sleep disorders are increasingly recognized as important factors in glucose metabolism and the development of type 2 diabetes .
sleep - disordered breathing ( sdb ) , a condition characterized by a reduction or complete cessation of airflow during sleep , has repeatedly been linked to impaired glucose tolerance and insulin resistance in clinic - based studies ( 1,2 ) and , more recently , also in population - based studies ( 3 ) .
another frequent sleep disorder , insomnia , which is defined as a subjective feeling of having difficulties initiating or maintaining sleep or having a feeling of nonrestorative sleep ( 4 ) , has also been linked to impaired glucose metabolism ( 5,6 ) .
most previous work has used the homa of insulin resistance and sometimes the homa of -cell function to estimate fasting insulin resistance and secretion , respectively ( 6,7 ) .
these methods are clearly limited in the setting of progressive insulin resistance and may be particularly limited in older adults , in whom peripheral insulin resistance is prevalent
. potentially better measures of insulin sensitivity and secretion can be derived from an oral glucose tolerance test ( ogtt ) ( 8,9 ) .
little research has been done on sleep disorders and glucose metabolism using these potentially more refined measures of insulin sensitivity and secretion .
recent data indicate that both sdb and insomnia symptoms are highly prevalent in patients with type 2 diabetes ( 1012 ) .
fewer studies have assessed the prospective association between these sleep disorders and the incidence of type 2 diabetes ( 13,14 ) , and these have mainly focused on young or middle - aged adults .
accordingly , we aimed to address several gaps in the literature , as follows : 1 ) to focus on an elderly cohort in whom there are limited data on sleep disorders , glucose metabolism , and type 2 diabetes ; 2 ) to use longitudinal measures of glucose metabolism ; and 3 ) to consider symptoms of both sdb and insomnia , both of which are common in older populations .
between 1989 and 1990 , a cohort of 5,201 participants was recruited from forsyth county , north carolina ; sacramento county , california ; washington county , maryland ; and pittsburgh , pennsylvania .
participants had to be 65 years of age , ambulatory and community dwelling , expected to remain in their communities for 3 years , and able to provide personal informed consent ( 15 ) . in 19921993 ,
an additional 687 predominantly african american participants were recruited , for a total of 5,888 participants .
participants were contacted every 6 months , alternating between telephone interviews and visits to field centers , from 19891990 through 19981999 .
sociodemographics ( i.e. , sex , age , race , marital status , and number of years of education completed ) , personal habits ( i.e. , smoking , alcohol consumption , and physical activity ) , and depressive symptoms were collected by questionnaires .
participants reported their usual frequency of consumption of beer , wine , and liquor , and the usual number of drinks consumed on each occasion , from which the number of drinks per week of alcoholic beverages was calculated .
physical activity ( in kilocalories per week ) was collected using a modified minnesota leisure - time activities questionnaire ( 16 ) .
symptoms of depression were collected using the modified center for epidemiologic studies depression scale of 030 ( 17 ) .
the participants were also asked about their medical history , and reported cardiovascular events ( i.e. , myocardial infarction and congestive heart failure [ chf ] ) were verified from objective information obtained from hospital and physician records , as previously described ( 18 ) .
each year , participants reported whether they used over - the - counter sleeping pills at least weekly .
study staff measured height , waist circumference , weight , and blood pressure at study examinations .
bmi was calculated as weight ( in kilograms ) divided by height squared ( in meters ) .
systolic blood pressure was measured twice , and the average of the two was used in the analyses .
medication use was assessed at baseline and annually from a validated medication inventory ( 20 ) .
participants were asked whether anyone had observed them having episodes where they stopped breathing for a while and then snorted or snored loudly , which we term  observed apnea .  they were also asked whether their spouse or roommate had complained about their loud snoring , labeled  bothersome snoring ,  and whether they were usually sleepy in the daytime , labeled  daytime sleepiness .  in addition , the participants reported on the following three insomnia symptoms : whether they usually had difficulties falling asleep , labeled  sleep initiation problems  ; experienced frequent nightly awakenings , labeled 
sleep maintenance problems  ; or usually woke up too early without being able to go back to sleep , labeled  early morning awakenings .
 the response options on all sleep questions were  yes ,   no ,  and  i do nt know . 
the participants were asked these questions annually from 19891990 to 19931994 . within a subgroup of cardiovascular health study ( chs )
participants who attended the sleep heart health study ( shhs ) ( 21 ) , we validated the self - reported sdb symptoms in the chs against the objectively measured sleep variables in the shhs .
we compared the median values of objectively measured sdb in the participants reporting to have sdb symptoms . in the subgroup of 1,000 participants
, we found higher obstructive apnea - hypopnea index values , defined as all desaturations of 4% , among those participants reporting observed apnea ( 8.7 desaturations / h ) compared with those without observed apnea ( 7.2 desaturations / h , p = 0.05 ) , and among those reporting bothersome snoring ( 8.8 desaturations / h ) compared with those without bothersome snoring ( 4.8 desaturations / h , p < 0.001 ) .
we also found increasing obstructive apnea - hypopnea index values with increasing number of sdb symptoms .
the participants reporting daytime sleepiness in the chs had a higher epworth sleepiness score in the shhs compared with those without daytime sleepiness in the chs ( median 9 and 6 , respectively ; p < 0.001 ) .
the insomnia symptoms in the chs were also compared with the objectively measured sleep latency ( i.e. , in minutes ) and sleep efficiency , defined as the percentage of time scored as sleep during the sleep period , in the shhs .
we found that participants with sleep initiation problems had longer sleep latency ( 18.8 min ) than those who did not report such problems ( 16.8 min , p = 0.14 ) and that those reporting problems with sleep maintenance had lower sleep efficiency than those without such problems ( 79.1% and 83.3% , respectively ; p < 0.001 ) .
those participants with early morning awakenings had less time in bed ( 7 min , p = 0.03 ) and a shorter total sleep time ( 11 min , p = 0.01 ) than those without this symptom . an ogtt was performed in 19891990 .
the venipuncture was performed in the morning during the visit after an overnight fast , and serum glucose levels were measured ( kodak ektachem 700 analyzer ; eastman kodak , rochester , ny ) ( 22 ) .
after the fasting venipuncture , 75 g of glucose was given orally to consenting nondiabetic participants .
fasting serum glucose levels were measured again in 19921993 , 19941995 ( nonfasting ) , 19961997 , and 19981999 .
we estimated insulin sensitivity using the gutt index ( gutt et al . ) , and insulin secretion using the stumvoll index ( stumvoll et al . ) .
incident type 2 diabetes was defined as new use of insulin or a hypoglycemic agent , a fasting glucose level of 7.0 mmol / l , or a nonfasting glucose level of 11.1 mmol / l .
for descriptive purposes , we provide the clinical characteristics of participants according to daytime sleepiness , which is a potential consequence of either sdb or insomnia .
we calculated the pearson  coefficient to assess the relationships between the dichotomous sleep variables .
missing data on baseline covariates were imputed using methods described previously ( 23 ) . using linear regression , we analyzed the cross - sectional associations of sleep symptoms with 2-h glucose levels and measures of insulin sensitivity and insulin secretion in 3,007 participants with information on sleep symptoms and glucose measurements , and without prevalent diabetes or chf , who were enrolled into the study in 19891990 . for cross - sectional analyses of fasting glucose
, we combined the 3,007 measurements from 19891990 with 2,378 measurements from 19921993 ( providing repeated measurements in the original cohort and incorporating the added african american cohort ) .
we fit generalized estimating equation models with an identity link function and unstructured within - group correlation .
since not all included participants attended both measurements , we had 5,385 observations from a total of 3,797 participants after excluding participants with missing sleep symptoms or glucose values , and those with prevalent diabetes or chf .
we next used cox proportional hazards models to examine the associations of sleep symptoms with the subsequent risk of incident type 2 diabetes , estimating hazard ratios ( hrs ) and 95% cis .
of the 5,888 enrolled participants , 3,528 participants were free of diabetes and chf at baseline and were included in the analyses ( supplementary fig .
the subjects stopped contributing person - time to the analyses when they received a diagnosis of type 2 diabetes or at the time of the last attended visit .
we allowed the sleep variables to vary yearly ( i.e. , to be time dependent ) to examine current effects . in some participants ,
the sdb symptoms resolved , but we do not have information about why this was the case . to examine the difference in risk between current and chronic symptoms , we reran the analyses by calculating the cumulative average of previous values of the sleep variables ( 0 or 1 ) each year and updating them in the model . because waist circumference is a particularly strong risk factor for type 2 diabetes ( 24 ) , we also allowed waist circumference to change over time in the same manner .
we replaced each missing value of the time - dependent variables by the last observed value of that variable .
we restricted our follow - up to 19981999 , as this was the last year that fasting glucose levels were measured .
first , we ran separate models for observed apnea , bothersome snoring , and daytime sleepiness .
since observed apnea and bothersome snoring are frequently used as markers for sdb ( 14 ) and daytime sleepiness is a potential sdb consequence , we assessed their joint associations by creating a cumulative variable coded  0  for no symptoms ,  1  for having one symptom , and  2  for two or more symptoms .
too few participants reported all three symptoms ( n = 63 ) to be categorized separately .
we treated insomnia symptoms similarly , first analyzing them separately and then combining symptoms into a cumulative variable based on the number of symptoms reported .
since daytime sleepiness also is a consequence of insomnia , we included it in the combined variable .
we adjusted for covariates in two multivariable models . in the first model , we adjusted for age , sex , race , waist circumference , and clinic site ( model 1 ) . in the second model
, we further adjusted for marital status ( never married , married , separated / divorced / widowed ) ; education ( < 12 years , 12 years , and 13 + years ) ; smoking ( never smoker , previous smoker , current smoker ) ; alcohol consumption ( < 1 drink , 16 drinks , and 7 drinks ) ; bmi ; physical activity ; depressive symptoms score ; cognitive function ; systolic blood pressure ; antihypertensive medication use ; levels of creatinine , albumin , and total cholesterol ; and previous myocardial infarction ( model 2 ) . in the analysis of the insomnia symptoms , we also adjusted for observed apnea ; adjustment for observed apnea in analyses of sdb symptoms did not meaningfully alter their association with diabetes .
those individuals living alone may be less likely to report sleep apnea or snoring , and we therefore excluded those participants living alone in a sensitivity analysis . because of the association between sdb and insomnia , we also excluded those participants with observed apnea in another sensitivity analysis .
we also conducted several prespecified stratified analyses to assess whether the associations of the sleep disorders with glucose metabolism and incident type 2 diabetes were modified by other factors .
we stratified by sex , age ( dichotomized at age 75 years ) , bmi ( dichotomized at 30 kg / m ) , waist circumference ( dichotomized at 95 cm ) , and race .
we tested for multiplicative interaction across strata with relevant cross - product terms . because sleep disorders are strongly associated with chronic diseases , we excluded those participants with prevalent heart disease . to examine whether the use of sleep medications changed the association between the sleep symptoms and type 2 diabetes , recognizing that it may be a cause or a consequence of sleep symptoms , we adjusted for this in separate sensitivity analyses .
we tested the proportionality of hazards using log - log curves and tests of interaction with time and found no violations .
we conducted all statistical analyses using stata 12 for windows ( stata corp . , college station , tx )
between 1989 and 1990 , a cohort of 5,201 participants was recruited from forsyth county , north carolina ; sacramento county , california ; washington county , maryland ; and pittsburgh , pennsylvania .
participants had to be 65 years of age , ambulatory and community dwelling , expected to remain in their communities for 3 years , and able to provide personal informed consent ( 15 ) . in 19921993 ,
an additional 687 predominantly african american participants were recruited , for a total of 5,888 participants .
participants were contacted every 6 months , alternating between telephone interviews and visits to field centers , from 19891990 through 19981999 .
sociodemographics ( i.e. , sex , age , race , marital status , and number of years of education completed ) , personal habits ( i.e. , smoking , alcohol consumption , and physical activity ) , and depressive symptoms were collected by questionnaires .
participants reported their usual frequency of consumption of beer , wine , and liquor , and the usual number of drinks consumed on each occasion , from which the number of drinks per week of alcoholic beverages was calculated .
physical activity ( in kilocalories per week ) was collected using a modified minnesota leisure - time activities questionnaire ( 16 ) .
symptoms of depression were collected using the modified center for epidemiologic studies depression scale of 030 ( 17 ) .
the participants were also asked about their medical history , and reported cardiovascular events ( i.e. , myocardial infarction and congestive heart failure [ chf ] ) were verified from objective information obtained from hospital and physician records , as previously described ( 18 ) .
each year , participants reported whether they used over - the - counter sleeping pills at least weekly .
study staff measured height , waist circumference , weight , and blood pressure at study examinations .
bmi was calculated as weight ( in kilograms ) divided by height squared ( in meters ) .
systolic blood pressure was measured twice , and the average of the two was used in the analyses .
medication use was assessed at baseline and annually from a validated medication inventory ( 20 ) .
participants were asked whether anyone had observed them having episodes where they stopped breathing for a while and then snorted or snored loudly , which we term  observed apnea .  they were also asked whether their spouse or roommate had complained about their loud snoring , labeled  bothersome snoring ,  and whether they were usually sleepy in the daytime , labeled  daytime sleepiness .  in addition , the participants reported on the following three insomnia symptoms : whether they usually had difficulties falling asleep , labeled  sleep initiation problems  ; experienced frequent nightly awakenings , labeled  sleep maintenance problems  ; or usually woke up too early without being able to go back to sleep , labeled 
the participants were asked these questions annually from 19891990 to 19931994 . within a subgroup of cardiovascular health study ( chs ) participants who attended the sleep heart health study ( shhs ) ( 21 )
, we validated the self - reported sdb symptoms in the chs against the objectively measured sleep variables in the shhs .
we compared the median values of objectively measured sdb in the participants reporting to have sdb symptoms . in the subgroup of 1,000 participants
, we found higher obstructive apnea - hypopnea index values , defined as all desaturations of 4% , among those participants reporting observed apnea ( 8.7 desaturations / h ) compared with those without observed apnea ( 7.2 desaturations / h , p = 0.05 ) , and among those reporting bothersome snoring ( 8.8 desaturations / h ) compared with those without bothersome snoring ( 4.8 desaturations / h , p < 0.001 ) .
we also found increasing obstructive apnea - hypopnea index values with increasing number of sdb symptoms .
the participants reporting daytime sleepiness in the chs had a higher epworth sleepiness score in the shhs compared with those without daytime sleepiness in the chs ( median 9 and 6 , respectively ; p < 0.001 ) .
the insomnia symptoms in the chs were also compared with the objectively measured sleep latency ( i.e. , in minutes ) and sleep efficiency , defined as the percentage of time scored as sleep during the sleep period , in the shhs .
we found that participants with sleep initiation problems had longer sleep latency ( 18.8 min ) than those who did not report such problems ( 16.8 min , p = 0.14 ) and that those reporting problems with sleep maintenance had lower sleep efficiency than those without such problems ( 79.1% and 83.3% , respectively ; p < 0.001 ) .
those participants with early morning awakenings had less time in bed ( 7 min , p = 0.03 ) and a shorter total sleep time ( 11 min , p = 0.01 ) than those without this symptom .
the venipuncture was performed in the morning during the visit after an overnight fast , and serum glucose levels were measured ( kodak ektachem 700 analyzer ; eastman kodak , rochester , ny ) ( 22 ) .
after the fasting venipuncture , 75 g of glucose was given orally to consenting nondiabetic participants .
fasting serum glucose levels were measured again in 19921993 , 19941995 ( nonfasting ) , 19961997 , and 19981999 .
we estimated insulin sensitivity using the gutt index ( gutt et al . ) , and insulin secretion using the stumvoll index ( stumvoll et al . ) .
incident type 2 diabetes was defined as new use of insulin or a hypoglycemic agent , a fasting glucose level of 7.0 mmol / l , or a nonfasting glucose level of 11.1 mmol / l .
for descriptive purposes , we provide the clinical characteristics of participants according to daytime sleepiness , which is a potential consequence of either sdb or insomnia . we calculated the pearson  coefficient to assess the relationships between the dichotomous sleep variables .
missing data on baseline covariates were imputed using methods described previously ( 23 ) . using linear regression , we analyzed the cross - sectional associations of sleep symptoms with 2-h glucose levels and measures of insulin sensitivity and insulin secretion in 3,007 participants with information on sleep symptoms and glucose measurements , and without prevalent diabetes or chf , who were enrolled into the study in 19891990 . for cross - sectional analyses of fasting glucose
, we combined the 3,007 measurements from 19891990 with 2,378 measurements from 19921993 ( providing repeated measurements in the original cohort and incorporating the added african american cohort ) .
we fit generalized estimating equation models with an identity link function and unstructured within - group correlation .
since not all included participants attended both measurements , we had 5,385 observations from a total of 3,797 participants after excluding participants with missing sleep symptoms or glucose values , and those with prevalent diabetes or chf .
we next used cox proportional hazards models to examine the associations of sleep symptoms with the subsequent risk of incident type 2 diabetes , estimating hazard ratios ( hrs ) and 95% cis .
of the 5,888 enrolled participants , 3,528 participants were free of diabetes and chf at baseline and were included in the analyses ( supplementary fig .
the subjects stopped contributing person - time to the analyses when they received a diagnosis of type 2 diabetes or at the time of the last attended visit .
we allowed the sleep variables to vary yearly ( i.e. , to be time dependent ) to examine current effects . in some participants ,
the sdb symptoms resolved , but we do not have information about why this was the case . to examine the difference in risk between current and chronic symptoms , we reran the analyses by calculating the cumulative average of previous values of the sleep variables ( 0 or 1 ) each year and updating them in the model . because waist circumference is a particularly strong risk factor for type 2 diabetes ( 24 ) , we also allowed waist circumference to change over time in the same manner .
we replaced each missing value of the time - dependent variables by the last observed value of that variable .
we restricted our follow - up to 19981999 , as this was the last year that fasting glucose levels were measured .
first , we ran separate models for observed apnea , bothersome snoring , and daytime sleepiness . since observed apnea and bothersome snoring
are frequently used as markers for sdb ( 14 ) and daytime sleepiness is a potential sdb consequence , we assessed their joint associations by creating a cumulative variable coded  0  for no symptoms ,  1  for having one symptom , and  2  for two or more symptoms .
too few participants reported all three symptoms ( n = 63 ) to be categorized separately .
we treated insomnia symptoms similarly , first analyzing them separately and then combining symptoms into a cumulative variable based on the number of symptoms reported . since daytime sleepiness also is a consequence of insomnia , we included it in the combined variable .
, we adjusted for age , sex , race , waist circumference , and clinic site ( model 1 ) . in the second model ,
we further adjusted for marital status ( never married , married , separated / divorced / widowed ) ; education ( < 12 years , 12 years , and 13 + years ) ; smoking ( never smoker , previous smoker , current smoker ) ; alcohol consumption ( < 1 drink , 16 drinks , and 7 drinks ) ; bmi ; physical activity ; depressive symptoms score ; cognitive function ; systolic blood pressure ; antihypertensive medication use ; levels of creatinine , albumin , and total cholesterol ; and previous myocardial infarction ( model 2 ) . in the analysis of the insomnia symptoms , we also adjusted for observed apnea ; adjustment for observed apnea in analyses of sdb symptoms did not meaningfully alter their association with diabetes .
those individuals living alone may be less likely to report sleep apnea or snoring , and we therefore excluded those participants living alone in a sensitivity analysis . because of the association between sdb and insomnia , we also excluded those participants with observed apnea in another sensitivity analysis .
we also conducted several prespecified stratified analyses to assess whether the associations of the sleep disorders with glucose metabolism and incident type 2 diabetes were modified by other factors .
we stratified by sex , age ( dichotomized at age 75 years ) , bmi ( dichotomized at 30 kg / m ) , waist circumference ( dichotomized at 95 cm ) , and race .
we tested for multiplicative interaction across strata with relevant cross - product terms . because sleep disorders are strongly associated with chronic diseases , we excluded those participants with prevalent heart disease . to examine
whether the use of sleep medications changed the association between the sleep symptoms and type 2 diabetes , recognizing that it may be a cause or a consequence of sleep symptoms , we adjusted for this in separate sensitivity analyses .
we tested the proportionality of hazards using log - log curves and tests of interaction with time and found no violations .
participants with daytime sleepiness tended to be older , heavier , less physically active , less educated , and more depressed , and to have higher blood pressure .
they also had a higher prevalence of observed apnea , bothersome snoring , and all three insomnia symptoms .
supplementary table 1 shows the correlations among the sleep variables . characteristics of the participants according to daytime sleepiness ( yes / no )
none of the individual sdb symptoms were associated with fasting glucose in the cross - sectional analyses ( table 2 ) .
there was , however , a graded trend toward increased fasting glucose levels with an increasing number of sdb symptoms .
participants experiencing daytime sleepiness had higher 2-h glucose levels than participants without this symptom , and the 2-h glucose level was much higher with an increasing number of sdb symptoms .
differences in mean fasting glucose examinations in 1989 and 1993 and 2-h glucose levels from the 1989 examination according to symptoms of sdb and insomnia sdb symptoms include daytime sleepiness , observed apnea , and bothersome snoring .
insomnia symptoms include sleep initiation problems , sleep maintenance problems , early morning awakenings , and daytime sleepiness .
model 1 , adjusted for age , sex , race , waist circumference , and clinic site .
model 2 , adjusted for age , sex , race , marital status , clinic site , education , systolic blood pressure , use of antihypertensive medications , physical activity , smoking , alcohol use , bmi , waist circumference , depression score , creatinine level , albumin level , cholesterol level , prevalent myocardial infarction , digit symbol substitution test results , and observed apnea ( for the insomnia symptoms , daytime sleepiness and bothersome snoring ) .
sleep initiation problems and sleep maintenance problems were associated with lower fasting glucose levels compared with those levels in participants who did not report these symptoms .
the cumulative number of insomnia symptoms was also associated with lower fasting glucose levels in a linear fashion ( p for trend = 0.003 ) .
however , we found no consistent association of any of these insomnia symptoms with 2-h glucose levels .
we found lower insulin sensitivity associated with each of the sdb symptoms , with an inverse graded relationship between the number of symptoms and insulin sensitivity .
we found no clear association between insomnia symptoms and insulin sensitivity or insulin secretion , except for an association of sleep maintenance problems with increased insulin secretion .
differences in mean indices of insulin sensitivity ( gutt index ) and insulin secretion ( stumvoll index ) from the 1989 examination according to symptoms of sdb and insomnia sdb symptoms include daytime sleepiness , observed apnea , and bothersome snoring .
insomnia symptoms include sleep initiation problems , sleep maintenance problems , early morning awakenings , and daytime sleepiness .
model 1 , adjusted for age , sex , race , waist circumference , and clinic site .
model 2 , adjusted for age , sex , race , marital status , clinic site , education , systolic blood pressure , use of antihypertensive medications , physical activity , smoking , alcohol use , bmi , waist circumference , depression score , creatinine levels , albumin levels , cholesterol levels , prevalent myocardial infarction , digit symbol substitution test results , and observed apnea ( for the insomnia symptoms , daytime sleepiness and bothersome snoring ) . among the 3,528 participants , type 2 diabetes developed in a total of 208 participants during a mean follow - up time of 5.1 years .
table 4 presents the adjusted hrs and 95% cis for incident diabetes in relation to time - dependent symptoms of sdb and insomnia , and their cumulative average .
participants reporting observed apnea , bothersome snoring , or daytime sleepiness had increased risks of the development of type 2 diabetes during the follow - up compared with those who did not report these symptoms .
the time - dependent observed apnea was more strongly associated with incident type 2 diabetes than the cumulative average observed apnea .
the cumulative number of sdb symptoms was also associated with increased risk of incident type 2 diabetes .
symptoms of sdb and insomnia and 10-year risk of incident type 2 diabetes sdb symptoms include daytime sleepiness , observed apnea , and bothersome snoring .
insomnia symptoms include sleep initiation problems , sleep maintenance problems , early morning awakenings , and daytime sleepiness .
model 1 , adjusted for age , sex , race , waist circumference , and clinic site .
model 2 , adjusted for age , sex , race , marital status , clinic site , education , systolic blood pressure , use of antihypertensive medications , physical activity , smoking , alcohol use , bmi , waist circumference , depression score , creatinine levels , albumin levels , cholesterol levels , prevalent myocardial infarction , digit symbol substitution test results , and observed apnea ( for the insomnia symptoms , daytime sleepiness and bothersome snoring ) .
we found no evidence of an association for any of the insomnia symptoms with incident type 2 diabetes . restricting
the analysis to those participants not living alone and to those without observed apnea or heart disease did not change the results considerably ( data not shown ) .
we also did not find evidence of effect modification by age , sex , race , bmi , or waist circumference .
the association of the sleep variables with glucose metabolism and type 2 diabetes risk did not change after adjustment for the use of sleep medications .
for example , in model 2 , among those participants having two or more sdb symptoms , the estimated 2-h glucose level was 0.39
mmol / l ( 95% ci 0.090.67 ) higher than in those without any sdb symptoms , and the hr for incident type 2 diabetes was 1.93 ( 95% ci 1.292.87 ) .
none of the individual sdb symptoms were associated with fasting glucose in the cross - sectional analyses ( table 2 ) .
there was , however , a graded trend toward increased fasting glucose levels with an increasing number of sdb symptoms .
participants experiencing daytime sleepiness had higher 2-h glucose levels than participants without this symptom , and the 2-h glucose level was much higher with an increasing number of sdb symptoms .
differences in mean fasting glucose examinations in 1989 and 1993 and 2-h glucose levels from the 1989 examination according to symptoms of sdb and insomnia sdb symptoms include daytime sleepiness , observed apnea , and bothersome snoring .
insomnia symptoms include sleep initiation problems , sleep maintenance problems , early morning awakenings , and daytime sleepiness .
model 1 , adjusted for age , sex , race , waist circumference , and clinic site .
model 2 , adjusted for age , sex , race , marital status , clinic site , education , systolic blood pressure , use of antihypertensive medications , physical activity , smoking , alcohol use , bmi , waist circumference , depression score , creatinine level , albumin level , cholesterol level , prevalent myocardial infarction , digit symbol substitution test results , and observed apnea ( for the insomnia symptoms , daytime sleepiness and bothersome snoring ) .
sleep initiation problems and sleep maintenance problems were associated with lower fasting glucose levels compared with those levels in participants who did not report these symptoms .
the cumulative number of insomnia symptoms was also associated with lower fasting glucose levels in a linear fashion ( p for trend = 0.003 ) .
however , we found no consistent association of any of these insomnia symptoms with 2-h glucose levels .
we found lower insulin sensitivity associated with each of the sdb symptoms , with an inverse graded relationship between the number of symptoms and insulin sensitivity .
we found no clear association between insomnia symptoms and insulin sensitivity or insulin secretion , except for an association of sleep maintenance problems with increased insulin secretion .
differences in mean indices of insulin sensitivity ( gutt index ) and insulin secretion ( stumvoll index ) from the 1989 examination according to symptoms of sdb and insomnia sdb symptoms include daytime sleepiness , observed apnea , and bothersome snoring .
insomnia symptoms include sleep initiation problems , sleep maintenance problems , early morning awakenings , and daytime sleepiness .
model 1 , adjusted for age , sex , race , waist circumference , and clinic site .
model 2 , adjusted for age , sex , race , marital status , clinic site , education , systolic blood pressure , use of antihypertensive medications , physical activity , smoking , alcohol use , bmi , waist circumference , depression score , creatinine levels , albumin levels , cholesterol levels , prevalent myocardial infarction , digit symbol substitution test results , and observed apnea ( for the insomnia symptoms , daytime sleepiness and bothersome snoring ) .
among the 3,528 participants , type 2 diabetes developed in a total of 208 participants during a mean follow - up time of 5.1 years . table 4
presents the adjusted hrs and 95% cis for incident diabetes in relation to time - dependent symptoms of sdb and insomnia , and their cumulative average .
participants reporting observed apnea , bothersome snoring , or daytime sleepiness had increased risks of the development of type 2 diabetes during the follow - up compared with those who did not report these symptoms .
the time - dependent observed apnea was more strongly associated with incident type 2 diabetes than the cumulative average observed apnea .
the cumulative number of sdb symptoms was also associated with increased risk of incident type 2 diabetes .
symptoms of sdb and insomnia and 10-year risk of incident type 2 diabetes sdb symptoms include daytime sleepiness , observed apnea , and bothersome snoring .
insomnia symptoms include sleep initiation problems , sleep maintenance problems , early morning awakenings , and daytime sleepiness .
model 1 , adjusted for age , sex , race , waist circumference , and clinic site .
model 2 , adjusted for age , sex , race , marital status , clinic site , education , systolic blood pressure , use of antihypertensive medications , physical activity , smoking , alcohol use , bmi , waist circumference , depression score , creatinine levels , albumin levels , cholesterol levels , prevalent myocardial infarction , digit symbol substitution test results , and observed apnea ( for the insomnia symptoms , daytime sleepiness and bothersome snoring ) .
we found no evidence of an association for any of the insomnia symptoms with incident type 2 diabetes .
restricting the analysis to those participants not living alone and to those without observed apnea or heart disease did not change the results considerably ( data not shown ) .
we also did not find evidence of effect modification by age , sex , race , bmi , or waist circumference .
the association of the sleep variables with glucose metabolism and type 2 diabetes risk did not change after adjustment for the use of sleep medications .
for example , in model 2 , among those participants having two or more sdb symptoms , the estimated 2-h glucose level was 0.39
mmol / l ( 95% ci 0.090.67 ) higher than in those without any sdb symptoms , and the hr for incident type 2 diabetes was 1.93 ( 95% ci 1.292.87 ) .
in this population of older adults who were free of type 2 diabetes at baseline , having observed apnea , bothersome snoring , and daytime sleepiness were associated with increased fasting glucose levels , increased 2-h glucose levels , decreased insulin sensitivity , and increased insulin secretion .
each symptom of sdb was associated with an increased risk of incident type 2 diabetes in a time - dependent manner .
when we combined them in a cumulative manner that suggested the presence of a more severe sdb , the risk of incident type 2 diabetes increased with an increasing number of symptoms . for the insomnia symptoms ,
we did not find a consistent association with glucose metabolism or incident type 2 diabetes , except for a fasting glucose level , where experiencing frequent awakenings through the night was associated with a decreased fasting glucose level .
surprisingly , there was also an inverse linear association between the number of insomnia symptoms and fasting glucose level .
similar to our findings , recent cross - sectional studies ( 7,25 ) have found sdb to be associated with glucose intolerance and insulin resistance .
these studies have relied on homa of insulin resistance and homa of -cell function derived from fasting glucose and insulin measurements , while we used the gutt index and the stumvoll index to account for both fasting and 2-h glucose measurements derived from an ogtt . the gutt index has been reported ( 26 ) to be sensitive to changes in glucose metabolism in individuals with moderate - to - severe sleep apnea who were treated with continuous positive airway pressure .
limited previous evidence of a prospective association between sdb symptoms and incident type 2 diabetes exists , and the studies have mainly been small and not always sufficiently powered to detect an association ( 27 ) .
similar to our findings , a study ( 28 ) objectively measuring sleep apnea in > 4,000 participants who were 4069 years of age reported an hr for incident type 2 diabetes of 1.69 ( 95% ci 1.042.96 ) among those participants with moderate - to - severe nocturnal intermittent hypoxia .
a large observational study ( 14 ) reported a relative risk of 2.25 ( 95% ci 1.712.40 ) for regular snorers compared with nonsnorers in almost 70,000 women in the nurses health study cohort .
this relative risk is slightly higher than that in our sample , which may reflect the additional adjustment for waist circumference in our study or indicate that the relative risk from snoring for the development of type 2 diabetes may be lower in older adults . in accordance with our findings , a recent study
( 5 ) reported increased rates of impaired glucose tolerance in sdb patients , but not in insomnia patients .
however , a recent meta - analysis ( 13 ) of 10 studies including > 100,000 participants found increased risks of the development of type 2 diabetes of 1.57 ( 95% ci 1.251.97 ) and 1.84 ( 95% ci 1.392.43 ) , respectively , for sleep initiation and sleep maintenance problems .
the participants in our study were all 65 years of age , and , as the amount of sleep may decrease with age , even in subjects without daytime sleepiness ( 29 ) , the causes and correlates of insomnia in the elderly may differ from those in younger populations , possibly explaining differences between study findings .
we observed differences in associations once specific insomnia symptoms were analyzed , with one analysis showing a negative association of fasting glucose levels with sleep maintenance symptoms .
this finding , as well as prior research , points to the need to consider each aspect of insomnia separately , as the health implications of sleep onset , sleep maintenance , and early morning awakenings may differ .
sleep disorders are not constant over a lifetime ( 30 ) , and this is the first prospective study to account for this by allowing the sleep exposure to change in yearly increments during the follow - up .
the effect of observed apnea when allowing it to change over the follow - up period appeared to be stronger compared with using the cumulative average , indicating that current or recent sleep disruption may be more important than previous / chronic symptoms in the development of type 2 diabetes .
the apparently stronger association of the more recent exposure of observed apnea is a new finding and needs to be confirmed by further studies .
the mechanisms that underlie our findings are largely unknown , but some have been suggested .
sleep deprivation , caused by sdb or insomnia , has been shown to increase the activity of orexin neurons that may act as a link between sdb and the metabolic effects ( 31 ) .
sleep deprivation can also cause increased sympathetic nervous activity , increasing the released levels of cortisol and catecholamines , leading to reduced insulin sensitivity and glucose tolerance ( 32,33 ) .
the corresponding increase in insulin secretion may lead to -cell exhaustion and impaired secretory capacity over time , resulting in diabetes . despite its clear strengths , which include the population - based design in a high - risk older population , the wide range of covariates , the ogtt - based measures of insulin sensitivity and secretion , and the repeated measures of multiple sleep symptoms , the study also has important limitations .
we used self - reported measures of sleep , which , while subjective , have the advantage of ready clinical applicability at low cost .
the participants were asked whether anyone had observed them having episodes where they stopped breathing for a while and then snorted or snored loudly or complained about loud snoring .
participants living alone may not have this knowledge and may have reported  no  rather than the option offered of 
although objective measures of sdb ( i.e. , polysomnography results ) exist , subjectively reported breath cessation is among the best clinical predictors of sleep apnea ( 34 ) , and self - reported snoring is a sensitive but less specific measure ( 35 ) . in a sensitivity analysis
, we restricted the analysis to those not living alone , and this changed our estimates minimally .
however , objective polysomnography data available in a subset indicated that the symptoms analyzed discriminated between groups with and without sdb symptoms . furthermore , because misclassification between these symptoms and sleep apnea is unlikely to be related to glucose or insulin levels
, our results may underestimate the true associations of sleep apnea with hyperglycemia and insulin resistance .
the difference in sleep latency between those reporting sleep initiation problems and those who did not was only 2 min , but , as insomnia is defined as a subjective feeling of having difficulties falling asleep , remaining asleep , or receiving restorative sleep lasting at least 1 month and causing daytime impairment ( 4 ) ; thus , such problems are not ideally evaluated by polysomnography ( 36 ) .
sdb and insomnia are different conditions than short sleep duration ( 37 ) , and people with insomnia symptoms could have normal or long durations of sleep ( 38 ) . also , some people with short sleep duration may not have insomnia symptoms or daytime sleepiness , as individuals vary substantially in the duration of sleep that is needed for restoration ( 39 ) .
although we adjusted for several potential confounders in our multivariable analyses , we can not exclude the possibility of uncontrolled confounding behind the observed associations .
however , any remaining confounder that is potentially able to influence our results would need to be strongly associated with both sleep symptoms and glucose metabolism , and generally be unrelated to the factors included in our models . several small interventional studies ( 26,40 ) suggest that sleep apnea therapy may improve insulin resistance , supporting a causal relationship between sdb and insulin resistance . of note , these interventional studies have in general excluded older individuals . in this population - based study of older adults , having observed apnea , bothersome snoring , and daytime sleepiness were associated with impaired glucose metabolism , insulin resistance , and risk of incident type 2 diabetes . for observed apnea , more recent exposure tended to be more strongly associated with subsequent risk of type 2 diabetes than chronic exposure .
the associations persisted after adjustment for total and central adiposity , suggesting that sdb may impair glucose metabolism independent of body fat .
in contrast to previous studies , we found no consistent association between the insomnia symptoms and glucose metabolism or incident type 2 diabetes .
further studies are needed to determine whether insomnia symptoms affect the risk of incident type 2 diabetes differently in older adults than in younger adults .
despite its clear strengths , which include the population - based design in a high - risk older population , the wide range of covariates , the ogtt - based measures of insulin sensitivity and secretion , and the repeated measures of multiple sleep symptoms , the study also has important limitations .
we used self - reported measures of sleep , which , while subjective , have the advantage of ready clinical applicability at low cost .
the participants were asked whether anyone had observed them having episodes where they stopped breathing for a while and then snorted or snored loudly or complained about loud snoring .
participants living alone may not have this knowledge and may have reported  no  rather than the option offered of 
although objective measures of sdb ( i.e. , polysomnography results ) exist , subjectively reported breath cessation is among the best clinical predictors of sleep apnea ( 34 ) , and self - reported snoring is a sensitive but less specific measure ( 35 ) . in a sensitivity analysis
, we restricted the analysis to those not living alone , and this changed our estimates minimally .
however , objective polysomnography data available in a subset indicated that the symptoms analyzed discriminated between groups with and without sdb symptoms .
furthermore , because misclassification between these symptoms and sleep apnea is unlikely to be related to glucose or insulin levels , our results may underestimate the true associations of sleep apnea with hyperglycemia and insulin resistance .
the difference in sleep latency between those reporting sleep initiation problems and those who did not was only 2 min , but , as insomnia is defined as a subjective feeling of having difficulties falling asleep , remaining asleep , or receiving restorative sleep lasting at least 1 month and causing daytime impairment ( 4 ) ; thus , such problems are not ideally evaluated by polysomnography ( 36 ) .
sdb and insomnia are different conditions than short sleep duration ( 37 ) , and people with insomnia symptoms could have normal or long durations of sleep ( 38 ) . also , some people with short sleep duration may not have insomnia symptoms or daytime sleepiness , as individuals vary substantially in the duration of sleep that is needed for restoration ( 39 ) .
although we adjusted for several potential confounders in our multivariable analyses , we can not exclude the possibility of uncontrolled confounding behind the observed associations .
however , any remaining confounder that is potentially able to influence our results would need to be strongly associated with both sleep symptoms and glucose metabolism , and generally be unrelated to the factors included in our models .
several small interventional studies ( 26,40 ) suggest that sleep apnea therapy may improve insulin resistance , supporting a causal relationship between sdb and insulin resistance .
in this population - based study of older adults , having observed apnea , bothersome snoring , and daytime sleepiness were associated with impaired glucose metabolism , insulin resistance , and risk of incident type 2 diabetes . for observed apnea
, more recent exposure tended to be more strongly associated with subsequent risk of type 2 diabetes than chronic exposure .
the associations persisted after adjustment for total and central adiposity , suggesting that sdb may impair glucose metabolism independent of body fat .
in contrast to previous studies , we found no consistent association between the insomnia symptoms and glucose metabolism or incident type 2 diabetes .
further studies are needed to determine whether insomnia symptoms affect the risk of incident type 2 diabetes differently in older adults than in younger adults .
 objectivewe examined the associations of symptoms of sleep - disordered breathing ( sdb ) , which was defined as loud snoring , stopping breathing for a while during sleep , and daytime sleepiness , and insomnia with glucose metabolism and incident type 2 diabetes in older adults.research design and methodsbetween 1989 and 1993 , the cardiovascular health study recruited 5,888 participants 65 years of age from four u.s . 
 communities . 
 participants reported sdb and insomnia symptoms yearly through 19891994 . in 19891990 
 , participants underwent an oral glucose tolerance test , from which insulin secretion and insulin sensitivity were estimated . 
 fasting glucose levels were measured in 19891990 and again in 19921993 , 19941995 , 19961997 , and 19981999 , and medication use was ascertained yearly . 
 we determined the cross - sectional associations of sleep symptoms with fasting glucose levels , 2-h glucose levels , insulin sensitivity , and insulin secretion using generalized estimated equations and linear regression models . 
 we determined the associations of updated and averaged sleep symptoms with incident diabetes in cox proportional hazards models . 
 we adjusted for sociodemographics , lifestyle factors , and medical history.resultsobserved apnea , snoring , and daytime sleepiness were associated with higher fasting glucose levels , higher 2-h glucose levels , lower insulin sensitivity , and higher insulin secretion . 
 the risk of the development of type 2 diabetes was positively associated with observed apnea ( hazard ratio [ hr ] 1.84 [ 95% ci 1.192.86 ] ) , snoring ( hr 1.27 [ 95% ci 0.951.71 ] ) , and daytime sleepiness ( hr 1.54 [ 95% ci 1.132.12 ] ) . in contrast , we did not find consistent associations between insomnia symptoms and glucose metabolism or incident type 2 diabetes.conclusionseasily collected symptoms of sdb are strongly associated with insulin resistance and the incidence of type 2 diabetes in older adults . monitoring 
 glucose metabolism in such patients may prove useful in identifying candidates for lifestyle or pharmacological therapy . 
 further studies are needed to determine whether insomnia symptoms affect the risk of diabetes in younger adults . 
Introduction
Research Design and Methods
Participant Recruitment
Interviews and Clinical Examinations
Sleep Symptoms
Glycemic Outcomes
Statistical Analysis
Results
Glucose Metabolism
Incident Type 2 Diabetes
Additional Analyses
Conclusions
Limitations
Summary
Supplementary Material