13. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487Y1495. 14. West SD, Nicoll DJ, Wallace TM, et al. Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax. 2007;62:969Y974. 15. International Diabetes Federation Taskforce on Epidemiology and Prevention. Shaw JE, Punjabi NM, Wilding JP, et al. Sleep-disordered breathing and type 2 diabetes: a report from the International Diabetes Federation Taskforce on Epidemiology and Prevention. Diabetes Res Clin Pract. 2008;81:2Y12. 16. Steiropoulos P, Papanas N, Nena E, et al. Continuous positive airway pressure treatment in patients with sleep apnoea: does it really improve glucose metabolism? Curr Diabetes Rev. 2010;6:156Y166. 17. Bhadriraju S, Kemp CR Jr, Cheruvu M, et al. Sleep apnea syndrome: implications on cardiovascular diseases. Crit Pathw Cardiol. 2008;7:248Y253. 18. Schulz R, Eisele HJ, Reichenberger F, et al. Obstructive sleep apnoea and metabolic syndrome. Pneumologie. 2008;62:88Y91. 19. Yang D, Liu Z, Yang H, et al. Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis. Sleep Breath. 2013;17:33Y38. 20. Hecht L, Mo¨hler R, Meyer G. Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis. Ger Med Sci. 2011;9:Doc20. 21. Iiyori N, Alonso LC, Li J, et al. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med. 2007;175:851Y857. 22. Polotsky VY, Li J, Punjabi NM, et al. Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol. 2003;552:253Y264. 23. Oltmanns KM, Gehring H, Rudolf S, et al. Hypoxia causes glucose intolerance in humans. Am J Respir Crit Care Med. 2004;169:1231Y1237. 24. Louis M, Punjabi NM. Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol (1985). 2009;106:1538Y1544. 25. Theorell-Haglo¨w J, Berne C, Janson C, et al. The role of obstructive sleep apnea in metabolic syndrome: a population-based study in women. Sleep Med. 2011;12:329Y334. 26. Nieto FJ, Peppard PE, Young TB. Sleep disordered breathing and metabolic syndrome. WMJ. 2009;108:263Y265. 27. Punjabi NM, Beamer BA. Alterations in glucose disposal in sleep-disordered breathing. Am J Respir Crit Care Med. 2009;179:235Y240. 28. Pamidi S, Wroblewski K, Broussard J, et al. Obstructive sleep apnea in young lean men: impact on insulin sensitivity and secretion. Diabetes Care. 2012;35:2384Y2389. 29. Nguyen DV, Shaw LC, Grant MB. Inflammation in the pathogenesis of microvascular complications in diabetes. Front Endocrinol (Lausanne). 2012;3:170. 30. Vincent AM, Callaghan BC, Smith AL, et al. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol. 2011;7:573Y583. 31. Minoguchi K, Yokoe T, Tazaki T, et al. Increased carotid intima-media thickness and serum inflammatory markers in obstructive sleep apnea. Am J Respir Crit Care Med. 2005;172:625Y630. 32. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab. 1997;82: 1313Y1316. 33. Ciftci TU, Kokturk O, Bukan N, et al. The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome. Cytokine. 2004;28:87Y91. 34. Punjabi NM, Beamer BA. C-reactive protein is associated with sleep disordered breathing independent of adiposity. Sleep. 2007;30:29Y34. 35. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin
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54. Spiegel K, Tasali E, Penev P, et al. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141:846Y850. 55. Scha¨fer H, Pauleit D, Sudhop T, et al. Body fat distribution, serum leptin, and cardiovascular risk factors in men with obstructive sleep apnea. Chest. 2002;122:829Y839. 56. Patel SR, Palmer LJ, Larkin EK, et al. Relationship between obstructive sleep apnea and diurnal leptin rhythms. Sleep. 2004;27:235Y239. 57. Sharma SK, Kumpawat S, Goel A, et al. Obesity, and not obstructive sleep apnea, is responsible for metabolic abnormalities in a cohort with sleep-disordered breathing. Sleep Med. 2007;8:12Y17. 58. Makino S, Handa H, Suzukawa K, et al. Obstructive sleep apnoea syndrome, plasma adiponectin levels, and insulin resistance. Clin Endocrinol (Oxf ). 2006;64:12Y19. 59. Harsch IA, Konturek PC, Koebnick C, et al. Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment. Eur Respir J. 2003;22:251Y257. 60. Spiegel K, Knutson K, Leproult R, et al. Sleep loss: a novel risk factor for insulin resistance and type 2 diabetes. J Appl Physiol (1985). 2005;99:2008Y2019. 61. Annecke T, Fischer J, Hartmann H, et al. Shedding of the coronary endothelial glycocalyx: effects of hypoxia/reoxygenation vs ischaemia/ reperfusion. Br J Anaesth. 2011;107:679Y686. 62. Yamauchi M, Kimura H. Oxidative stress in obstructive sleep apnea: putative pathways to the cardiovascular complications. Antioxid Redox Signal. 2008;10:755Y768. 63. Godoy J, Mellado P, Tapia J, et al. Obstructive sleep apnea as an independent stroke risk factor: possible mechanisms. Curr Mol Med. 2009;9:203Y209. 64. Ip MS, Lam B, Chan LY, et al. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med. 2000;162:2166Y2171. 65. Hak AE, Pols HA, Stehouwer CD, et al. Markers of inflammation and cellular adhesion molecules in relation to insulin resistance in nondiabetic elderly: the Rotterdam study. J Clin Endocrinol Metab. 2001;86:4398Y4405. 66. Halse R, Pearson SL, McCormack JG, et al. Effects of tumor necrosis factor-alpha on insulin action in cultured human muscle cells. Diabetes. 2001;50:1102Y1109. 67. Ip MS, Lam B, Ng MM, et al. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med. 2002;165:670Y676. 68. Brondel L, Romer MA, Nougues PM, et al. Acute partial sleep deprivation increases food intake in healthy men. Am J Clin Nutr. 2010;91:1550Y1559. 69. Spiegel K, Tasali E, Leproult R, et al. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol. 2009;5:253Y261. 70. Chaput JP, Klingenberg L, Sjo¨din A. Do all sedentary activities lead to weight gain: sleep does not. Curr Opin Clin Nutr Metab Care. 2010;13:601Y607. 71. Surani S, Subramanian S. Effect of continuous positive airway pressure therapy on glucose control. World J Diabetes. 2012;3:65Y70.
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Treating Obstructive Sleep Apnea With Continuous Positive Airway Pressure Benefits Type 2 Diabetes Management Weiguang Zhong, MD, PhD,*Þ Yongming Gorge Tang, PhD,Þþ Xiaoning Zhao, PhD,Þþ Frisca Yan Go, MD,*Þ Ronald M. Harper, PhD,§ and Hongxiang Hui, MD, PhDÞ|| Abstract: Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are both common major public health concerns. Epidemiological and clinical evidence postulates that OSA may be a causal factor in the pathogenesis of T2DM. This review examines recent empirical developments in theory, research, and practice regarding T2DM and OSA. We first examined the data from 10 studies that covered 281 patients with T2DM who used continuous positive airway pressure therapy, followed by research that describes how hypoxia/reoxygenation in OSA may be key triggers that initiate or contribute to the status of insulin resistance and inflammation. We then propose mechanisms that may relate diabetes with OSA. The issues that should be addressed in the future are outlined. We suggest that intervention with continuous positive airway pressure may improve diabetic symptoms and should be encouraged for patients with diabetes. Key Words: obstructive sleep apnea, continuous positive airway pressure, type 2 diabetes, insulin resistance, inflammation (Pancreas 2014;43: 325Y330)
T
ype 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by high blood glucose level in the context of insulin resistance (IR) and relative insulin deficiency. Longterm complications from high blood glucose level can include heart disease, stroke, diabetic retinopathy, kidney failure, and poor peripheral circulation, leading to amputation. Diabetes management, maintaining blood glucose levels at a normal or near-normal level at 70 to 130 mg/dL or 3.9 to 7.2 mmol/L, is usually achieved by increasing exercise, dietary modification, and use of medications such as metformin or insulin. However, the success in maintaining glycemic control is significantly associated with age, race/ethnicity, duration of diabetes, type and number
From the *UCLA Sleep Disorders Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; †International Center for Metabolic Diseases, School of Biotechnology, Beijiao Hospital, Southern Medical University, Guangzhou, People’s Republic of China; ‡Cedars-Sinai Medical Center, Los Angeles, CA; §Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; and ||Department of Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA. Received for publication March 14, 2013; accepted September 27, 2013. Reprints: Hongxiang Hui, MD, PhD, Life Science Bldg, 8 FL, Southern Medical University, Guangzhou, People’s Republic of China (e (TNF->), interleukin 6 (IL-6), monocyte chemoattractant protein 1, and others. These proinflammatory molecules are active participants in the development of IR and the increased risk of cardiovascular disease associated with obesity.29 Animal and cell culture studies have demonstrated preferential activation of inflammatory pathways by intermittent hypoxia, which is an integral feature of OSA. In diabetes with OSA, repetitive hypoxia and reoxygenation converge to exacerbate the inflammation in diabetes.30
Proinflammatory Cytokines Elevated levels of both TNF-> and IL-6 have been reported in diabetes. Both TNF-> and IL-6 are increased in patients with OSA compared with the BMI-matched controls,31Y33 and AHI is related to these cytokines independent of obesity.34,35 In addition, multiple studies have reported a decrease of TNF->36,37 and IL-6 levels after CPAP treatment.
Nuclear Factor-JB Activation Nuclear factor-JB (NF-JB) is a heterodimer protein composed of different combinations of members of the Rel family * 2014 Lippincott Williams & Wilkins
CPAP Benefits Type 2 Diabetes Management
of transcription factors. The Rel/NF-JB family of transcription factors is involved mainly in induced stress, immune system, and inflammatory responses. The expression of NF-JB transcript and protein is increased in the mitochondria and contributes to enhanced oxidative stress in type 2 diabetes, and the treatment with the blockers of NF-JB attenuates mitochondrial oxidative stress and protects against cardiac dysfunction through modulation of cardiac NF-JB activity.38 Cultured cell lines exposed to intermittent hypoxia show selective activation of NF-JB.39 Both human OSA and mice exposed to intermittent hypoxia showed increased activation of NF-JB and increased nitric oxide syntheses.40 Nuclear factorJBYbinding activity in circulating neutrophils and monocytes isolated from OSA subjects is elevated compared with that of the control subjects and was reversed by CPAP treatment in some subjects with severe OSA.41,42
C-Reactive Protein C-reactive protein (CRP) is released from the liver as a response to inflammatory processes in the body when fighting an infection or producing inflammation to an irritant in the body. Studies comparing otherwise healthy obese men with and without OSA report that OSA is accompanied by increased C-reactive protein levels after controlling for BMI in both adults31,34,43 and children.44 Continuous positive airway pressure therapy is able to reduce levels of CRP among patients with OSA.39,45,46,89 On the other hand, negative results are also reported in several studies,47Y50 suggesting that the issue is controversial.
Adipokines as Mediators of Metabolic Dysfunction in OSA Leptin is an important adipokine that regulates appetite and energy expenditure. Several recent studies demonstrated higher leptin levels in subjects with OSA compared with the BMImatched control subjects, suggesting a relative leptin-resistant state in OSA.51Y53 Spiegel et al54 reported that restricted sleep of 4 hours per night for 2 nights resulted in an increase of 28% of ghrelin levels and an 18% reduction in leptin levels compared with 10 hours of sleep per night for 2 nights. However, others also reported that the association between these 2 is not significant after adjusting for obesity.55,56 Adiponectin is another adipocyte-derived molecule with antiinflammatory and insulin-sensitizing properties in vitro, and hypoadiponectinemia has been suggested to play an important role in the development of diabetes mellitus or metabolic syndrome.41 However, several studies relating adiponectin to OSA have been negative, showing no significant independent relationship between these 2,57,58 whereas 1 study showed a trend of decreased adiponectin levels with OSA severity independent of IR and BMI.42 Ghrelin, a hunger-stimulating hormone produced in the stomach, is a 28-amino acid peptide and affects appetite regulation. Higher levels of ghrelin are associated with obesity and are lowered after weight loss.55 Higher ghrelin levels also accompany short or restricted sleep, such as in patients with OSA, and those levels can be reduced after 2 days of CPAP therapy.59
Relational Mechanisms Intermittent hypoxia and arousals activate the sympathetic nervous system, which is followed by the release of contrainsulin hormones, such as adrenaline and nonadrenaline. Moreover, IL-6, NF-JB, oxidative stress, and adipokines leptin, resistin, and adiponectin are more frequently expressed. Finally, OSA-induced disturbances of the physiologic sleep profile itself may cause impaired glucose tolerance.60 www.pancreasjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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Hypoxia/Reoxygenation in OSA Induces Stress Responses, Oxidative Stress, and Production of Reactive Oxygen Species Repetitive episodes of hypoxia/reoxygenation during transient cessation of breathing in OSA promote systemic oxidative stress and inflammation.61 In mice, repetitive cycles of intermittent hypoxemia followed by reoxygenation (8 weeks) activate several nicotinamide adenine dinucleotide phosphate oxidases and trigger the formation of reactive oxygen species, eliciting the release of inflammatory cytokines such as TNF-> and IL-6 and CRP. In a cross-sectional study of 128 subjects, Yamauchi and Kimura62 investigated the relationship between the severity of OSA and oxidative stress and found that increased OSA severity is associated with enhanced oxidative stress. Several molecular markers related to these changes have been reported in patients with OSA and include increased circulating free radicals, increased lipid peroxidation, decreased antioxidant capacity, elevation of tumor necrosis factor and interleukins, increased levels of the proinflammatory nuclear transcription factor JB, decreased circulating nitric oxide, and elevation of vascular adhesion molecules and vascular endothelial growth factor.63 The repetitive hypoxia/reoxygenation in OSA induces inflammatory cytokines, and reactive oxygen species contributes to the development of IR, A-cell dysfunction, and impaired glucose tolerance and leads ultimately to the diabetic disease state.64 In addition, these observations suggest that the alleviation of oxidative stress might be a useful strategy in the treatment of patients with diabetes associated with sleep apnea.
OSA Increased Level of Catecholamines Arousals are transient cortical activations during sleep that may occur because of interrupted ventilation in OSA. Mice exposed for 35 days to intermittent hypoxia showed increased levels of catecholamines and elevated blood pressure. Increased sympathetic nervous system activity has been linked to IR. A restricted sleep time of 4 hours per night leads to considerably increased sympathetic activity and a nearly 40% slower rate
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of glucose clearance when compared with 8 hours of sleep. Fragmented sleep achieved by auditory and mechanical stimuli (approximately 30 events per hour) leads to decreased IS and to an increase in morning serum cortisol levels, likely a consequence of increased nocturnal sympathetic activity. Hypoxia and hypercapnia caused by sleep-disordered breathing provoke sympathetic nervous activity, releasing epinephrine, norepinephrine, and cortisol. Sympathetic hyperactivity and increased catecholamine impair glucose homeostasis and induce IR by increasing glycogenolysis and gluconeogenesis.
OSA Induces Pancreatic A-Cell Damage Low oxygen levels during periods of obstruction also seem to play an important role in the pathophysiologic status of the pancreas. Hypoxia and reoxygenation regulate the activity of pancreatic cells through hypoxia-inducible factor 1>65,66 and trigger a cascade of events, including autonomic activation, alterations in neuroendocrine function, and release of potent proinflammatory mediators such as TNF-> and IL-6,5 ultimately resulting in damage of pancreatic A-cells and inducing IR and T2DM.52,67
OSA Changes Appetite and Balance of Energy Expenditure Reduced sleep duration either increases energy intake and/or reduces energy expenditure. Lack of sleep decreases plasma leptin levels, increases plasma ghrelin and cortisol levels, alters glucose homeostasis, and activates the orexin system, all of which affects appetite.68,69 Lack of sleep can also lead to weight gain and obesity by increasing the time available for eating and by making it more difficult to maintain a healthy lifestyle (Fig. 1).70 In summary, the potential mechanisms underlying the link between OSA, IR, and glucose intolerance include activation of the sympathetic nervous system and hypothalamic-pituitary axis, changes in the inflammatory pathways, and hypoxic injury to tissues (pancreas, hypothalamic and endothelia cells).
FIGURE 1. Obstructive sleep apnea deteriorates or induces type 2 diabetes. IGTT indicates intravenous glucose tolerance test.
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Future Directions Relatively little systematic work has been done to substantiate that OSA induces diabetes or to determine that diabetes causes OSA at a pathophysiologic or molecular level. Although most studies support the suggestion that CPAP treatment benefits diabetes management,71 some studies suggest that it is not the case. Continuous positive airway pressure has also failed to improve IR,47Y49,55 leptin levels,64,68 TNF->, or IL-6 in several studies. There is clearly a need for future, largescale, randomized, well-controlled CPAP studies with better compliance to therapy and long-term follow-up to fully investigate the effects of CPAP treatment on glucose control. Some people may find wearing a CPAP mask uncomfortable or constricting; for those patients, bilevel positive airway pressure or other OSA treatments such as an oral appliance may be an option. For patients with central sleep apnea, adaptive servoventilation, a device that uses a different algorithm to adjust bilevel pressures, is a more effective treatment than CPAP to eliminate complex central sleep apnea and improve glucose metabolism in patients with OSA with T2DM. In summary, substantial evidence is emerging that suggests benefits between OSA intervention and diabetes management, and further attempts to use such interventions will lead to novel and effective strategies to control glycemia in diabetes. ACKNOWLEDGMENTS We greatly thank Ms Ying Peng for her help in figure preparation.
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