REVIEW

CURRENT
OPINION Sleep and diabetes
Silke Ryan a,b

Purpose of review
Abnormal sleep duration, including short and long sleep, and sleep disorders, in particular obstructive
sleep apnea (OSA), have evolved as major public health concerns attributed to their high prevalence and
significant links with mortality and comorbid conditions. There is compelling evidence of an independent
association of such sleep disturbances with the development, control, and progression of disorders affecting
glucose metabolism such as type 2 diabetes (T2D). However, little is known of the underlying
pathophysiological mechanisms and the potential interactions of these sleep disturbances in this process.
The present review explores emerging evidence in this field.
Recent findings
Cross-sectional and longitudinal analyses of large cohorts support the association of abnormal sleep
duration and T2D. However, significant methodological limitations hinder the conclusive interpretation of
the data. OSA is a fast-emerging risk factor for the development and control of T2D. Experimental studies
support a key role of intermittent hypoxia as the hallmark feature of OSA in the pathophysiology.
Summary
The present review highlights the need for large-scale, multicenter, prospective studies in order to determine
the causative role of sleep disturbances in diabetes. There is also a clear demand of a greater
understanding of the detailed pathophysiological mechanisms.
Keywords
diabetes, intermittent hypoxia, obstructive sleep apnea, sleep, sleep duration, sleep fragmentation

INTRODUCTION and identifying potential treatment strategies are

Type 2 diabetes (T2D) characterized by hyperglyce- clear research priorities. The present review will focus
mia, insulin resistance, and relative impairment in on recent epidemiological, clinical, and experimen-
insulin secretion constitutes a dramatic global public tal evidence relating to the complex relationship
health burden. The prevalence of T2D has risen between disturbed sleep and T2D and will provide
alarmingly in the past decade with over 400 million a brief direction for further research on this subject.
people worldwide suffering from the condition,
which in large part is linked to the obesity epidemic
THE ASSOCIATION OF SLEEP DURATION
and sedentary lifestyles [1]. Furthermore, there is now
AND TYPE 2 DIABETES
fast emerging evidence that disturbed sleep, includ-
ing abnormal sleep duration, fragmented sleep, or In recent years, there has been mounting evidence of
sleep disorders, especially obstructive sleep apnea an association between abnormal sleep duration and
(OSA), play a causative role in the development of numerous adverse health outcomes including mor-
T2D and this likely represents a problem of immense tality, obesity, hypertension, and cardiovascular dis-
magnitude. More than 30% of adults sleep either too ease. Furthermore, various studies have linked both
little (defined as 6 h sleep per day) or too much short sleep and long sleep duration to insulin resis-
(9 h sleep per day) [2–4]. At least 10% of the popu- tance, incident T2D, and poor glycemic control in
lation suffer from a clinically significant sleep disor-
der and the prevalence of moderate to severe and a
Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital
thus, likely clinically significant, OSA has been esti- and bSchool of Medicine, University College Dublin, Dublin, Ireland
mated as 14% in men and 5% in women and is rapidly Correspondence to Silke Ryan, Department of Respiratory Medicine, St.
rising because of the close relationship of OSA with Vincent’s University Hospital, Elm Park, Dublin 4, Ireland.
obesity [5,6]. Hence, defining the detailed relation- Tel: +353 1 221 3702; fax: +353 1 221 3126; e-mail: [email protected]
ship between sleep disturbances and glycemic Curr Opin Pulm Med 2018, 24:555–560
health, understanding the detailed mechanisms DOI:10.1097/MCP.0000000000000524

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Sleep and respiratory neurobiology

development of various cardiometabolic outcomes

KEY POINTS and hence, lack of adjustment for this important
 There is fast increasing evidence of an association of confounder makes it difficult to draw definitive con-
short and long sleep duration with T2D but multiple clusions of the effect of sleep duration. In support of
potential confounding factors make a conclusion of a this concern, a recent cross-sectional analysis of the
causal relationship difficult. Nagahama study of over 7,000 individuals identified
an independent association of OSA and obesity, but
 Experimental short-term sleep restriction leads to various
metabolic disturbances but the underlying mechanisms not of sleep duration, with prevalent diabetes and
and the relevance of these findings to long-term short hypertension [15]. In addition, many studies have
sleep remain poorly explored. assessed sleep duration as a fixed rather than a
dynamic parameter ignoring the potential change
 There is mounting support of an independent
in behavior over time. However, this aspect is likely
association of OSA with glucose disorders and a recent
randomized-controlled trial found a positive impact with important and a recent longitudinal analysis of the
CPAP therapy of 6 months duration. Sleep Heart Health Study on 5,784 patients identified
that both, a shift from long (9 h sleep/night) to
 Experimental studies highlight the key role of adipose short (<7 h sleep/night) sleep duration and the pro-
tissue inflammation in the pathogenesis of glucose
gression of short to long sleep were independently
disorders in OSA and both hallmark features,
intermittent hypoxia and sleep fragmentation, are associated with mortality, adjusted for multiple
contributing to this feature. potential confounders including the severity of
&
OSA [16 ]. In addition, timing of sleep may also be
important as recently suggested from a large commu-
nity-based study, demonstrating that later sleep tim-
patients with diabetes [7–10] and data from the ing is associated with higher insulin resistance in
NHANES study of over 130 000 participants have both patients with diabetes and without diabetes
pointed to a U-shaped association between sleep [17]. In line with this concept, night shift has also
duration and T2D risk similar to the relationship of been associated with worsen diabetic control [18].
sleep duration with other adverse outcomes such as These data underline the complexity of this subject
mortality and various cardiovascular diseases [7]. and as long as studies do not appropriately account
Recent reports have provided added strength to for all these possible confounding factors, a definitive
this subject. Maskarinec et al. [11] preformed a lon- conclusion of the causal relationship between sleep
gitudinal analysis of a multiethnic cohort of over duration and diabetes remains outstanding. Further-
150,000 participants from Hawaii and California over more, we require a better understanding of the mech-
a mean follow-up of 7.9 years. Although the associa- anisms underlying this relationship. Experimental
tion of short sleep duration with diabetes failed to short-term sleep restriction in humans leads to
reach statistical significance, long sleep, character- increased calorie intake, weight gain, insulin resis-
ized by at least 9 h sleep/night, remained an indepen- tance, and possibly impaired insulin secretion
dent predictor for incident diabetes. The detrimental [19,20]. Sympathetic excitation, inflammation, and
impact of long sleep on incident diabetes has been alterations of the 24-h cortisol profile with blunting
further highlighted in a recent meta-analysis with an of the usual nocturnal decline have been proposed to
adjusted risk ratio of 1.26 [12]. However, significant be the underlying mechanistic links [21]. However,
methodological limitations have made an interpre- some of these alterations have been found to be
tation of the existing data difficult. An important transient and how these results correlate with diabe-
caveat is the reliance on self-reported sleep duration tes as a consequence of long-term sleep restriction
in most of the studies. Two independent studies have remains unknown. Interestingly, a recent longitudi-
recently addressed this issue, and although there is a nal study determined an independent association of
significant correlation of subjective sleep duration sleep duration with plasma levels of caspase 8, which
with objective measures, this correlation is only mod- is a marker of b-cell apoptotic activity and increased
erate at best with wrist acticraphy and even less with circulating caspase 8 independently predicted the
polysomnographic evaluation of sleep [13,14]. Indi- onset of diabetes by years [22]. Prolonged sleep
viduals usually overestimate their sleep duration restriction has also been suggested to decrease the
by up to 1 h and this may have led to a misclassifica- expression of genes encoding cholesterol transporter
tion in previous studies. A further important limita- and to increase inflammatory gene expression but
tion is that many studies did not account further detailed studies are required to investigate
appropriately for concomitant OSA. OSA alters sleep these links [23]. We also lack mechanistic insight
duration through sleep fragmentation but itself is into the effect of long sleep duration on glycemic
independently associated with mortality and the health. This question has been subject of a recent

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 Sleep and diabetes Ryan

review, which concluded that the negative conse- categories, OSA severity remained an independent
quences of long sleep may arise as a result of poor predictor of insulin resistance, underlying the addi-
&&
sleep quality, sleep disorders, sedentary lifestyle, or tive impact of OSA even in very obese patients [30 ].
unhealthy dietary choices rather than of any direct The detrimental effects of OSA on glucose metabo-
metabolic effects [24]. lism also extend to gestational diabetes. A meta-anal-
In summary, there are still many unanswered ysis of 9,795 participants enrolled in epidemiological
questions surrounding the association of sleep dura- observational studies suggested that women with
tion with T2D and associated conditions and we sleep-disordered breathing (SDB), that is OSA or snor-
require further large-scale well designed epidemio- ing, have an about three-fold increased risk for gesta-
logical and translational studies before definite con- tional diabetes in comparison to women without SDB
clusions can be drawn. adjusted for BMI [31]. Similar figures were also sug-
gested by very recent data from the National Perinatal
Information Centre of the United States, containing
THE ASSOCIATION OF OBSTRUCTIVE data on over 1.5 million gravidas, although obtaining
SLEEP APNEA AND DIABETES the diagnosis of OSA through discharge records was a
OSA characterized by repeated pharyngeal collapse significant limitation [32]. The presence of OSA may
during sleep leading to intermittent hypoxia, sleep also contribute to poor diabetic control in patients
fragmentation, and excessive daytime sleepiness rep- with T2D supported by data from the European Sleep
resents an increasing public health burden. It is a Apnoea Database cohort containing over 1100 par-
highly prevalent disorder and represents a significant ticipants demonstrating an independent association
risk factor for the development of numerous comor- of OSA severity with levels of glycated hemoglobin
bid conditions, mainly affecting the cardiovascular (HbA1c) [26].
system, neurological and metabolic function. There Beside the direct influence of OSA on the devel-
is fast accumulating evidence of an independent opment of glucose disorders, there is further concern
association of OSA with diseases concerning glucose of a potential association of OSA with diabetes-
metabolism such as T2D, insulin resistance, glucose related end-organ damage and recent studies have
intolerance or metabolic syndrome [25–27]. This added support of such links. In particular, previous
association seems to be at least in part irrespective reports have pointed towards an association of OSA
of the degree of obesity and in fact, OSA and obesity with diabetic-associated kidney disease [33]. Corrob-
may exert synergistic negative effects on glucose orating further on these data, Stadler et al. [34] evalu-
metabolism. In support, Nagayoshi et al. performed ated the association of OSA and renal function in a
a prospective analysis of 1,453 patients without dia- large outpatient cohort of patients with T2D and
betes of two community-based studies with polysom- using a cross-sectional design, OSA severity was an
nographic evaluation at baseline and over a median independent predictor of lower estimated glomerular
follow-up time of 13 years, severe OSA was associated filtration rate and increased albuminuria, the latter
with a significantly increased risk of incident T2D in also been reported from a Japanese cohort of patients
&
comparison to patients without OSA [28 ]. Impor- with T2D [35]. Furthermore, a recent longitudinal
tantly, this association remained significant after study performed in two diabetes centers in the United
adjustment for various anthropometric measures Kingdom identified an independent association of
and was similarly seen in nonobese and obese OSA severity with the progression of preproliferative
patients complementing the existing literature sug- and proliferative diabetic retinopathy [36].
gesting indeed a causal link between OSA and risk of The significant burden of T2D in OSA puts a key
diabetes. The association is also independent of the focus on the potential impact of continuous positive
potential confounding effects of sleep duration as airway pressure (CPAP) therapy as first-line treat-
recently highlighted in a systematic review and ment for OSA, however a benefit on glycemic health
meta-analysis on this topic [29]. Insulin resistance with this treatment remains uncertain. Several ran-
often precedes the development of T2D and an domized controlled trials have yielded differing
expanding evidence base is supportive of the exis- results [37–41]. However, the methodology of these
tence of an independent link with OSA. Attempts to studies varied significantly in terms of patient num-
evaluate the relationship of OSA with insulin resis- bers, duration of treatment, and compliance with
tance are again complicated by the pivotal role played CPAP. Furthermore, treatment response likely dif-
by obesity driving the metabolic dysregulation. fers between nonobese and obese patients and in an
To address this question, Murphy et al. performed a extensive review on this subject the authors com-
case-control study in 186 individuals without signif- mented that improvement in glucose control with
icant comorbidities and individuals were stratified CPAP in obese patients is unlikely to be expected
into different weight categories. Throughout all without concomitant weight loss [42]. A variety of

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Sleep and respiratory neurobiology

studies published over the last year have continued rise in the rates of OSA and metabolic diseases.
to address this subject. A longitudinal analysis of Results from the prospective, multicentre Spanish
718 patients with OSA over a median follow-up of NANOS study indeed suggested a probable indepen-
5 months stressed again the issue of CPAP adherence dent interaction between these two conditions, but
identifying an improvement in glycemic health importantly, both, CPAP therapy and adenotonsil-
only in patients with excellent compliance defined lar surgery, improved blood glucose levels in com-
as at least 80% of nights with a mean duration of at parison to untreated children measured 1 year after
least 6 h/night [43]. Analysis was, however, not baseline [50]. However, RCTs on this subject are so
adjusted for the presence of T2D at baseline, far lacking.
although the authors commented that the type of A major research priority in the field is the
therapy for diabetes did not influence the results. detailed understanding of the pathophysiological
Two RCTs published in the same issue of the Ameri- mechanisms underlying the development and pro-
can Journal of Respiratory and Critical Care Medicine gression of diabetes in OSA. A large body of evidence
have been added recently to the field and reflective arising from cell culture, animal and human studies
of the ongoing controversy have yielded different indicate that the two hallmark features of OSA,
&& &&
results [44 ,45 ]. Both studies were similar in namely intermittent hypoxia and sleep fragmenta-
design, investigating the glycemic control in tion, play a pivotal role in this process. Intermittent
patients with T2D and OSA after 6 months of treat- hypoxia, characterized by repetitive short cycles of
ment. Whereby the study by Shah et al. found no rapid desaturation and reoxygenation, is the by far
difference with CPAP in comparison to standard best studied triggering factor and in experimental
care, the study by Martinez-Ceron et al. saw a signif- models in rodents and humans intermittent hyp-
icant better improvement in HbA1c with CPAP oxia leads to several metabolic alterations, including
therapy. Although baseline characteristics were sim- higher fasting glucose and insulin levels, insulin
&&
ilar, there were some differences between both trials resistance, or glucose intolerance [30 ,51–54].
which may indeed explain the different outcomes. There are several potential mechanisms by which
First, in the study by Shah et al. diabetic control at intermittent hypoxia mediates its effect on glucose
baseline was better and patients on insulin therapy metabolic dysfunction, which collectively result in
were excluded, which may have led to the failure of pancreatic b-cell dysfunction and in insulin resis-
CPAP to further improve HbA1c. Second, the mode tance in the insulin target organs liver, skeletal
of positive airway pressure (PAP) was different in muscle, and adipose tissue [54–56]. Given the close
both trials. The negative study by Shah et al. used link of OSA with obesity, the latter has attracted
PAP in auto-adjusting mode in contrast to the posi- specific attention and there is fast rising support that
tive study by Martinez-Ceron et al., applying fixed- intermittent hypoxia results in the expression and
pressure CPAP supporting results from several secretion of proinflammatory mediators from vis-
reports suggesting that fixed CPAP is more beneficial ceral adipose tissue and subsequent insulin resis-
in improving cardiometabolic outcomes [46–48]. tance [57]. Using a comprehensive translational
The study by Martinez-Ceron et al. also stressed design, Murphy et al. provided recently further
the importance of an adequate treatment length. mechanistic insight demonstrating that intermit-
Although there was no difference between CPAP or tent hypoxia leads to morphological changes of
control in glycemic parameters after 3 months, the adipose tissue with polarization of macrophages
HbA1c and insulin resistance improved after towards an M1-pro-inflammatory phenotype inde-
6 months of active treatment associated with a pendent of obesity and subsequent impaired adi-
reduction in circulating proinflammatory media- pose tissue functionality with inhibition of the
&&
tors. These results provide a potential explanation insulin-signaling pathway [30 ]. Importantly,
for the lack of benefit with CPAP in some previous removal of the epididymal (visceral) fat in C57BL6
randomized-controlled trials. There is also growing mice has been shown to prevent the intermittent
support for a benefit of CPAP treatment in gesta- hypoxia-induced metabolic disturbances [58]. Sleep
tional diabetes. Using a randomized-controlled fragmentation as a result of recurrent arousals is
design, a recent study from Taiwan reported an another potentially important triggering factor for
improvement in insulin secretion and insulin sen- metabolic dysfunction, although not yet as exten-
sitivity following 2 weeks of CPAP associated with a sively studied. The research group of David Gozal
potentially improved pregnancy outcome [49]. Of has developed a murine model of sleep fragmenta-
major concern but as yet poorly explored is the tion, which has provided important insight into
potential impact of OSA on metabolic function in pathophysiological responses and similar to the
children and adolescents. With the growing preva- changes induced by intermittent hypoxia, sleep
lence of obesity in this age group, there is a similar fragmentation induces proinflammatory changes

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 Sleep and diabetes Ryan

of the visceral adipose tissue accompanied by tissue- REFERENCES AND RECOMMENDED

specific and systemic insulin resistance [59 ]. These
&
READING
Papers of particular interest, published within the annual period of review, have
studies lend further support of the importance of been highlighted as:
adipose tissue inflammation induced by intermit- & of special interest
&& of outstanding interest
tent hypoxia and sleep fragmentation in glucose
disorders in OSA; however, the exact contribution 1. Global report on diabetes. Geneva: World Health Organization; 2016.
and interplay of these mechanistic links in the 2. Kakizaki M, Kuriyama S, Nakaya N, et al. Long sleep duration and cause-
specific mortality according to physical function and self-rated health: the
human disease process will require further detailed Ohsaki Cohort Study. J Sleep Res 2013; 22:209–216.
investigation The possible relevance of the dysfunc- 3. Liu Y, Wheaton AG, Chapman DP, et al. Prevalence of healthy sleep duration
among adults–United States, 2014. MMWR Morb Mortal Wkly Rep 2016;
tional adipose tissue in the human condition of OSA 65:137–141.
has been lately proposed by a case–control study 4. Luckhaupt SE, Tak S, Calvert GM. The prevalence of short sleep duration by
industry and occupation in the National Health Interview Survey. Sleep 2010;
revealing increased expression of adipose tissue 33:149–159.
tumor necrosis factor-a expression in patients with 5. Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleep-
disordered breathing in adults. Am J Epidemiol 2013; 177:1006–1014.
OSA, but the technically necessary focus on subcu- 6. Institute of Medicine Committee on Sleep Medicine and Research;
taneous rather than visceral adipose tissue in human Colten HR, Altevogt BM, editors. Sleep disorders and sleep deprivation:
an unmet public health problem. Washington, DC: National Academic Press;
studies remains a significant limitation [60]. 2006.
7. Jackson CL, Redline S, Kawachi I, et al. Association between sleep
duration and diabetes in black and white adults. Diabetes Care 2013;
36:3557–3565.
CONCLUSION AND FUTURE DIRECTIONS 8. Knutson KL, Ryden AM, Mander BA, et al. Role of sleep duration and quality in
the risk and severity of type 2 diabetes mellitus. Arch Intern Med 2006;
Diabetes and associated conditions represent an 166:1768–1774.
enormous public health burden and there is a clear 9. Pyykkonen AJ, Isomaa B, Pesonen AK, et al. Sleep duration and insulin
resistance in individuals without type 2 diabetes: the PPP-Botnia study.
need to develop strategies to identify and counteract Ann Med 2014; 46:324–329.
prevailing factors. Recent studies have provided con- 10. Yaggi HK, Araujo AB, McKinlay JB. Sleep duration as a risk factor for the
development of type 2 diabetes. Diabetes Care 2006; 29:657–661.
siderably evidence of a causal link of either abnormal 11. Maskarinec G, Jacobs S, Amshoff Y, et al. Sleep duration and incidence of
sleep duration or OSA with the development and type 2 diabetes: the Multiethnic Cohort. Sleep Health 2018; 4:27–32.
12. Jike M, Itani O, Watanabe N, et al. Long sleep duration and health outcomes: a
control of T2D and associated conditions. However, systematic review, meta-analysis and meta-regression. Sleep Med Rev 2018;
the relative contribution of these conditions, the 39:25–36.
13. Jackson CL, Patel SR, Jackson WB 2nd, et al. Agreement between self-
complex interactions, and the potentially synergistic reported and objectively measured sleep duration among white, black,
effects of sleep disturbances and OSA and other sleep Hispanic, and Chinese adults in the United States: multi-ethnic study of
atherosclerosis. Sleep 2018; 41: doi: 10.1093/sleep/zsy057.
disorders on metabolic perturbations are still poorly 14. Matthews KA, Patel SR, Pantesco EJ, et al. Similarities and differences in
understood. Furthermore, the benefit of therapeutic estimates of sleep duration by polysomnography, actigraphy, diary, and self-
reported habitual sleep in a community sample. Sleep Health 2018;
interventions remains uncertain. We urgently 4:96–103.
require large-scale, multicentre, prospective studies 15. Matsumoto T, Murase K, Tabara Y, et al. Impact of sleep characteristics and
obesity on diabetes and hypertension across genders and menopausal
with objective evaluation of sleep disturbances and status: the Nagahama study. Sleep 2018; 41: doi: 10.1093/sleep/zsy071.
sleep disorders to investigate this subject in greater 16. Aurora RN, Kim JS, Crainiceanu C, et al. Habitual sleep duration and all-cause
& mortality in a general community sample. Sleep 2016; 39:1903–1909.
detail. There is also a clear demand for a greater Sleep Heart Health Study demonstrates independent association of shift from
understanding of the detailed pathophysiological long-to short sleep duration or vice versa with mortality
17. Knutson KL, Wu D, Patel SR, et al. Association between sleep timing, obesity,
mechanisms. Experimental and translational studies diabetes: the Hispanic Community Health Study/Study of Latinos (HCHS/
need to focus on the investigation of different causa- SOL) Cohort Study. Sleep 2017; 40: doi: 10.1093/sleep/zsx014.
18. Manodpitipong A, Saetung S, Nimitphong H, et al. Night-shift work is
tive factors and pathophysiological pathways in com- associated with poorer glycaemic control in patients with type 2 diabetes.
bination. Such studies will be critical to identify J Sleep Res 2017; 26:764–772.
19. Donga E, van Dijk M, van Dijk JG, et al. A single night of partial sleep
potential novel therapeutic strategies and to guide deprivation induces insulin resistance in multiple metabolic pathways in
the design of future randomized controlled trials in healthy subjects. J Clin Endocrinol Metab 2010; 95:2963–2968.
20. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and
patients with sleep disturbances and/or sleep disor- endocrine function. Lancet 1999; 354:1435–1439.
ders who are at risk of metabolic disorders. 21. Koren D, Taveras EM. Association of sleep disturbances with obesity, insulin
resistance and the metabolic syndrome. Metabolism 2018; 84:67–75.
22. Svensson T, Svensson AK, Kitlinski M, et al. Plasma concentration of caspase-
Acknowledgements 8 is associated with short sleep duration and the risk of incident diabetes
mellitus. J Clin Endocrinol Metab 2018; 103:1592–1600.
None. 23. Aho V, Ollila HM, Kronholm E, et al. Prolonged sleep restriction induces
changes in pathways involved in cholesterol metabolism and inflammatory
responses. Sci Rep 2016; 6:24828.
Financial support and sponsorship 24. Tan X, Chapman CD, Cedernaes J, et al. Association between long sleep
duration and increased risk of obesity and type 2 diabetes: A review of
S.R. is supported by an Emerging Investigator Grant from possible mechanisms. Sleep Med Rev 2017; 40:127–134.
the Health Research Board (HRB) of Ireland. 25. Ip MS, Lam B, Ng MM, et al. Obstructive sleep apnea is independently
associated with insulin resistance. Am J Respir Crit Care Med 2002;
165:670–676.
Conflicts of interest 26. Kent BD, Grote L, Ryan S, et al. Diabetes mellitus prevalence and control in
sleep-disordered breathing: the European Sleep Apnea Cohort (ESADA)
There are no conflicts of interest. study. Chest 2014; 146:982–990.

1070-5287 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-pulmonarymedicine.com 559

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Sleep and respiratory neurobiology

27. Punjabi NM, Sorkin JD, Katzel LI, et al. Sleep-disordered breathing and insulin 44. Martinez-Ceron E, Barquiel B, Bezos AM, et al. Effect of continuous positive
resistance in middle-aged and overweight men. Am J Respir Crit Care Med && airway pressure on glycemic control in patients with obstructive sleep apnea
2002; 165:677–682. and type 2 diabetes. a randomized clinical trial. Am J Respir Crit Care Med
28. Nagayoshi M, Punjabi NM, Selvin E, et al. Obstructive sleep apnea and 2016; 194:476–485.
& incident type 2 diabetes. Sleep Med 2016; 25:156–161. RCT showing that CPAP therapy for 6 months leads to improved glycemic control
In a large community-based study severe OSA was associated with greater risk of 45. Shaw JE, Punjabi NM, Naughton MT, et al. The effect of treatment of
incident T2D && obstructive sleep apnea on glycemic control in type 2 diabetes. Am J Respir
29. Reutrakul S, Thakkinstian A, Anothaisintawee T, et al. Sleep characteristics in Crit Care Med 2016; 194:486–492.
type 1 diabetes and associations with glycemic control: systematic review RCT failing to demonstrate a benefit with CPAP therapy on glycemic control
and meta-analysis. Sleep Med 2016; 23:26–45. 46. Marrone O, Cibella F, Pepin JL, et al. Fixed but not autoadjusting positive
30. Murphy AM, Thomas A, Crinion SJ, et al. Intermittent hypoxia in obstructive airway pressure attenuates the time-dependent decline in glomerular filtration
&& sleep apnoea mediates insulin resistance through adipose tissue inflamma- rate in patients with OSA. Chest 2018; 154:326–334.
tion. Eur Respir J 2017; 49:; pii: 1601731. 47. Patruno V, Aiolfi S, Costantino G, et al. Fixed and autoadjusting continuous
Comprehensive translational study demonstrating that intermittent hypoxia positive airway pressure treatments are not similar in reducing cardiovascular
induces a pro-inflammatory phenotype of the adipose tissue risk factors in patients with obstructive sleep apnea. Chest 2007; 131:
31. Luque-Fernandez MA, Bain PA, Gelaye B, et al. Sleep-disordered breathing 1393–1399.
and gestational diabetes mellitus: a meta-analysis of 9,795 participants 48. Pepin JL, Tamisier R, Baguet JP, et al. Fixed-pressure CPAP versus auto-
enrolled in epidemiological observational studies. Diabetes Care 2013; adjusting CPAP: comparison of efficacy on blood pressure in obstructive
36:3353–3360. sleep apnoea, a randomised clinical trial. Thorax 2016; 71:726–733.
32. Bourjeily G, Danilack VA, Bublitz MH, et al. Obstructive sleep apnea in 49. Chirakalwasan N, Amnakkittikul S, Wanitcharoenkul E, et al. Continuous
pregnancy is associated with adverse maternal outcomes: a national cohort. positive airway pressure therapy in gestational diabetes with obstructive
Sleep Med 2017; 38:50–57. sleep apnea: a randomized controlled trial. J Clin Sleep Med 2018; 14:
33. Tahrani AA, Ali A, Raymond NT, et al. Obstructive sleep apnea and diabetic 327–336.
nephropathy: a cohort study. Diabetes Care 2013; 36:3718–3725. 50. Alonso-Alvarez ML, Teran-Santos J, Gonzalez Martinez M, et al. Metabolic
34. Stadler S, Zimmermann T, Franke F, et al. Association of sleep-disordered biomarkers in community obese children: effect of obstructive sleep apnea
breathing with diabetes-associated kidney disease. Ann Med 2017; and its treatment. Sleep Med 2017; 37:1–9.
49:487–495. 51. Drager LF, Li J, Reinke C, et al. Intermittent hypoxia exacerbates metabolic
35. Nishimura A, Kasai T, Kikuno S, et al. Effect of sleep-disordered breathing on effects of diet-induced obesity. Obesity 2011; 19:2167–2174.
albuminuria in 273 patients with type 2 diabetes. J Clin Sleep Med 2018; 52. Louis M, Punjabi NM. Effects of acute intermittent hypoxia on glucose meta-
14:401–407. bolism in awake healthy volunteers. J Appl Physiol 2009; 106:1538–1544.
36. Altaf QA, Dodson P, Ali A, et al. Obstructive sleep apnea and retinopathy in 53. Poulain L, Thomas A, Rieusset J, et al. Visceral white fat remodelling con-
patients with type 2 diabetes. A longitudinal study. Am J Respir Crit Care Med tributes to intermittent hypoxia-induced atherogenesis. Eur Respir J 2014;
2017; 196:892–900. 43:513–522.
37. Coughlin SR, Mawdsley L, Mugarza JA, et al. Cardiovascular and metabolic 54. Wang N, Khan SA, Prabhakar NR, et al. Impairment of pancreatic beta-cell
effects of CPAP in obese males with OSA. Eur Respir J 2007; 29:720–727. function by chronic intermittent hypoxia. Exp Physiol 2013; 98:1376–1385.
38. Hoyos CM, Killick R, Yee BJ, et al. Cardiometabolic changes after continuous 55. Drager LF, Jun JC, Polotsky VY. Metabolic consequences of intermittent
positive airway pressure for obstructive sleep apnoea: a randomised sham- hypoxia: relevance to obstructive sleep apnea. Best Pract Res Clin Endocrinol
controlled study. Thorax 2012; 67:1081–1089. Metab 2010; 24:843–851.
39. Lam JC, Lam B, Yao TJ, et al. A randomised controlled trial of nasal continuous 56. Kent BD, McNicholas WT, Ryan S. Insulin resistance, glucose intolerance
positive airway pressure on insulin sensitivity in obstructive sleep apnoea. Eur and diabetes mellitus in obstructive sleep apnoea. J Thorac Dis 2015;
Respir J 2010; 35:138–145. 7:1343–1357.
40. Weinstock TG, Wang X, Rueschman M, et al. A controlled trial of CPAP 57. Ryan S. Adipose tissue inflammation by intermittent hypoxia: mechanistic link
therapy on metabolic control in individuals with impaired glucose tolerance between obstructive sleep apnoea and metabolic dysfunction. J Physiol
and sleep apnea. Sleep 2012; 35:617–625. 2017; 595:2423–2430.
41. West SD, Nicoll DJ, Wallace TM, et al. Effect of CPAP on insulin resistance 58. Poulain L, Mathieu H, Thomas A, et al. Intermittent hypoxia-induced insulin
and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax resistance is associated with alterations in white fat distribution. Sci Rep
2007; 62:969–974. 2017; 7:11180.
42. Jullian-Desayes I, Joyeux-Faure M, Tamisier R, et al. Impact of obstructive 59. Gozal D, Khalyfa A, Qiao Z, et al. Protein-tyrosine phosphatase-1B mediates
sleep apnea treatment by continuous positive airway pressure on cardiometa- & sleep fragmentation-induced insulin resistance and visceral adipose tissue
bolic biomarkers: a systematic review from sham CPAP randomized con- inflammation in mice. Sleep 2017; 40:.
trolled trials. Sleep Med Rev 2015; 21:23–38. In murine model, sleep fragmentation leads to insulin resistance and adipose tissue
43. Ioachimescu OC, Anthony J Jr, Constantin T, et al. VAMONOS (Veterans dysfunction
Affairs’ Metabolism, Obstructed and Non-Obstructed Sleep) Study: effects of 60. Thorn CE, Knight B, Pastel E, et al. Adipose tissue is influenced by hypoxia of
CPAP therapy on glucose metabolism in patients with obstructive sleep obstructive sleep apnea syndrome independent of obesity. Diabetes Metab
apnea. J Clin Sleep Med 2017; 13:455–466. 2017; 43:240–247.

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