the alarming increase in overweight and obesity has played a pivotal role in the rise of type 2 diabetes prevalence .
the obesity epidemic has also been associated with an increased prevalence of sleep disturbances , particularly obstructive sleep apnea ( osa ) ( 2,3 ) . over the past decade , both laboratory and epidemiologic studies
have identified poor sleep quality and osa as putative novel risk factors for type 2 diabetes ( 46 ) .
osa is a treatable chronic sleep disorder characterized by recurrent episodes of complete ( apnea ) or partial ( hypopnea ) obstruction of the upper airway .
osa leads to intermittent hypoxemia and hypercapnia , increased oxidative stress , cortical microarousals , sleep fragmentation , and chronic sleep loss .
hypopnea index ( ahi ) 5 events per hour , in nondiabetic obese adults have ranged from 50 to 68% ( 7,8 ) . in recent years
, evidence has accumulated to indicate that osa is both a risk factor for type 2 diabetes and an exceptionally frequent comorbidity with an adverse impact on glycemic control .
five independent studies , totaling nearly 1,400 patients with type 2 diabetes , have shown that the prevalence of osa ( assessed by polysomnography [ psg ] ) ranges between 58 and 86% ( 9,10 ) .
independent of adiposity and other known confounders  between the presence and severity of osa and insulin resistance and glucose intolerance in nondiabetic adults ( 1114 ) .
two studies that used the gold standard of in - laboratory psg to accurately quantify the severity of osa reported a robust association between increasing osa severity and increasing levels of hemoglobin a1c ( hba1c ) in patients with type 2 diabetes , after controlling for multiple potential confounders ( 9,15 ) . while the findings of these two studies suggested that the effective treatment of osa may be a nonpharmacologic strategy to improve glucose control , the results of the only randomized , placebo - controlled clinical trial examining the impact of continuous positive airway pressure ( cpap ) treatment on hba1c in patients with type 2 diabetes were surprisingly disappointing ( 16 ) .
one potential reason for the failure of osa treatment to improve chronic glycemic control in patients with type 2 diabetes is insufficient cpap use .
notably , the mean nightly cpap use in this clinical trial was 3.6 h. as most of rapid eye movement ( rem ) sleep occurs in the early morning hours before habitual awakening , one possibility is that with suboptimal adherence to cpap therapy , obstructive apneas and hypopneas during rem sleep were disproportionately untreated compared with events in non - rem ( nrem ) sleep .
this may be relevant to glycemic control because it is now well established that compared with nrem sleep , rem sleep is associated with greater sympathetic activity in healthy subjects as well as in patients with osa ( 1719 ) .
further , compared with events in nrem sleep , obstructive apneas and hypopneas during rem sleep last nearly 30 s longer and are associated with significantly larger oxygen desaturation ( 2022 ) . therefore , obstructive events during rem sleep , as compared with nrem sleep , may have a larger adverse effect on insulin release and action .
this issue has major clinical implications for the duration of cpap use that is needed to reverse the negative consequences of osa on glycemic control in type 2 diabetes .
we have therefore performed a detailed analysis comparing the contributions of nrem versus rem osa to glycemic control as assessed by levels of hba1c in a large cohort of adults with type 2 diabetes .
we prospectively recruited subjects with established type 2 diabetes using an advertisement posted in the primary care and endocrinology clinics at the university of chicago , inviting participation in a research study on sleep and diabetes .
eligible individuals had to meet the criteria for type 2 diabetes based on physician diagnosis using standard criteria ( 23 ) . in order to include individuals with newly diagnosed type 2 diabetes , we also recruited in the community using an advertisement inviting subjects at risk for type 2 diabetes based on age and adiposity to participate in a research study on sleep and metabolism .
all participants without an established diagnosis of type 2 diabetes had to undergo a standard 75-g oral glucose tolerance test and meet the american diabetes association guidelines for the diagnosis of type 2 diabetes ( 23 ) .
all participants were in stable condition and , when on pharmacological treatment , on a stable antidiabetic medication regimen for the preceding 3 months .
exclusion criteria were unstable cardiopulmonary conditions , neurological disorders , psychiatric disease , shift work , chronic insomnia , or any prior or current treatment for osa ( upper airway surgery , cpap therapy , oral appliances , or supplemental oxygen ) .
we previously reported the association of osa severity categories ( no , mild , moderate , and severe osa ) with chronic glycemic control in type 2 diabetes using 60 of the participants included in this analysis ( 9 ) .
the study was approved by the university of chicago institutional review board , and all participants gave written informed consent .
subjects were admitted to the clinical resource center or the sleep research laboratory of the sleep , health , and metabolism center at the university of chicago to undergo an overnight in - laboratory psg .
self - reported ethnicity - based diabetes risk was categorized as low - risk category ( non - hispanic whites ) and high - risk category ( african americans , hispanics , and asians ) .
the duration of type 2 diabetes and the number of medications were verified by questionnaires as well as review of the patients medical records .
hba1c values ( defined as the proportion of hemoglobin that is glycosylated ) were obtained from the patient s chart if assessed during the previous three months ( n = 17,15% of subjects ) or measured on a single blood sample drawn on the morning after the psg ( n = 98 , 85% of the subjects ) .
hba1c was measured by bio - rad variant classic boronate affinity - automated high - performance liquid chromatography ( bio - rad , hercules , ca ) .
the intra - assay coefficient of variation was 0.51.0% , and the interassay coefficient of variation was 2.22.4% .
bedtimes were from 11:00 p.m.12:00 a.m. until 7:00 a.m.8:00 a.m. each subject was recorded for a minimum of 7 h to determine the presence and severity of obstructive respiratory events across the entire night .
psg ( neurofax eeg 1100 system , nihon kohden , foothill ranch , ca ) included recordings of six electroencephalographic channels , bilateral electro - oculograms , chin and tibialis electromyogram , electrocardiogram , airflow by nasal pressure transducer and oronasal thermocouples , chest and abdominal wall motion by piezo electrode belts , and oxygen saturation by finger pulse oximeter .
all psgs were staged and scored according to the 2007 american academy of sleep medicine manual for the scoring of sleep and related events ( 24 ) .
apneas were defined as total cessation of airflow for at least 10 s ( obstructive if respiratory effort was present and central if respiratory effort was absent ) .
hypopneas were scored if the magnitude of the ventilation signal decreased by at least 50% of the baseline amplitude of the nasal pressure transducer for at least 10 s and were associated with either a 3% or greater drop in oxygen saturation as measured by finger pulse oximetry or an electroencephalographic microarousal ( 24 ) .
the total ahi was defined as the number of obstructive apneas and obstructive hypopneas per hour of sleep .
given the minimal presence of central apneas , we did not include these events in the calculation of ahi .
the median central apnea index was 0.001 ( interquartile range of 0.0010.41 ) , and the highest central apnea index was 5 .
a subject was considered to have mild osa if the ahi was 514 , moderate osa if the ahi was 1529 , and severe osa if the ahi was 30 .
rem ahi was calculated as the number of apneas and hypopneas during rem sleep divided by total time in rem sleep in hours .
nrem ahi was calculated by dividing the number of apneas and hypopneas during nrem sleep by total time in nrem sleep in hours .
the oxygen desaturation index ( odi ) was defined as the total number of oxygen desaturations of at least 3% per total sleep time ( tst ) in hours .
the microarousal index ( mai ) was calculated as the total number of microarousals per hour of sleep .
differences between subjects with and without osa were tested using the student t test or mann  whitney nonparametric test for continuous variables .
categorical variables were reported as proportions and were compared using the  square test or fisher s exact test .
five multivariate linear models were successively fitted to examine associations between hba1c and measures of osa severity after controlling for multiple covariates .
model 1 included demographic variables traditionally associated with glycemic control , namely , age , sex , ethnicity - based diabetes risk , bmi , years of type 2 diabetes , and insulin use .
lastly , model 5 included all the covariates in model 1 plus nrem ahi and rem ahi .
since there are individuals who have a significant number of apneas and hypopneas during rem sleep while having an overall ahi below 5 ( hence no osa based on current definitions ) , we included all 115 subjects ( with or without osa ) in the multivariate regression models in order to explore the entire spectrum of rem and nrem events ( ahi , odi , and mai ) .
we formally ruled out any evidence of collinearity among the variables entered in the models using standard statistics , including  tolerance  and  variance inflation factor  ( spss statistics v20 , ibm , armonk , ny )
. values for hba1c , years of type 2 diabetes , and rem and nrem ahi were submitted to natural log ( ln ) transformation . in order to deal with zero values , the total ahi , rem ahi , and nrem ahi were log transformed using the formula ahi = log(ahi + 0.01 ) .
only one outlier was identified ( low hba1c ) , and sensitivity analysis excluding this subject was performed confirming the association between hba1c and measures of rem osa severity .
goodness of fit of the models was assessed using diagnostic plots . in order to estimate the effect size of increasing severity of osa on hba1c in a clinically useful manner
, models were fitted to estimate the change in adjusted hba1c based on quartiles of rem and nrem ahi .
the models included all the covariates in model 5 ( age , sex , ethnicity - based diabetes risk , bmi , years of type 2 diabetes , and insulin use ) and replaced lnrem ahi with rem ahi quartiles while keeping lnnrem ahi in the model .
this process was repeated , and lnnrem ahi was replaced with nrem ahi quartiles while keeping lnrem ahi in the model .
similar models were fitted for rem and nrem odi and mai quartiles . to simulate the impact of various durations of nocturnal cpap therapy on hba1c , we calculated the mean profiles of cumulative minutes of rem and nrem sleep over 8 h of total recording time from the 115 polysomnograms .
we then estimated mean percentages of rem and nrem sleep left untreated after 4 , 6 , and 7 h of optimal cpap treatment eliminating all events .
for each duration of cpap use , we entered the number of rem and nrem obstructive events left untreated in a regression model predicting hba1c after adjustment for age , sex , ethnicity - based diabetes risk , bmi , years of type 2 diabetes , and insulin use .
all statistical analyses were performed using spss statistics v20 and verified using stata ( v10.1 , college station , tx ) .
we prospectively recruited subjects with established type 2 diabetes using an advertisement posted in the primary care and endocrinology clinics at the university of chicago , inviting participation in a research study on sleep and diabetes .
eligible individuals had to meet the criteria for type 2 diabetes based on physician diagnosis using standard criteria ( 23 ) . in order to include individuals with newly diagnosed type 2 diabetes , we also recruited in the community using an advertisement inviting subjects at risk for type 2 diabetes based on age and adiposity to participate in a research study on sleep and metabolism .
all participants without an established diagnosis of type 2 diabetes had to undergo a standard 75-g oral glucose tolerance test and meet the american diabetes association guidelines for the diagnosis of type 2 diabetes ( 23 ) .
all participants were in stable condition and , when on pharmacological treatment , on a stable antidiabetic medication regimen for the preceding 3 months .
exclusion criteria were unstable cardiopulmonary conditions , neurological disorders , psychiatric disease , shift work , chronic insomnia , or any prior or current treatment for osa ( upper airway surgery , cpap therapy , oral appliances , or supplemental oxygen ) .
we previously reported the association of osa severity categories ( no , mild , moderate , and severe osa ) with chronic glycemic control in type 2 diabetes using 60 of the participants included in this analysis ( 9 ) .
the study was approved by the university of chicago institutional review board , and all participants gave written informed consent .
subjects were admitted to the clinical resource center or the sleep research laboratory of the sleep , health , and metabolism center at the university of chicago to undergo an overnight in - laboratory psg .
self - reported ethnicity - based diabetes risk was categorized as low - risk category ( non - hispanic whites ) and high - risk category ( african americans , hispanics , and asians ) .
the duration of type 2 diabetes and the number of medications were verified by questionnaires as well as review of the patients medical records .
hba1c values ( defined as the proportion of hemoglobin that is glycosylated ) were obtained from the patient s chart if assessed during the previous three months ( n = 17,15% of subjects ) or measured on a single blood sample drawn on the morning after the psg ( n = 98 , 85% of the subjects ) .
hba1c was measured by bio - rad variant classic boronate affinity - automated high - performance liquid chromatography ( bio - rad , hercules , ca ) .
the intra - assay coefficient of variation was 0.51.0% , and the interassay coefficient of variation was 2.22.4% .
bedtimes were from 11:00 p.m.12:00 a.m. until 7:00 a.m.8:00 a.m. each subject was recorded for a minimum of 7 h to determine the presence and severity of obstructive respiratory events across the entire night .
psg ( neurofax eeg 1100 system , nihon kohden , foothill ranch , ca ) included recordings of six electroencephalographic channels , bilateral electro - oculograms , chin and tibialis electromyogram , electrocardiogram , airflow by nasal pressure transducer and oronasal thermocouples , chest and abdominal wall motion by piezo electrode belts , and oxygen saturation by finger pulse oximeter .
all psgs were staged and scored according to the 2007 american academy of sleep medicine manual for the scoring of sleep and related events ( 24 ) .
apneas were defined as total cessation of airflow for at least 10 s ( obstructive if respiratory effort was present and central if respiratory effort was absent ) .
hypopneas were scored if the magnitude of the ventilation signal decreased by at least 50% of the baseline amplitude of the nasal pressure transducer for at least 10 s and were associated with either a 3% or greater drop in oxygen saturation as measured by finger pulse oximetry or an electroencephalographic microarousal ( 24 ) .
the total ahi was defined as the number of obstructive apneas and obstructive hypopneas per hour of sleep .
given the minimal presence of central apneas , we did not include these events in the calculation of ahi .
the median central apnea index was 0.001 ( interquartile range of 0.0010.41 ) , and the highest central apnea index was 5 .
a subject was considered to have mild osa if the ahi was 514 , moderate osa if the ahi was 1529 , and severe osa if the ahi was 30 .
rem ahi was calculated as the number of apneas and hypopneas during rem sleep divided by total time in rem sleep in hours .
nrem ahi was calculated by dividing the number of apneas and hypopneas during nrem sleep by total time in nrem sleep in hours .
the oxygen desaturation index ( odi ) was defined as the total number of oxygen desaturations of at least 3% per total sleep time ( tst ) in hours . the microarousal index ( mai )
differences between subjects with and without osa were tested using the student t test or mann  whitney nonparametric test for continuous variables .
categorical variables were reported as proportions and were compared using the  square test or fisher s exact test .
five multivariate linear models were successively fitted to examine associations between hba1c and measures of osa severity after controlling for multiple covariates .
model 1 included demographic variables traditionally associated with glycemic control , namely , age , sex , ethnicity - based diabetes risk , bmi , years of type 2 diabetes , and insulin use .
lastly , model 5 included all the covariates in model 1 plus nrem ahi and rem ahi .
since there are individuals who have a significant number of apneas and hypopneas during rem sleep while having an overall ahi below 5 ( hence no osa based on current definitions ) , we included all 115 subjects ( with or without osa ) in the multivariate regression models in order to explore the entire spectrum of rem and nrem events ( ahi , odi , and mai ) .
we formally ruled out any evidence of collinearity among the variables entered in the models using standard statistics , including  tolerance  and  variance inflation factor 
. values for hba1c , years of type 2 diabetes , and rem and nrem ahi were submitted to natural log ( ln ) transformation . in order to deal with zero values , the total ahi , rem ahi , and nrem ahi were log transformed using the formula ahi = log(ahi + 0.01 ) .
only one outlier was identified ( low hba1c ) , and sensitivity analysis excluding this subject was performed confirming the association between hba1c and measures of rem osa severity .
goodness of fit of the models was assessed using diagnostic plots . in order to estimate the effect size of increasing severity of osa on hba1c in a clinically useful manner
, models were fitted to estimate the change in adjusted hba1c based on quartiles of rem and nrem ahi .
the models included all the covariates in model 5 ( age , sex , ethnicity - based diabetes risk , bmi , years of type 2 diabetes , and insulin use ) and replaced lnrem ahi with rem ahi quartiles while keeping lnnrem ahi in the model .
this process was repeated , and lnnrem ahi was replaced with nrem ahi quartiles while keeping lnrem ahi in the model .
similar models were fitted for rem and nrem odi and mai quartiles . to simulate the impact of various durations of nocturnal cpap therapy on hba1c , we calculated the mean profiles of cumulative minutes of rem and nrem sleep over 8 h of total recording time from the 115 polysomnograms .
we then estimated mean percentages of rem and nrem sleep left untreated after 4 , 6 , and 7 h of optimal cpap treatment eliminating all events .
for each duration of cpap use , we entered the number of rem and nrem obstructive events left untreated in a regression model predicting hba1c after adjustment for age , sex , ethnicity - based diabetes risk , bmi , years of type 2 diabetes , and insulin use .
all statistical analyses were performed using spss statistics v20 and verified using stata ( v10.1 , college station , tx ) .
therefore , the study was completed by 131 participants . those who obtained less than 4 h of tst during the psg were not included in the analysis ( n = 7 ) .
participants were also excluded if the psg data could not be interpreted due to multiple artifacts in the airflow signal ( n = 8) .
one patient showed severe oxygen desaturation not explained by apneas or hypopneas consistent with significant hypoventilation .
of the 115 subjects included in the study , 56.5% were women , 58.3% were african american , 68.7% were obese , and the mean bmi was 34.5 kg / m .
the median duration of type 2 diabetes was 4 years , and a quarter of the subjects were not on any antidiabetic medication .
i.e. , neuropathy , nephropathy , retinopathy , coronary artery disease , or peripheral arterial disease ) .
mild osa was present in 27% , moderate osa in 28.7% , and severe osa in 29.6% of the subjects .
there were no significant differences in sex , race , bmi , years of type 2 diabetes , number of antidiabetic medications , insulin use , and hba1c level between subjects with and without osa , but participants without osa were on average 9 years younger than those with osa .
the lack of statistically significant differences in bmi and hba1c may have been related to the small number of subjects without osa .
there were no significant differences in total recording time and percentage of slow wave sleep between subjects with and without osa .
however , subjects with osa had significantly less tst and percentage of rem sleep and significantly higher wake after sleep onset . within the participants with osa ( n = 98 ) ,
rem ahi , rem odi , and rem mai were all significantly higher than nrem ahi , nrem odi , and nrem mai .
the odi was more than fourfold higher during rem than nrem sleep , but differences in mai were more modest .
demographic and clinical features of 115 patients with type 2 diabetes table 2 describes the results of the five multivariate linear regression models predicting hba1c .
model 3 shows that nrem ahi was not associated with hba1c ( p = 0.070 ) .
in contrast , in model 4 , rem ahi was independently associated with hba1c ( p = 0.001 ) . in model 5 ,
rem ahi ( p = 0.008 ) remained a significant predictor of hba1c even after adjusting for nrem ahi ( p = 0.762 ) . in the final fully adjusted model 5 ,
the independent predictors of increased hba1c were rem ahi ( p = 0.008 ) , race risk ( p = 0.001 ) , years of type 2 diabetes ( p = 0.001 ) , and insulin use ( p < 0.001 ) .
similar results were obtained when nrem ahi and rem ahi were replaced by the total number of events in nrem and rem sleep , respectively ( p = 0.023 for rem events and p = 0.355 for nrem events ) .
multivariate linear regression models predicting natural log of hba1c in patients with type 2 diabetes in order to estimate the effect size of increasing levels of rem ahi and nrem ahi on hba1c , we performed multivariate linear regression models using quartiles of rem ahi and nrem ahi .
1 , after adjustment for age , sex , bmi , race risk , years of type 2 diabetes , insulin use , and lnnrem ahi , increasing quartiles of rem ahi were significantly associated with increasing levels of hba1c ( p = 0.044 for linear trend ) . the mean adjusted
hba1c increased from 6.3% in subjects with rem ahi < 12.3 events per hour ( lowest quartile ) to 7.3% in subjects with rem ahi > 47 events per hour ( highest quartile ) .
similarly , quartiles of rem odi and rem mai were significantly associated with increasing levels of hba1c .
the mean adjusted hba1c increased from 6.5% in the lowest quartile of rem odi to 7.5% in the highest quartile ( p = 0.039 for linear trend ) . similarly ,
the mean adjusted hba1c increased from 7.6% in the lowest quartile of rem mai to 8.9% in the highest quartile ( p = 0.003 for linear trend ) .
in contrast , increasing levels of nrem ahi , nrem odi , and nrem mai quartiles were not associated with hba1c ( fig .
1 ) . adjusted mean hba1c values for rem and nrem ahi , odi , and mai quartiles .
for all the panels , multivariate linear regression models were fitted to estimate the mean natural ln hba1c adjusted for demographic variables traditionally associated with glycemic control such as age , sex , ethnicity - based diabetes risk , bmi , ln years of type 2 diabetes , and insulin use .
in addition , panels are adjusted for ( a ) lnnrem ahi , ( b ) lnrem ahi , ( c ) lnnrem odi , ( d ) lnrem odi , ( e ) lnnrem mai , and ( f ) lnrem mai . age and bmi are centered at their means : 55 years old and 35 kg / m , respectively .
the corresponding -coefficients for each quartile were then exponentiated to convert from ln hba1c to the standard values of hba1c .
figure 2a illustrates the predominance of rem sleep in the later part of sleep . in our cohort , 3 and 4 h after lights off , on average only 25 and 40% of rem sleep had occurred , respectively .
optimally titrated cpap use for 3 or 4 h would treat only 25 or 40% of rem sleep , respectively , and would leave most obstructive events during rem sleep untreated .
figure 2b and c illustrate the simulated impact of 4 , 6 , and 7 h of cpap use in men and women with low and high race / ethnicity - based diabetes risk .
this simulation clearly shows that the metabolic benefit of 4 h of cpap use , often considered as adequate cpap compliance , is modest , while a much more clinically significant effect can be obtained when treatment is extended to 6 h and beyond .
cumulative minutes of rem and nrem sleep over 8 h of bedtime ( a ) and simulation of various hours of cpap use in men and women with type 2 diabetes based on race / ethnicity - based diabetes risk ( b and c ) .
a : data are summarized as mean  sd of cumulative rem and nrem sleep minutes from lights off to lights on in 115 subjects with type 2 diabetes .
the mean duration of rem and nrem sleep in our cohort was 82 and 298 min , respectively .
using cpap for 3 or 4 h from the time lights are turned off will cover only 25 or 40% of rem sleep , respectively , and will leave most obstructive events during rem sleep untreated .
b and c : simulation of the impact of 4 , 6 , and 7 h of cpap use in four groups of subjects based on sex and race / ethnicity - related diabetes risk . with this simulation ,
4 h of cpap use would treat 40% of rem sleep and would lead to a drop in adjusted hba1c of 0.230.28% .
in contrast , 7 h of cpap therapy would treat 87% of rem sleep and lead to a decrease in adjusted hba1c between 0.87 and 1.1% .
this study reveals that hba1c , a measure of chronic glycemic control in patients with type 2 diabetes , is adversely associated with obstructive apneas and hypopneas that occur in rem sleep ( rem ahi ) but not in nrem sleep ( nrem ahi ) .
the independent association between rem ahi , rem odi , and rem mai and hba1c is robust and of clinical significance , with a difference of 1.0% hba1c between the lowest and highest quartiles of rem ahi as well as rem odi and of 1.3% hba1c between the lowest and highest quartiles of rem mai after adjusting for all the covariates .
these effect sizes are comparable to what would be expected from widely used antidiabetic medications .
the severity of osa in our cohort was greater in rem sleep than in nrem sleep , as evidenced by a higher ahi and a nearly fourfold higher odi .
thus , despite the shorter duration of rem sleep , exposure to the adverse consequences of osa , particularly intermittent hypoxemia , was greater during rem than nrem sleep .
surprisingly , in our diabetic participants with osa , nrem ahi only predicted approximately 25% of the variance of rem ahi .
whether hyperglycemia plays a role in this relative independence of the severity of rem osa relative to nrem osa remains to be determined .
multiple mechanistic pathways are likely to be involved in the link between rem osa and poorer glycemic control in subjects with type 2 diabetes .
when compared with nrem sleep or quiet wakefulness , rem sleep is associated with increased sympathetic activation and reduced vagal tone in normal subjects and even more so in patients with osa ( 1719 ) .
most endocrine organs releasing hormones involved in glucose regulation are sensitive to changes in sympathovagal balance .
well - documented examples relevant to metabolic risk are pancreatic insulin secretion , hepatic glucose production , and adipocyte regulation of energy balance ( 2527 ) .
in addition , peptidergic factors originating from the intestine ( glucagon - like peptide-1 and glucose - dependent insulinotropic polypeptide ) augment the insulin response induced by nutrients .
the secretion of these incretin hormones is intimately linked to autonomous nervous system ( 2830 ) .
however , it is important to point out that the impact of osa on sympathetic activation in patients with type 2 diabetes of long duration remains unclear and that long - standing hyperglycemia may lead to reduction in sympathetic activity .
lastly , obstructive apneas and hypopneas during rem sleep lead to greater degrees of hypoxemia than in nrem sleep ( 21,22 ) . in the present cohort , rem odi was indeed much greater than nrem odi .
intermittent hypoxemia has been shown to be toxic to -cell function in murine models of sleep apnea ( 31,32 ) .
the findings from our analyses strongly suggest that rem - related obstructive respiratory events are of clinical significance for the severity of type 2 diabetes .
two recent studies that performed continuous interstitial glucose monitoring simultaneously with psg directly support our hypothesis that rem - related osa may have adverse metabolic consequences ( 33,34 )
. one of these studies included 13 obese patients with type 2 diabetes with severe osa and compared them with 13 obese patients with type 2 diabetes without osa with similar demographic characteristics .
although there was no difference in the mean diurnal glycemic level between the two groups , the mean glycemic level was 38% higher during rem sleep in those with osa ( 33 ) .
they found that in the absence of osa , rem sleep leads to a larger decline in interstitial glucose concentration than nrem sleep .
in contrast , osa during nrem sleep had no impact on interstitial glucose concentrations ( 34 ) .
taken together , the evidence from studies assessing interstitial glucose levels supports our finding that obstructive events during rem sleep are adversely associated with glucose metabolism .
while our participants did not meet any proposed definition of rem - related or rem - predominant osa ( 35,36 ) , our findings suggest that failure to recognize and treat osa in rem sleep may be of critical clinical significance for glycemic control in diabetic patients . in clinical practice , 4 h of nightly cpap use is considered adequate adherence to therapy ( 37 ) . indeed , a randomized controlled trial of cpap therapy in patients with type 2 diabetes reported an average use of 3.6 h per night ( 16 ) . the severity of residual osa was not estimated .
the disappointing results of cpap trial in type 2 diabetes may reflect the failure to treat rem osa due to insufficient cpap use , leaving most obstructive events during rem sleep untreated .
alternatively , there may be other factors beyond poor cpap adherence that led to a lack of improvement in glycemic control such as a poor reserve in -cell function .
our analyses show that based on the distribution of cumulative rem sleep in our cohort , cpap therapy for the first 4 h after lights off would leave 60% of obstructive events during rem sleep untreated and would be associated with a decrease in the adjusted hba1c by only 0.250.28% .
in contrast , 7 h of optimal cpap therapy would be associated with a decrease in the adjusted hba1c by 0.871.1% .
first , we used hba1c , the most commonly used measure in clinical practice , to assess glycemic control . therefore , we can not ascertain whether the mediating pathways linking rem ahi to hba1c involve increased insulin resistance or impaired -cell function .
moreover , we only measured hba1c at a single time point , which was not consistently on the same day as psg .
however , treatment was stable for the preceding 3 months in all participants , and hba1c was measured on the morning after the psg in 98 out of 115 participants ( 85% ) .
although hba1c reflects glycemic control 10 to 12 weeks before the assay , it mostly reflects glucose fluctuations during the last 6 weeks of the measurement . despite our efforts to ensure treatment stability in the prior 3 months
, we can not exclude the possibility that fluctuations in adherence to medications may have influenced hba1c levels .
our study did not assess associations between rem osa and glucose control in subjects with prediabetes or normal glucose tolerance .
we also had a large proportion of african americans and subjects requiring little or no antidiabetic medications .
therefore , it would be important for our findings to be replicated in larger and more diverse cohorts , including participants with more diabetes complications and/or longer disease duration as well as individuals with prediabetes or with normal glucose tolerance but at high risk for type 2 diabetes .
also , we did not have a measure of habitual sleep duration , which may be important in evaluating chronic exposure to rem osa , and our only measure of adiposity was the bmi .
lastly , the cross - sectional nature of the study does not address the direction of causality .
indeed , only rigorously designed intervention studies will provide causal evidence between disordered breathing during rem sleep and glucose metabolism dysregulation . in summary ,
our findings support the notion that osa in rem sleep has a strong and clinically significant association with glycemic control in subjects with type 2 diabetes .
since rem sleep is dominant during the latter part of the sleep period , rem - related osa may often remain untreated with 4 h of cpap use .
our analyses suggest that to achieve clinically significant improvement in glycemic control in patients with type 2 diabetes , cpap use may need to be extended beyond 6 h per night . further research is needed to elucidate the mechanistic pathways linking osa during rem sleep and adverse metabolic outcomes .
 objectiveseverity of obstructive sleep apnea ( osa ) has been associated with poorer glycemic control in type 2 diabetes . 
 it is not known whether obstructive events during rapid eye movement ( rem ) sleep have a different metabolic impact compared with those during non - rem ( nrem ) sleep . 
 treatment of osa is often limited to the first half of the night , when nrem rather than rem sleep predominates . 
 we aimed to quantify the impact of osa in rem versus nrem sleep on hemoglobin a1c ( hba1c ) in subjects with type 2 diabetes.research design and methodsall participants underwent polysomnography , and glycemic control was assessed by hba1c.resultsour analytic cohort included 115 subjects ( 65 women ; age 55.2  9.8 years ; bmi 34.5  7.5 kg / m2 ) . in a multivariate linear regression model , 
 rem apnea  
 hypopnea index ( ahi ) was independently associated with increasing levels of hba1c ( p = 0.008 ) . 
 in contrast , nrem ahi was not associated with hba1c ( p = 0.762 ) . 
 the mean adjusted hba1c increased from 6.3% in subjects in the lowest quartile of rem ahi to 7.3% in subjects in the highest quartile of rem ahi ( p = 0.044 for linear trend ) . 
 our model predicts that 4 h of continuous positive airway pressure ( cpap ) use would leave 60% of rem sleep untreated and would be associated with a decrease in hba1c by approximately 0.25% . 
 in contrast , 7 h of cpap use would cover more than 85% of rem sleep and would be associated with a decrease in hba1c by as much as 1%.conclusionsin type 2 diabetes , osa during rem sleep may influence long - term glycemic control . 
 the metabolic benefits of cpap therapy may not be achieved with the typical adherence of 4 h per night . 
Introduction
Research Design and Methods
Participants
Experimental Protocol
PSG
Statistical Analysis
Results
Conclusions
Supplementary Material