Obstructive sleep apnea and type 2 diabetes
© I. Holzapfel Publishers 2010
Published: 4 November 2010
Type 2 diabetes and obstructive sleep apnea (OSA) are diseases with high prevalence and major public health impact. There is evidence that regular snoring and OSA are independently associated with alterations in glucose metabolism. Thus, OSA might be a risk factor for the development of type 2 diabetes. Possible causes might be intermittent hypoxia and sleep fragmentation, which are typical features of OSA. OSA might also be a reason of ineffective treatment of type 2 diabetes. There is further evidence that the treatment of OSA by continuous positive airway pressure (CPAP) therapy might correct metabolic abnormalities in glucose metabolism. It is assumed that this depends on therapy compliance to CPAP. On the other hand, there are also hints in the literature that type 2 diabetes per se might induce sleep apnea, especially in patients with autonomic neuropathy. Pathophysiological considerations open up new insights into that problem. Based on the current scientific data, clinicians have to be aware of the relations between the two diseases, both from the sleep medical and the diabetological point of view. The paper summarizes the most important issues concerning the different associations of OSA and type 2 diabetes.
Are regular snoring and OSA risk factors for diabetes?
Does CPAP treatment influence glucose metabolism?
May diabetes induce OSA?
Connections among OSA, hypoxic ventilatory responses, diabetes, and the gluco-sensing by carotid body chemoreceptors.
Are Regular Snoring and Osa Risk Factors for Diabetes?
An increasing number of studies support the hypothesis, that habitual snoring and OSA have an impact on glucose metabolism both in diabetics and non-diabetics . OSA might induce insulin resistance and increase the risk of developing type 2 diabetes. In a 10-years follow-up study in 69852 nurses aged 40-65 years regular snoring was independently associated with a two-fold increased risk of developing a diabetes . Also, in hypertensive men OSA is - besides obesity - a risk factor for diabetes. In the study of Elmasry et al  the prevalence of OSA defined by an apnea-hypopnea-index (AHI) of at least 20 per hour was 36.0% in the diabetic group vs. 14.5% in non-diabetic hypertensive men. Individuals suffering from OSA in combination with a waist-to-hip-ratio of at least 1 had an odds ratio of 11.8 for development of type 2 diabetes. Our own population-based study in Turkey, which included 1946 individuals, investigated the possible association between OSA syndrome, metabolic syndrome, and insulin resistance. In this study, however, OSA syndrome was associated with metabolic syndrome rather than with insulin resistance, which was estimated by homeostatic model assessment (HOMA) . The reason for this opposite finding could be a high percentage of metabolic syndrome within the female population. In any case, the prevalence of OSA is increased in type 2 diabetes and vice versa. Depending on the definition of OSA and OSA syndrome, the prevalence of diabetes in OSA patients seems to be in a range of 15-30% [7, 8]. Preliminary data of our own working group also show a high prevalence of sleep disordered breathing in type 2 diabetics, with nearly 50% of patients showing a respiratory disturbance index (RDI) of at least 5 per hour and 7.5% of patients with additionally increased daytime sleepiness documented in the Epworth Sleepiness Scale (ESS) score of more than 9 (B. Tautz, personal communication). A recent study went further and investigated whether the severity of OSA is a predictor of glycemic control in type 2 diabetics . In that study, 60 consecutive diabetics were recruited from outpatient clinics and underwent full polysomnography. HbA1c was taken as indicative of the glycemic control. After controlling for age, sex, race, body mass index (BMI), the number of anti-diabetic medications, the level of individual exercise, the years of suffering from diabetes, and the total sleep time, there was a significant impact of the severity of OSA on the glucose control, expressed in a higher HbA1c in patients with more severe sleep apnea.
To summarize, regular snoring and OSA are independently associated with alterations in glucose metabolism and metabolic syndrome. They seem to be risk factors for the development and for ineffective treatment of diabetes.
Does CPAP Treatment Influence Glucose Metabolism?
Several studies have investigated the effect of continuous positive airway pressure (CPAP) ventilation on glucose metabolism both in diabetics and non-diabetics. Most of the studies have shown that CPAP has an impact on diabetic metabolism in terms of a better glucose control in both groups. One of the earliest studies was that of Brooks et al  who investigated the insulin responsiveness before and during CPAP in 10 very obese OSA patients. CPAP significantly improved insulin responsiveness in those patients within 4 months of treatment. In a comparable study, Harsch et al  also have reported improvement in insulin sensitivity in obese diabetics. The effect, however, was seen after 3 months of CPAP and not immediately like that in non-obese non-diabetics . Obesity seems to be the most important cofactor which influences the CPAP effect on glucose metabolism. In a recent placebo-controlled CPAP intervention study in OSA patients without diabetes, insulin sensitivity is immediately enhanced by CPAP, but the improvement holds out after 12 weeks of treatment only in the patients with moderate obesity . In contrast to those findings, a randomized, double blind placebo-controlled study does not find any significant improvement of glycemic control or insulin resistance in male type 2 diabetics after a CPAP treatment period of 3 months . A limitation of the study, however, is that the daily average usage of CPAP was just about 3.5 h, which would be regarded as non-compliance of therapy according to the international guidelines of sleep medicine.
To summarize, CPAP - at least in case of good adherence to therapy - may improve insulin sensitivity in diabetic OSA patients. In case of accompanying obesity, the CPAP effect can only be seen after several months of treatment.
May Diabetes Induce OSA?
According to a small number of papers autonomic neuropathy (AN), which is present in diabetics in 20-30% of the cases, seems to play a role in the development of sleep disordered breathing [15–18]. Diabetics with AN, in general, have an increased mortality. If AN is present, central hypercapnic respiratory drive is increased and peripheral chemical drive is decreased. If AN is located in central and peripheral chemoreceptors and in the glossopharyngeal (IX), vagal (X), or proprioceptive nerves, that may have an impact on the chemical control of breathing and, by means of a reduced muscle tone, also on the dilation of the pharynx, all of which may result in sleep disordered breathing. According to these pathophysiological considerations, Ficker et al  have shown that OSA is more often prevalent in diabetics with AN. Six of 23 diabetics with AN (26%) had an AHI of at least 10 per h, whereas there were no OSA patients in the non-AN group. Two other studies by Bottini et al [20, 21] have confirmed these results. These authors also show that the prevalence of increased AHI (≥ 10 per h) in diabetics is increased for up to 28%. The risk of OSA is particularly increased in obese diabetics with AN, and these patients have the most profound oxygen desaturations during sleep. The authors, however, do not find central posthyperventilatory sleep apneas or periodic breathing in diabetics with AN . They ascribe the lack of central apneas to reduced peripheral CO2 chemosensitivity, which is a major determinant of such apneas, even though central CO2 drive increases. In our previous study in 198 OSA patients with diabetes, we have investigated the question of whether diabetics with AN and OSA suffer from a reduced perception of clinical symptoms of OSA, notably from excessive daytime sleepiness . We found that the prevalence of AN in diabetics with OSA is high (35%), but it is also present in non-diabetic OSA patients (13%). Perception of clinical symptoms, however, does not differ significantly between diabetic OSA patients with and without AN. What makes a difference is that diabetic OSA patients with AN suffer from the most profound oxygen desaturations during sleep, which also have been demonstrated by Bottini et al .
To summarize, the prevalence of sleep disordered breathing is increased in diabetics with AN. Most of the respiratory events are obstructive apneas. Diabetic OSA patients with AN suffer from the most profound oxygen desaturations during sleep, but typical clinical symptoms of OSA do not differ between diabetics with and without AN. Hence, diabetic AN may, to an extent, contribute to the high prevalence of OSA in diabetics in general.
Connections Among OSA, Hypoxic Ventilatory Responses, Diabetes, and the Gluco-Sensing by Carotid Body Chemoreceptors
The reverse, the influence of OSA uncomplicated by diabetes on the carotid body-mediated control of ventilation is more difficult to conceive and the information is meager and contentious. In humans, there seems to be a consistent impression that in the longlasting apnea/hypopnea syndrome the hypoxic chemoreflex is dampened [28–30]. A possible mechanism of the decline, which worsens hypoxic episodes during sleep, could be dysfunctioning dopaminergic pathway in the carotid body . Others, however, report no significant alterations in the hypoxic ventilator responses [31, 32], or evidently higher responses . The mechanisms underlying the influence of sleep related breathing disorders on the hypoxic chemoreflex are not readily explainable. In humans, these mechanisms are usually ascribed to metabolic and circulatory sequelae of the syndrome, such as obesity and atherosclerosis (24). However, the carotid body is definitely affected by episodes of intermittent hypoxia. Intermittent hypoxia is known to activate Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) signaling pathway which, in turn, induces HIF-1α transcriptional activity aimed at recruiting adaptable processes in response to intermittent hypoxia . CaMKII is a memory consolidating enzyme which has to do with neural plasticity and long-term potentiation; a feature characteristic of carotid body function in intermittent hypoxia. Long-term potentiation is indeed noted in the ventilatory responses to hypoxia in humans in whom intermittent hypoxia is modeled, but it is a feature of short rather than longlasting disorders [35, 36]. The CaMKII pathway has no major bearing on the HIF-1α induction in sustained hypoxia  in which the lack of oxygen, by itself, decreases the rate of O2-dependent proline hydroxylation and degradation of HIF-1α . The carotid body is bound to be exposed to sustained hypoxia in diabetes due to the proliferation of connective tissue and parenchymal degeneration . Therefore, the sleep apnea syndrome complicated by diabetes gives rise to a complex and as yet poorly understood interaction between two synergistic molecular mechanism leading to the activation of HIF-1α and a spate of homeostatic processes.
It seems even more difficult to conceive the role of OSA in the development of diabetes. The carotid body glomus cell is a polymodal receptor neuron that detects low blood glucose which increases afferent discharge rate emanating from the organ. The glucosensing process utilizes the same neurotransmitter signaling pathways as does hypoxic stimulation . It may thus be so that in the hypoxia of the sleep apnea combined with diabetes all signal responsive resources in the carotid body are used up and carotid glucosensor malfunction cannot initiate counter regulatory processes to prevent an increase in blood glucose. We put forward this hypothesis as a plausible mechanism by which sleep apnea may increase propensity for the development of diabetes, independent of other metabolic-related issues. Hyperglycemia, in turn, acutely attenuates carotid body discharge rate , and in the longer term causes degeneration of carotid body parenchyma , which would explain dampened carotid body hypoxic reactivity in both sleep apnea and diabetes. The entwined interrelationships between sleep apnea, diabetes, and carotid body chemo- and gluco-sensing are open to further exploration.
Conflicts of interest
The authors declare that they have no competing interests.
Profs. M. Pokorski and C. Di giulio were supported by grant from Convenzione tra l'Universita degli Studi "G.d'Annunzio" di Chieti e Pescara.
- Tasali E, Ip MSM: Obstructive sleep apnea and metabolic syndrome. Proc Am Thor Soc 2008, 5: 207–17. 10.1513/pats.200708-139MGView ArticleGoogle Scholar
- Tasali E, Mokhlesi B, Van Cauter E: Obstructive sleep apnea and type 2 diabetes. Chest 2008, 133: 496–506. 10.1378/chest.07-0828View ArticlePubMedGoogle Scholar
- Shaw JE, Punjabi NM, Wilding JP, Alberti KgMM, Zimmet PZ: Sleep-disordered breathing in type 2 diabetes. Diab Res Clin Prac 2008, 81: 2–12. 10.1016/j.diabres.2008.04.025View ArticleGoogle Scholar
- Al-Delaimy WK, Manson JE, Willett WC, Stampfer MJ, Hu FB: Snoring as a risk factor for type II diabetes mellitus: A prospective study. Am J Epidemiology 2002, 155: 387–93. 10.1093/aje/155.5.387View ArticleGoogle Scholar
- Elmasry A, Lindberg E, Berne C, Janson C, Gislason T, Tageldin MA, Boman G: Sleep-disordered breathing and glucose metabolism in hypertensive men: a population-based study. J Int Med 2001, 249: 153–61. 10.1046/j.1365-2796.2001.00787.xView ArticleGoogle Scholar
- Onat A, Hergenc G, Uyarei H, yazici M, Tuncer M, Dogan Y, Can G, Rasche K: OSAS is associated with metabolic syndrome rather than insulin resistance. Sleep Breath 2007, 11: 23–30. 10.1007/s11325-006-0077-7View ArticlePubMedGoogle Scholar
- Reichmuth K, Austin D, Skatrud JB, young T: Association of sleep apnea and type II diabetes: A populationbased study. Am J Respir Crit Care Med 2005, 172: 590–5. 10.1164/rccm.200410-1332OCView ArticleGoogle Scholar
- Meslier N, Gagnadoux F, Giraud P, Person C, Ouksel H, Urban T, Racineux JL: Impaired glucose-insulin metabolism in males with OSAS. Eur Respir J 2003, 22: 156–60. 10.1183/09031936.03.00089902View ArticlePubMedGoogle Scholar
- Aronsohn RS, Whitmore H, Cauter EV, Tasali E: Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am J Respir Crit Care Med 2010, 181: 507–13. 10.1164/rccm.200909-1423OCPubMed CentralView ArticlePubMedGoogle Scholar
- Brooks B, Cistulli PA, Borkman M, Ross G, Mcghee S, Grunstein RR, Sullivan CE, Yue DK: OSA in obese noninsulin-dependent diabetic patients: Effect of CPAP treatment on insulin responsiveness. J Clin Endocrinol Metab 1994, 79: 1681–5. 10.1210/jc.79.6.1681PubMedGoogle Scholar
- Harsch IA, Schahin SP, Brückner K, Radespiel-Tröger M, Fuchs FS, Hahn Eg, Konturek PC, Lohmann T, Ficker JH: The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with OSAS and type 2 diabetes. Respiration 2004, 71: 252–9. 10.1159/000077423View ArticlePubMedGoogle Scholar
- Harsch IA, Schahin SP, Radespiel-Tröger M, Weintz O, Jahreiß H, Fuchs FS, Wiest GH, Hahn E, Lohmann T, Konturek PC, Ficker JH: Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with OSAS. Am J Respir Crit Care Med 2004, 169: 156–62.View ArticlePubMedGoogle Scholar
- Lam JCM, Lam B, Yao TJ, Lai AYK, Ooi CG, Tam S, Lam KSL, Ip MSM: A randomised controlled trial of nasal CPAP on insulin sensitivity in OSA. Eur Respir J 2010, 35: 138–145. 10.1183/09031936.00047709View ArticlePubMedGoogle Scholar
- West SD, Nicoli DJ, Wallace TM, Matthews DR, Stradling JR: Effect of CPAP on insulin resistance and HbA1c in men with OSA and type 2 diabetes. Thorax 2007, 62: 969–74. 10.1136/thx.2006.074351PubMed CentralView ArticlePubMedGoogle Scholar
- Montserrat JM, Cochrane GM, Wolf C, Picado C, Rosa J, Agusti VA: Ventilatory control in diabetes mellitus. Eur Respir Dis 1985, 67: 112–7.Google Scholar
- Tantucci C, Bottini P, Dottorini ML, Puxeddu E, Casucci G, Scionti L, Sorbini CA: Ventilatory response to exercise in diabetic subjects with autonomic neuropathy. J Appl Physiol 1996, 81: 1978–86.PubMedGoogle Scholar
- Tantucci C, Scionti L, Bottini P, Dottorini ML, Puxeddu E, Casucci G, Sorbini CA: Influence of autonomic neuropathy of different severities on the hypercapnic drive to breathing in diabetic patients. Chest 1997, 112: 145–53. 10.1378/chest.112.1.145View ArticlePubMedGoogle Scholar
- Tantucci C, Bottini P, Fiorani C, Dottorini ML, Santeusanio F, Provinciali L, Sorbini CA, Casucci G: Cerebro-vascular reactivity and hypercapnic respiratory drive autonomic neuropathy. J Appl Physiol 2001, 90: 889–96.PubMedGoogle Scholar
- Ficker JH, Dertinger SH, Siegfried W, König HJ, Pentz M, Sailer D, Katalinic A, Hahn EG: OSA and diabetes mellitus: the role of cardiovascular autonomic neuropathy. Eur Respir J 1998, 11: 14–9. 10.1183/09031936.98.11010014View ArticlePubMedGoogle Scholar
- Bottini P, Dottorini ML, Cordoni MC, Casucci G, Tantucci C: Sleep-disordered breathing in non obese diabetic subjects with autonomic neuropathy. Eur Respir J 2003, 22: 654–60. 10.1183/09031936.03.00070402View ArticlePubMedGoogle Scholar
- Bottini P, Redolfi S, Dottorini ML, Tantucci C: Autonomic neuropathy increases the risk of OSA in obese diabetics. Respiration 2008, 75: 265–71. 10.1159/000100556View ArticlePubMedGoogle Scholar
- Keller T, Hader C, de Zeeuw J, Rasche K: Obstructive sleep apnea: the effect of diabetes and autonomic neuropathy. J Physiol Pharmacol 2007,58(Suppl 5):313–8.PubMedGoogle Scholar
- Pokorski M, Dymecka A, Antosiewicz J: Carotid body morphology in diabetic rats. International Conference 'Advances in Pneumology', Wuppertal, Germany 2007. (Abstract)Google Scholar
- Kadoglou NP, Avgerinos ED, Liapis CD: An update on markers of carotid atherosclerosis in patients with Type 2 diabetes. Biomark Med 2010, 4: 601–9. 10.2217/bmm.10.79View ArticlePubMedGoogle Scholar
- Nishimura M, Miyamoto K, Suzuki A, Yamamoto H, Tsuji M, Kishi F, Kawakami Y: Ventilatory and heart rate responses to hypoxia and hypercapnia in patients with diabetes mellitus. Thorax 1989, 44: 251–7. 10.1136/thx.44.4.251PubMed CentralView ArticlePubMedGoogle Scholar
- O'Halloran KD, Mcguire M, O'Hare T, MacDermott M, Bradford A: Upper airway EMG responses to acute hypoxia and asphyxia are impaired in streptozotocin-induced diabetic rats. Respir Physiol Neurobiol 2003, 138: 301–8. 10.1016/j.resp.2003.09.001View ArticlePubMedGoogle Scholar
- Pokorski M, Antosiewicz J, Dymecka A: Hypoxic ventilation in diabetic rats. Eur Resp J 2007,30(Suppl 51):598s. (Abstract P3532)Google Scholar
- Veasey SC, Zhan G, Fenik P, Pratico D: Long-term intermittent hypoxia: reduced excitatory hypoglossal nerve output. Am J Respir Crit Care Med 2004, 170: 665–72. 10.1164/rccm.200403-261OCView ArticlePubMedGoogle Scholar
- Osanai S, Akiba Y, Fujiuchi S, Nakano H, Matsumoto H, Ohsaki Y, Kikuchi K: Depression of peripheral chemo-sensitivity by a dopaminergic mechanism in patients with obstructive sleep apnoea syndrome. Eur Respir J 1999, 13: 418–23. 10.1183/09031936.99.13241899View ArticlePubMedGoogle Scholar
- Tafil-Klawe M, Klawe JJ, Sikorski W, Drzewiecka B: Reflex respiratory responses to progressive hyperoxic hypercapnia and normocapnic hypoxia in normocapnic and hypercapnic obstructive sleep apnea patients. J Physiol Pharmacol 2004,55(Suppl 3):135–8.PubMedGoogle Scholar
- Radwan L, Maszczyk Z, Koziej M, Franczuk M, Koziorowski A, Kowalski J, Zielinski J: Respiratory responses to chemical stimulation in patients with obstructive sleep apnoea. Monaldi Arch Chest Dis 2000, 55: 96–100.PubMedGoogle Scholar
- Wang W, Kang J, Jin GM, Wang QY, Hou XM, Yu RJ: Respiratory control in obstructive sleep apnea hypopnea syndrome. Zhonghua Nei Ke Za Zhi 2004, 43: 647–50. (Article in Chinese)PubMedGoogle Scholar
- Radwan L, Maszczyk Z, Koziej M, Franczuk M, Koziorowski A, Kowalski J, Zielinski J: Chemical control of breathing in patients with obstructive sleep apnea. 1997, 65: 446–56.Google Scholar
- Yuan G, Nanduri J, Bhasker CR, Semenza GL, Prabhakar NR: Ca 2+ /calmodulin kinase-dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia. J Biol Chem 2005, 280: 4321–8.View ArticlePubMedGoogle Scholar
- Lee DS, Badr MS, Mateika JH: Progressive augmentation and ventilatory long-term facilitation are enhanced in sleep apnoea patients and are mitigated by antioxidant administration. J Physiol 2009, 587: 5451–67. 10.1113/jphysiol.2009.178053PubMed CentralView ArticlePubMedGoogle Scholar
- Mahamed S, Mitchell GS: Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea? Exp Physiol 2007, 92: 27–37.View ArticlePubMedGoogle Scholar
- Premkumar DR, Mishra RR, Overholt JL, Simonson MS, Cherniack NS, Prabhakar NR: L-type Ca 2+ channel activation regulates induction of c-fos transcription by hypoxia. J Appl Physiol 2000, 88: 1898–906.PubMedGoogle Scholar
- Kline DD, Peng YJ, Manalo DJ, Semenza GL, Prabhakar NR: Defective carotid body function and impaired ventilator responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha. Proc Natl Acad Sci USA 2002, 99: 821–6. 10.1073/pnas.022634199PubMed CentralView ArticlePubMedGoogle Scholar
- Zhang M, Buttigieg J, Nurse CA: Neurotransmitter mechanisms mediating low-glucose signalling in cocultures and fresh tissue slices of rat carotid body. J Physiol 2007, 578: 735–50. 10.1113/jphysiol.2006.121871PubMed CentralView ArticlePubMedGoogle Scholar
- Alvarez-Buylla R, de Alvarez-Buylla ER: Carotid sinus receptors participate in glucose homeostasis. Respir Physiol 1988, 72: 347–60. 10.1016/0034-5687(88)90093-XView ArticlePubMedGoogle Scholar