Sleep Disturbances and Glucose Metabolism in Older Adults

2050 Diabetes Care Volume 38, November 2015

Sleep Disturbances and Glucose Linn Beate Strand,1,2,3 Mercedes Carnethon,4 Mary Lou Biggs,5 Metabolism in Older Adults: The Luc Djousse,´ 6 Robert C. Kaplan,7 David S. Siscovick,8 John A. Robbins,9 Cardiovascular Health Study Susan Redline,1,10 Sanjay R. Patel,1,10 Imre Janszky,3,11 and 1,2 Diabetes Care 2015;38:2050–2058 | DOI: 10.2337/dc15-0137 Kenneth J. Mukamal

OBJECTIVE 1Beth Israel Deaconess Medical Center, Depart- We examined the associations of symptoms of sleep-disordered breathing (SDB), ment of Medicine, Boston, MA which was deﬁned as loud snoring, stopping breathing for a while during sleep, 2Department of Nutrition, Harvard School of and daytime sleepiness, and insomnia with glucose metabolism and incident Public Health, Boston, MA 3Department of Public Health and General Prac-

EPIDEMIOLOGY/HEALTH SERVICES RESEARCH type 2 diabetes in older adults. tice, Norwegian University of Science and Tech- nology, Trondheim, Norway RESEARCH DESIGN AND METHODS 4Department of Preventive Medicine, Feinberg Between 1989 and 1993, the Cardiovascular Health Study recruited 5,888 partic- School of Medicine, Northwestern University, ‡ Chicago, IL ipants 65 years of age from four U.S. communities. Participants reported SDB 5 – – Department of Biostatistics, University of and insomnia symptoms yearly through 1989 1994. In 1989 1990, participants Washington, Seattle, WA underwent an oral glucose tolerance test, from which insulin secretion and insulin 6Department of Medicine, Division of Aging, sensitivity were estimated. Fasting glucose levels were measured in 1989–1990 Brigham and Women’s Hospital, Harvard and again in 1992–1993, 1994–1995, 1996–1997, and 1998–1999, and medication Medical School, and Boston Veterans Health- care, Boston, MA use was ascertained yearly. We determined the cross-sectional associations of 7Department of Epidemiology & Population sleep symptoms with fasting glucose levels, 2-h glucose levels, insulin sensitivity, Health, Albert Einstein College of Medicine, and insulin secretion using generalized estimated equations and linear regression Bronx, NY 8 models. We determined the associations of updated and averaged sleep symp- Cardiovascular Health Research Unit, Depart- ments of Medicine and Epidemiology, University toms with incident diabetes in Cox proportional hazards models. We adjusted for of Washington, Seattle, WA sociodemographics, lifestyle factors, and medical history. 9University of California, Davis, Sacramento, CA 10Division of Sleep and Circadian Disorders, RESULTS Brigham and Women’s Hospital, Boston, MA 11 Observed apnea, snoring, and daytime sleepiness were associated with higher Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden fasting glucose levels, higher 2-h glucose levels, lower insulin sensitivity, and Corresponding author: Linn Beate Strand, higher insulin secretion. The risk of the development of type 2 diabetes was [email protected]. – positively associated with observed apnea (hazard ratio [HR] 1.84 [95% CI 1.19 Received 20 January 2015 and accepted 27 July 2.86]), snoring (HR 1.27 [95% CI 0.95–1.71]), and daytime sleepiness (HR 1.54 [95% 2015. CI 1.13–2.12]). In contrast, we did not ﬁnd consistent associations between in- This article contains Supplementary Data online somnia symptoms and glucose metabolism or incident type 2 diabetes. at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc15-0137/-/DC1. CONCLUSIONS A full list of principal Cardiovascular Health Study Easily collected symptoms of SDB are strongly associated with insulin resistance investigators and institutions can be found at and the incidence of type 2 diabetes in older adults. Monitoring glucose metab- CHS-NHLBI.org. olism in such patients may prove useful in identifying candidates for lifestyle or © 2015 by the American Diabetes Association. Readers may use this article as long as the work is pharmacological therapy. Further studies are needed to determine whether in- properly cited, the use is educational and not for somnia symptoms affect the risk of diabetes in younger adults. proﬁt, and the work is not altered. care.diabetesjournals.org Strand and Associates 2051

Sleep disorders are increasingly recognized Pennsylvania. The cohort was identified Sleep Symptoms as important factors in glucose metabolism using Medicare eligibility lists of the Participants were asked whether any- and the development of type 2 diabetes. Health Care Finance Administration. one had observed them having episodes Sleep-disordered breathing (SDB), a condi- Participants had to be $65 years of where they stopped breathing for a tion characterized by a reduction or com- age, ambulatory and community dwell- while and then snorted or snored loudly, plete cessation of airflow during sleep, has ing, expected to remain in their commu- which we term “observed apnea.” They repeatedly been linked to impaired glucose nities for 3 years, and able to provide were also asked whether their spouse or tolerance and insulin resistance in clinic- personal informed consent (15). In roommate had complained about their based studies (1,2) and, more recently, 1992–1993, an additional 687 predom- loud snoring, labeled “bothersome also in population-based studies (3). An- inantly African American participants snoring,” and whether they were usually other frequent sleep disorder, insomnia, were recruited, for a total of 5,888 sleepy in the daytime, labeled “daytime which is defined as a subjective feeling of participants. sleepiness.” having difficulties initiating or maintaining In addition, the participants reported sleep or having a feeling of nonrestorative Interviews and Clinical Examinations on the following three insomnia symp- sleep(4),hasalsobeenlinkedtoimpaired Participants were contacted every 6 toms: whether they usually had diffi- glucose metabolism (5,6). months, alternating between telephone culties falling asleep, labeled “sleep Most previous work has used the interviews and visits to field centers, initiation problems”; experienced fre- HOMA of insulin resistance and some- from 1989–1990 through 1998–1999. quent nightly awakenings, labeled times the HOMA of b-cell function to Sociodemographics (i.e., sex, age, race, “sleep maintenance problems”;orusu- estimate fasting insulin resistance and marital status, and number of years of ally woke up too early without being secretion, respectively (6,7). These education completed), personal habits able to go back to sleep, labeled “early methods are clearly limited in the set- (i.e., smoking, alcohol consumption, morning awakenings.” The response op- ting of progressive insulin resistance and physical activity), and depressive tions on all sleep questions were “yes,” and may be particularly limited in older symptoms were collected by question- “no,” and “I don’t know.” The partici- adults, in whom peripheral insulin resis- naires. Participants reported their usual pants were asked these questions an- tance is prevalent. Potentially better frequency of consumption of beer, nually from 1989–1990 to 1993–1994. measures of insulin sensitivity and se- wine, and liquor, and the usual number Within a subgroup of Cardiovascular cretion can be derived from an oral glu- of drinks consumed on each occasion, Health Study (CHS) participants who at- cose tolerance test (OGTT) (8,9). Little from which the number of drinks per tended the Sleep Heart Health Study research has been done on sleep disor- week of alcoholic beverages was calcu- (SHHS) (21), we validated the self- ders and glucose metabolism using lated. Physical activity (in kilocalories reported SDB symptoms in the CHS these potentially more refined mea- per week) was collected using a modi- against the objectively measured sleep sures of insulin sensitivity and secretion. fied Minnesota Leisure-Time Activities variables in the SHHS. We compared the Recent data indicate that both SDB questionnaire (16). Symptoms of de- median values of objectively measured and insomnia symptoms are highly prev- pression were collected using the mod- SDB in the participants reporting to have alent in patients with type 2 diabetes ified Center for Epidemiologic Studies SDB symptoms. In the subgroup of (10–12). Fewer studies have assessed Depression scale of 0–30 (17). ;1,000 participants, we found higher the prospective association between The participants were also asked obstructive apnea-hypopnea index val- these sleep disorders and the incidence about their medical history, and reported ues, defined as all desaturations of of type 2 diabetes (13,14), and these have cardiovascular events (i.e., myocardial in- $4%, among those participants reporting mainly focused on young or middle-aged farction and congestive heart failure observed apnea (8.7 desaturations/h) adults. [CHF]) were verified from objective infor- compared with those without observed Accordingly, we aimed to address sev- mation obtained from hospital and physi- apnea (7.2 desaturations/h, P =0.05), eral gaps in the literature, as follows: 1) cian records, as previously described (18). and among those reporting bother- to focus on an elderly cohort in whom Each year, participants reported whether some snoring (8.8 desaturations/h) there are limited data on sleep disor- they used over-the-counter sleeping pills compared with those without bother- ders, glucose metabolism, and type 2 di- at least weekly. some snoring (4.8 desaturations/h, P , abetes; 2) to use longitudinal measures Study staff measured height, waist 0.001). We also found increasing ob- of glucose metabolism; and 3) to con- circumference, weight, and blood pres- structive apnea-hypopnea index values sider symptoms of both SDB and insom- sure at study examinations. BMI was cal- with increasing number of SDB symp- nia, both of which are common in older culated as weight (in kilograms) divided toms. The participants reporting day- populations. by height squared (in meters). Systolic time sleepiness in the CHS had a blood pressure was measured twice, higher Epworth sleepiness score in the RESEARCH DESIGN AND METHODS and the average of the two was used SHHS compared with those without Participant Recruitment in the analyses. Cognitive impairment daytime sleepiness in the CHS (median Between 1989 and 1990, a cohort of was assessed using the Digit Symbol 9and6,respectively;P , 0.001). The 5,201 participants was recruited from Substitution Test (19). Medication insomnia symptoms in the CHS were Forsyth County, North Carolina; Sacra- use was assessed at baseline and also compared with the objectively mento County, California; Washington annually from a validated medication measured sleep latency (i.e., in mi- County, Maryland; and Pittsburgh, inventory (20). nutes) and sleep efficiency, defined as 2052 Sleep and Glucose Metabolism Diabetes Care Volume 38, November 2015

the percentage of time scored as sleep dur- glucose measurements, and without daytime sleepiness. Since observed ap- ing the sleep period, in the SHHS. We found prevalent diabetes or CHF, who were nea and bothersome snoring are fre- that participants with sleep initiation prob- enrolled into the study in 1989–1990. quently used as markers for SDB (14) lems had longer sleep latency (18.8 min) For cross-sectional analyses of fasting and daytime sleepiness is a potential than those who did not report such prob- glucose, we combined the 3,007 mea- SDB consequence, we assessed their lems (16.8 min, P = 0.14) and that those surements from 1989–1990 with 2,378 joint associations by creating a cumula- reporting problems with sleep mainte- measurements from 1992–1993 (pro- tive variable coded “0” for no symp- nance had lower sleep efficiency than those viding repeated measurements in the toms, “1” for having one symptom, without such problems (79.1% and 83.3%, original cohort and incorporating the and “2” for two or more symptoms. respectively; P , 0.001). Those participants added African American cohort). We fit Too few participants reported all three with early morning awakenings had less generalized estimating equation models symptoms (n = 63) to be categorized time in bed (7 min, P = 0.03) and a shorter with an identity link function and un- separately. We treated insomnia symp- total sleep time (11 min, P = 0.01) than structured within-group correlation. toms similarly, first analyzing them sep- those without this symptom. Since not all included participants at- arately and then combining symptoms tended both measurements, we had into a cumulative variable based on Glycemic Outcomes 5,385 observations from a total of the number of symptoms reported. An OGTT was performed in 1989–1990. 3,797 participants after excluding par- Since daytime sleepiness also is a conse- The venipuncture was performed in the ticipants with missing sleep symptoms quence of insomnia, we included it in morning during the visit after an over- or glucose values, and those with prev- the combined variable. night fast, and serum glucose levels alent diabetes or CHF. The participant We adjusted for covariates in two were measured (Kodak Ektachem 700 selection process is illustrated in Supple- multivariable models. In the first model, Analyzer; Eastman Kodak, Rochester, mentary Fig. 2. we adjusted for age, sex, race, waist cir- NY) (22). After the fasting venipuncture, We next used Cox proportional hazards cumference, and clinic site (Model 1). In 75 g of glucose was given orally to con- models to examine the associations of the second model, we further adjusted senting nondiabetic participants. A sec- sleep symptoms with the subsequent for marital status (never married, mar- ond venipuncture was performed 2 h risk of incident type 2 diabetes, estimat- ried, separated/divorced/widowed); ed- later to obtain a 2-h glucose value. Fast- ing hazard ratios (HRs) and 95% CIs. Of the ucation (,12 years, 12 years, and 13+ ing serum glucose levels were measured 5,888 enrolled participants, 3,528 partic- years); smoking (never smoker, previous again in 1992–1993, 1994–1995 (non- ipants were free of diabetes and CHF at smoker, current smoker); alcohol con- fasting), 1996–1997, and 1998–1999. baseline and were included in the analy- sumption (,1drink,1–6drinks,and Supplementary Fig. 1 shows the time- ses (Supplementary Fig. 3). The subjects $7 drinks); BMI; physical activity; de- line for the collection of sleep symptoms stopped contributing person-time to the pressive symptoms score; cognitive and the glycemic outcomes. analyses when they received a diagnosis function; systolic blood pressure; anti- We estimated insulin sensitivity using of type 2 diabetes or at the time of the hypertensive medication use; levels of the Gutt index (Gutt et al. [8]), and in- last attended visit. We used the exact creatinine, albumin, and total choles- sulin secretion using the Stumvoll index marginal method to handle ties. terol; and previous myocardial infarc- (Stumvoll et al. [9]). We allowed the sleep variables to tion (Model 2). In the analysis of the Incident type 2 diabetes was defined vary yearly (i.e., to be time dependent) insomnia symptoms, we also adjusted as new use of insulin or a hypoglycemic to examine current effects. In some par- for observed apnea; adjustment for ob- agent, a fasting glucose level of $7.0 ticipants, the SDB symptoms resolved, served apnea in analyses of SDB symp- mmol/L, or a nonfasting glucose level but we do not have information about toms did not meaningfully alter their of $11.1 mmol/L. why this was the case. To examine the association with diabetes. difference in risk between current and Those individuals living alone may be Statistical Analysis chronic symptoms, we reran the analy- less likely to report sleep apnea or snor- For descriptive purposes, we provide ses by calculating the cumulative aver- ing, and we therefore excluded those the clinical characteristics of partici- age of previous values of the sleep participants living alone in a sensitivity pants according to daytime sleepiness, variables (0 or 1) each year and updating analysis. Because of the association be- which is a potential consequence of ei- them in the model. Because waist cir- tween SDB and insomnia, we also ther SDB or insomnia. We calculated the cumference is a particularly strong risk excluded those participants with ob- Pearson F coefficient to assess the rela- factor for type 2 diabetes (24), we also served apnea in another sensitivity tionships between the dichotomous allowed waist circumference to change analysis. We also conducted several pre- sleep variables. Missing data on baseline over time in the same manner. We specified stratified analyses to assess covariates were imputed using methods replaced each missing value of the whether the associations of the sleep described previously (23). time-dependent variables by the last disorders with glucose metabolism and Using linear regression, we analyzed observed value of that variable. We re- incident type 2 diabetes were modified the cross-sectional associations of sleep stricted our follow-up to 1998–1999, as by other factors. We stratified by sex, symptoms with 2-h glucose levels and this was the last year that fasting glu- age (dichotomized at age 75 years), BMI measures of insulin sensitivity and insu- cose levels were measured. (dichotomized at 30 kg/m2), waist circum- lin secretion in 3,007 participants with First, we ran separate models for ob- ference (dichotomized at 95 cm), and race. informationonsleepsymptomsand served apnea, bothersome snoring, and We tested for multiplicative interaction care.diabetesjournals.org Strand and Associates 2053

across strata with relevant cross-product andtohavehigherbloodpressure. symptoms was also associated with terms. Because sleep disorders are strongly They also had a higher prevalence of lower fasting glucose levels in a linear associated with chronic diseases, we ex- observed apnea, bothersome snoring, fashion (P for trend = 0.003). However, cluded those participants with prevalent and all three insomnia symptoms. Sup- we found no consistent association of heart disease. plementary Table 1 shows the correla- any of these insomnia symptoms with To examine whether the use of sleep tions among the sleep variables. 2-h glucose levels. medications changed the association We then examined insulin sensitivity between the sleep symptoms and type Glucose Metabolism and secretion (Table 3). We found lower 2 diabetes, recognizing that it may be a None of the individual SDB symptoms insulin sensitivity associated with each of cause or a consequence of sleep symp- were associated with fasting glucose in the SDB symptoms, with an inverse graded toms, we adjusted for this in separate the cross-sectional analyses (Table 2). relationship between the number of sensitivity analyses. We tested the pro- There was, however, a graded trend to- symptoms and insulin sensitivity. We portionality of hazards using log-log ward increased fasting glucose levels found similar corresponding results with curves and tests of interaction with with an increasing number of SDB symp- SDB symptoms and greater insulin secre- time and found no violations. We con- toms. Participants experiencing daytime tion. We found no clear association be- ducted all statistical analyses using Stata sleepiness had higher 2-h glucose levels tween insomnia symptoms and insulin 12 for Windows (Stata Corp., College than participants without this symptom, sensitivity or insulin secretion, except for Station, TX). andthe2-hglucoselevelwasmuch an association of sleep maintenance prob- higher with an increasing number of lems with increased insulin secretion. RESULTS SDB symptoms. The characteristics of participants ac- Sleep initiation problems and sleep Incident Type 2 Diabetes cording to reported daytime sleepiness maintenance problems were associated Among the 3,528 participants, type 2 di- are presented in Table 1. Participants with lower fasting glucose levels com- abetes developed in a total of 208 partic- with daytime sleepiness tended to be pared with those levels in participants ipants during a mean follow-up time of older, heavier, less physically active, who did not report these symptoms. 5.1 years. Table 4 presents the adjusted less educated, and more depressed, The cumulative number of insomnia HRs and 95% CIs for incident diabetes in relation to time-dependent symptoms of SDB and insomnia, and their cumulative Table 1—Characteristics of the participants according to daytime sleepiness (yes/ average. Participants reporting observed no) apnea, bothersome snoring, or daytime Daytime sleepiness (N =3,528) sleepiness had increased risks of the de- No Yes velopment of type 2 diabetes during the Variable (n =2,993) (n =535) P value follow-up compared with those who did Age (years) 72.1 (5.3) 73.6 (5.8) ,0.001 not report these symptoms. The time- Waist circumference (cm) 92.7 (12.6) 94.7 (13.3) ,0.001 dependent observed apnea was more Systolic blood pressure (mmHg) 138.1 (19.7) 141.1 (20.8) 0.001 strongly associated with incident type 2 Physical activity (kcal/week) 1,963.4 (2,192.0) 1,476.8 (1,725.9) ,0.001 diabetes than the cumulative average observed apnea. The cumulative number of BMI (kg/m2) 26.1 (4.3) 26.8 (5.0) 0.01 SDB symptoms was also associated with Depression score 4.0 (4.2) 6.2 (5.0) ,0.001 increased risk of incident type 2 diabetes. Creatinine (mmol/L) 92 (25) 96 (30) 0.001 We found no evidence of an associa- Albumin (g/dL) 40.0 (2.9) 39.8 (2.9) 0.02 tion for any of the insomnia symptoms Total cholesterol (mmol/L) 5.6 (1.0) 5.5 (1.0) 0.24 with incident type 2 diabetes. Digit symbol substitution test score 38.3 (13.0) 33.3 (14.0) ,0.001 Fasting glucose (mmol/L) 5.5 (0.5) 5.6 (0.6) 0.14 Additional Analyses Male sex (%) 58.7 54.0 0.04 Restricting the analysis to those partici- White race (%) 89.0 85.4 0.05 pants not living alone and to those with- Current smokers (%) 11.5 13.1 0.13 out observed apnea or heart disease did Married (%) 75.0 70.5 0.02 not change the results considerably (data Observed apnea (%) 7.2 12.0 ,0.001 not shown). We also did not ﬁnd evidence Bothersome snoring (%) 21.8 33.1 ,0.001 of effect modiﬁcation by age, sex, race, Sleep initiation problems (%) 19.2 31.0 ,0.001 BMI, or waist circumference. Sleep maintenance problems (%) 60.8 75.0 ,0.001 The association of the sleep variables Early morning awakenings (%) 27.8 49.4 ,0.001 with glucose metabolism and type 2 dia- Heavy drinkers (%) 15.4 12.9 0.03 betes risk did not change after adjustment College graduate (%) 46.4 36.1 ,0.001 for the use of sleep medications. For ex- Use of antihypertensive medications (%) 41.5 44.3 0.22 ample, in Model 2, among those partici- Prevalent myocardial infarction (%) 7.1 6.5 0.63 pants having two or more SDB symptoms, the estimated 2-h glucose level was Data are reported as mean (SD), unless otherwise indicated. 0.39 mmol/L (95% CI 0.09–0.67) higher 2054 Sleep and Glucose Metabolism Diabetes Care Volume 38, November 2015

than in those without any SDB symptoms, and the HR for incident type 2 diabetes

value was 1.93 (95% CI 1.29–2.87). P omnia CONCLUSIONS In this population of older adults who were 0.59 0.004 0.64 0.02 – – free of type 2 diabetes at baseline, having 0.21 to 0.410.03 to 0.37 0.53 0.10 0.05 to 0.34 0.16 0.28 to 0.14 0.52 0.28 to 0.070.12 to 0.25 0.26 0.47 0.43 to 0.00 0.05 0.18 to 0.29 0.65 0.38 to 0.24 0.66 0.37 to 0.64 0.61 observed apnea, bothersome snoring, and 2 2 2 2 2 2 2 2 2 2 daytime sleepiness were associated with increased fasting glucose levels, increased 0.07 0.05 0.21 0.07 2-h glucose levels, decreased insulin sensi- = 3,007) 2 2 2 2 N tivity, and increased insulin secretion. Each symptom of SDB was associated with an increased risk of incident type 2 diabetes value B 95% CI

P in a time-dependent manner. When we

tenance problems, early morning awakenings, and combined them in a cumulative manner that suggested the presence of a more clinic site, education, systolic blood pressure, use of 0.62 0.001 0.35 0.11 0.71 0.05 0.35 0.06 severe SDB, the risk of incident type 2 di- – –

evel, cholesterol level, prevalent myocardial infarction, digit abetes increased with an increasing Model 1 Model 2 0.23 to 0.400.09 to 0.32 0.61 0.26 0.10 0.17 0.04 to 0.36 0.110.20 to 0.22 0.14 0.91 0.21 to 0.140.09 to 0.27 0.67 0.33 0.07 0.43 to 0.00 0.05 0.14 to 0.33 0.44 0.05 0.30 to 0.30 0.99 0.26 to 0.74 0.34 0.13 2 2 2 2 2 2 2 2 2 2 number of symptoms. For the insomnia symptoms, we did not ﬁnd a consistent association with glucose metabolism or in- 0.04 0.22 2 2 cident type 2 diabetes, except for a fasting glucose level, where experiencing frequent awakenings through the night was n associated with a decreased fasting glucose level. Surprisingly, there was also an inverse linear association between the value B 95% CI

P number of insomnia symptoms and fasting glucose level. Similar to our ﬁndings, recent cross- 0.1 0.01 339 0.00 0.02 0.001 1,897 2

2 sectional studies (7,25) have found SDB 0.11 0.008 287 0.30 0.01 – to be associated with glucose intoler- 0.02 to 0.080.01 to 0.06 0.18 0.12 242 695 0.08 0.12 0.07 to 0.00 0.03 634 0.01 0.01 to 0.06 0.160.03 444 to 0.03 0.38 0.86 0.15 761 0.16 0.04 to 0.02 0.47 930 0.09 0.06 to 0.00 0.08 1,044 0.08 to 0.00 0.03 720 0.09 0.12 to 0.04 0.352 95 0.24

0.11 to ance and insulin resistance. These stud- 0.07 to 2 2 2 2 2 2 2 2 2 2 2 ies have relied on HOMA of insulin resistance and HOMA of b-cell function

= 5,385) 2-h glucose (mmol/L) ( derived from fasting glucose and in- 0.04 0.04 0.01 0.03 0.04 0.07 0.04 N 2 2 2 2 2 2 2 sulin measurements, while we used the Gutt index and the Stumvoll index to account for both fasting and 2-h glu- value B 95% CI

P cose measurements derived from an OGTT. The Gutt index has been reported (26) to be sensitive to changes in glu- 0.01 0.009 0.01 0.12 2 2 cose metabolism in individuals with 0.07 0.07 0.03 0.11 0.01 0.06 0.02 – –

Fasting glucose (mmol/L) ( moderate-to-severe sleep apnea who Model 1 Model 2 0.02 to 0.080.01 to 0.05 0.19 0.20 0.03 0.03 0.06 to 0.01 0.21 0.03 to 0.03 0.89 0.00 0.03 to 0.03 0.91 0.06 to 0.05 0.19 0.09 to 0.01 0.09 0.09 to 0.08 0.90 were treated with continuous positive 0.06 to 0.06 to 2 2 2 2 2 2 2 2 2 2 airway pressure. Limited previous evidence of a pro-

B 95% CI spective association between SDB symp- 0.02 0.04 0.03 0.02 0.04 0.01 2 2 2 2 2 2 toms and incident type 2 diabetes exists, and the studies have mainly been small

n 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 40–69 years of age 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 ins

— reported an HR for incident type 2 di- –

3 467 0.06 0.01 abetes of 1.69 (95% CI 1.04 2.96) among – 1 1,310 0.00 2 1 1,828 2 1,266 3 607 4 150 those participants with moderate-to-severe Table 2 Daytime sleepinessObserved apnea 801Bothersome snoringSDB symptoms 1,113 0.03 402 0.02 0.03 0.00 Linear trendSleep initiationSleep maintenance 3,311 1,099 0.05 0.06 0.02 0.01 Early morningInsomnia symptoms 1,630 0.00 Linear trendSDB symptoms include daytimedaytime sleepiness, sleepiness. observed Model apnea, 1,antihypertensive and adjusted medications, bothersome for snoring. physical age,symbol sex, Insomnia activity, substitution race, symptoms smoking, waist test include alcohol circumference, results, sleep use, and and initiation BMI, observed clinic waist problems, site. apnea circumference, sleep Model (for main depression the 2, score, adjusted insomnia creatinine for symptoms, level, age, daytime sex, albumin sleepiness race, l nocturnal and marital bothersome status, snoring). intermittent hypoxia. 0.17 A large 0.013 0.21 0.58 care.diabetesjournals.org Strand and Associates 2055 atm leies oe ,ajse o g,sex, age, for adjusted 1, Model sleepiness. daytime ierted01 .700 0.29 0.05 0.47 0.11 observ sleepiness, daytime include symptoms SDB trend Linear nonasymptoms Insomnia D symptoms SDB yblsbttto etrsls n bevdana(o h nonasmtm,dyiesepns n ohroesnoring). bothersome and sleepiness daytime symptoms, insomnia the (for apnea observed and results, test use, substitution alcohol symbol smoking, activity, physical medications, antihypertensive ierted0020010020.01 0.002 0.001 0.002 930 0.01 634 1,897 morning Early maintenance Sleep initiation Sleep trend Linear ohroesoig695 snoring Bothersome al 3 Table bevdana242 444 apnea Observed sleepiness Daytime insomnia observational study (14) reported a rel- 3339 ,4 1.42 1,044 27201 2 1761 495

– ative risk of 2.25 (95% CI 1.71–2.40) for 3287 regular snorers compared with nons- —

ifrne nma nie fislnsniiiy(utidx n nui erto Suvl ne)fo h 99eaiainacrigt sympt to according examination 1989 the from index) (Stumvoll secretion insulin and index) (Gutt sensitivity insulin of indices mean in Differences norers 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 n our study or indicate that the relative risk from snoring for the development 2 2 2 2 2 2 2 2 2 2 of type 2 diabetes may be lower in 4.34 0.65 1.32 1.72 2.85 1.13 0.98 2.03 3.35 2.95 B95%CIolder adults. In accordance with our ﬁndings, a re- 2 2 2 cent study (5) reported increased rates 2 2 2 2 2 2 2 2 2 .6to 7.26 .2to 4.02 .8to 5.28 . to 6.4 .8t .806 0.21 0.66 2.28 to 3.58 .4t .90.26 0.99 to 3.64 .0t .301 1.56 0.19 3.53 to 0.70 .6t .20.08 0.22 to 3.66 .6t .50.25 2.05 to 7.76 .2t .50.21 0.65 0.36 to 2.92 1.09 to 3.03 .0t .209 0.72 0.99 1.72 to 1.70 of impaired glucose tolerance in SDB pa- oe oe oe oe 2 Model 1 Model 2 Model 1 Model dana n ohroesoig nonasmtm nld le ntainpolm,sepmain sleep problems, initiation sleep include symptoms Insomnia snoring. bothersome and apnea, ed

ae as icmeec,adcii ie Mode site. clinic and circumference, waist race, tients, but not in insomnia patients. 2 2 2 2 However, a recent meta-analysis (13) .40.03 0.24 nui estvt ( sensitivity Insulin .30.004 1.43 .30.05 0.03 .20.01 0.62 of 10 studies including .100,000 participants found increased risks of the de-

P velopment of type 2 diabetes of 1.57 au 5 CI 95% B value – M,witcrufrne ersinsoe raiielvl,albumin levels, creatinine score, depression circumference, waist BMI, (95% CI 1.25 1.97) and 1.84 (95% CI 1.39–2.43), respectively, for sleep initi- N ation and sleep maintenance problems. ,0)Islnsecretion Insulin 3,007) = 2 2 2 2 2 2 2 2 2 2.452 4.76 0.72 1.45 1.36 0.92 0.21 2.51 3.40 The participants in our study were all $65 years of age, and, as the amount of sleep may decrease with age, even in 2 2 2 2 2 2 2 2 2 2 2 2 subjects without daytime sleepiness .3to 7.63 .7to 4.47 .4to 6.44 .6to 4.86 .9t .209 29.9 0.98 3.22 to 2.79 .5t .007 49.9 0.77 1.60 to 3.05 .2t .402 37.8 0.29 3.64 to 0.52 .6t .701 952.5 49.5 0.14 0.47 to 3.36 .1t .805 2. 7.31 126.1 0.59 3.58 to 6.31 .3t .90.32 42.9 0.89 0.84 to 2.73 1.89 to 2.32 .3t .804 372.3 43.7 0.42 2.48 to 1.03 (29), the causes and correlates of insomnia in the elderly may differ from 2 2 2 2 ,ajse o g,sx ae aia status, marital race, sex, age, for adjusted 2, l .90019. 53t 6. .0 3212.7 83.2 0.008 166.5 to 25.3 95.9 0.001 1.89 .600 698.6 56.9 0.01 0.56 .700 217.0 82.1 0.03 0.37 .800 40.0 0.04 0.18 those in younger populations, possibly explaining differences between study ﬁndings.

P We observed differences in associa- au 5 CI 95% B value tions once speciﬁc insomnia symptoms were analyzed, with one analysis show-

2 ing a negative association of fasting

2.9 glucose levels with sleep maintenance symptoms. This ﬁnding, as well as prior 2 2 2 2 2 research, points to the need to consider 2 11t 0. .16.3 0.41 100.9 to 41.1 . o16000 33.4 0.08 106.0 to 6.2 35t 9001 25.1 0.15 89.0 to 13.5 61t 030.90 40.3 to 46.1 65t 6601 25.1 0.17 96.6 to 16.5 . o9. .930.0 0.09 92.8 to 6.9 each aspect of insomnia separately, as – – – – – 0. .25.64.5 52.76 0.02 105.2 5. .37. 1.3 75.8 0.03 157.2 6500 38.9 0.04 96.5 4. .490.8 0.04 244.9 5100 42.8 0.04 85.1 the health implications of sleep onset, ees hlseo ees rvln ycrilifrto,digit infarction, myocardial prevalent levels, cholesterol levels, sleep maintenance, and early morning

lncst,euain ytlcbodpesr,ueof use pressure, blood systolic education, site, clinic awakenings may differ. Sleep disorders are not constant over a P eac rbes al onn wknns and awakenings, morning early problems, tenance ﬁ

au 5 CI 95% B value lifetime (30), and this is the rst prospective study to account for this by allowing the sleep exposure to change in yearly

2 increments during the follow-up. The 14.0 effect of observed apnea when allowing it to change over the follow-up period

2 appeared to be stronger compared 2 2 2 2 2 2 2 2 06t 1. 0.14 212.3 to 30.6 37t 050.25 90.5 to 23.7 61t 610.34 76.1 to 26.1 75t 010.87 80.1 to 67.5 83t 030.54 30.3 to 58.3 16t 160.26 81.6 to 21.6 29t 300.40 83.0 to 32.9 . o8. 0.10 85.9 to 8.1 . o8. 0.05 85.8 to 0.2 with using the cumulative average, in- – – – 100.6 5. 0.05 150.3 dicating that current or recent sleep dis- 5. 0.02 153.6

m fSBand SDB of oms ruption may be more important than previous/chronic symptoms in the development of type 2 diabetes. The ap- , P parently stronger association of the 0.001 value more recent exposure of observed apnea is a new ﬁnding and needs to be conﬁrmed by further studies. 2056 Sleep and Glucose Metabolism Diabetes Care Volume 38, November 2015

Table 4—Symptoms of SDB and insomnia and 10-year risk of incident type 2 diabetes Model 1 Model 2 Events/person-time (208/29,234) HR 95% CI P value HR 95% CI P value Daytime sleepiness 56/5,016 Time dependent 1.62 1.19–2.21 0.002 1.58 1.15–2.18 0.005 Cumulative average 1.63 1.09–2.42 0.02 1.56 1.03–2.36 0.04 Observed apnea 24/1,626 Time dependent 1.98 1.28–3.05 0.002 1.86 1.20–2.88 0.006 Cumulative average 1.54 0.90–2.64 0.12 1.44 0.84–2.48 0.19 Bothersome snoring 88/10,307 Time dependent 1.30 0.97–1.75 0.08 1.28 0.95–1.72 0.11 Cumulative average 1.36 0.96–1.93 0.09 1.33 0.93–1.90 0.12 SDB symptoms 1 82/10,572 1.37 1.00–1.87 0.05 1.34 0.98–1.84 0.07 2–3 40/3,034 2.12 1.44–3.13 ,0.001 2.00 1.35–2.98 0.001 Linear trend ,0.001 0.001 Sleep initiation problems 41/5,999 Time dependent 1.05 0.74–1.49 0.79 0.99 0.69–1.43 0.96 Cumulative average 1.03 0.69–1.54 0.88 0.94 0.61–1.43 0.77 Sleep maintenance problems 133/18,838 Time dependent 0.94 0.71–1.26 0.69 0.87 0.65–1.17 0.36 Cumulative average 0.92 0.66–1.28 0.61 0.84 0.60–1.18 0.33 Early morning awakenings 68/9,183 Time dependent 1.06 0.79–1.41 0.71 0.99 0.73–1.34 0.95 Cumulative average 0.95 0.68–1.33 0.76 0.87 0.61–1.24 0.43 Insomnia symptoms 1 79/10,240 1.18 0.83–1.69 0.36 1.14 0.80–0.64 0.48 2 49/6,899 1.07 0.72–1.60 0.73 0.95 0.62–1.43 0.79 3 22/3,238 1.13 0.68–1.88 0.63 0.98 0.57–1.67 0.94 4 4/903 0.71 0.25–1.98 0.51 0.57 0.20–1.62 0.29 Linear trend 0.95 0.42 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).

The mechanisms that underlie our secretion, and the repeated measures living alone, and this changed our esti- findings are largely unknown, but some of multiple sleep symptoms, the study mates minimally. However, objective have been suggested. Sleep deprivation, also has important limitations. polysomnography data available in a caused by SDB or insomnia, has been We used self-reported measures of subset indicated that the symptoms an- shown to increase the activity of orexin sleep,which,whilesubjective,have alyzed discriminated between groups neurons that may act as a link between the advantage of ready clinical applica- with and without SDB symptoms. Fur- SDB and the metabolic effects (31). bility at low cost. The participants were thermore, because misclassification be- Sleep deprivation can also cause in- asked whether anyone had observed tween these symptoms and sleep apnea creased sympathetic nervous activity, them having episodes where they stop- is unlikely to be related to glucose or increasing the released levels of cortisol ped breathing for a while and then insulin levels, our results may underes- and catecholamines, leading to reduced snorted or snored loudly or complained timate the true associations of sleep ap- insulin sensitivity and glucose tolerance about loud snoring. Participants living nea with hyperglycemia and insulin (32,33). The corresponding increase in alone may not have this knowledge resistance. The difference in sleep la- insulin secretion may lead to b-cell ex- and may have reported “no” rather tency between those reporting sleep ini- haustion and impaired secretory capac- than the option offered of “Idon’t tiation problems and those who did not ity over time, resulting in diabetes. know.” Although objective measures of was only 2 min, but, as insomnia is de- SDB (i.e., polysomnography results) ex- fined as a subjective feeling of having Limitations ist, subjectively reported breath cessa- difficulties falling asleep, remaining Despite its clear strengths, which in- tion is among the best clinical predictors asleep, or receiving restorative sleep clude the population-based design in a of sleep apnea (34), and self-reported lasting at least 1 month and causing day- high-risk older population, the wide snoring is a sensitive but less specific time impairment (4); thus, such problems range of covariates, the OGTT-based measure (35). In a sensitivity analysis, are not ideally evaluated by polysom- measures of insulin sensitivity and we restricted the analysis to those not nography (36). care.diabetesjournals.org Strand and Associates 2057

Information about sleep duration was N01-HC-85081, N01-HC-85082, N01-HC-85083, 13. Cappuccio FP, D’Elia L, Strazzullo P, Miller not available in CHS. SDB and insomnia and N01-HC-85086 and grant U01-HL-080295, MA. Quantity and quality of sleep and incidence are different conditions than short sleep with an additional contribution from the National of type 2 diabetes: a systematic review and Institute of Neurological Disorders and Stroke. meta-analysis. Diabetes Care 2010;33:414–420 duration (37), and people with insomnia Additional support was provided by National In- 14. Al-Delaimy WK, Manson JE, Willett WC, symptoms could have normal or long stitute on Aging grant R01-AG-023629. Stampfer MJ, Hu FB. Snoring as a risk factor durations of sleep (38). Also, some peo- Duality of Interest. No potential conflicts of for type II diabetes mellitus: a prospective ple with short sleep duration may not interest relevant to this article were reported. study. Am J Epidemiol 2002;155:387–393 Author Contributions. L.B.S. and K.J.M. con- 15. Tell GS, Fried LP, Hermanson B, Manolio TA, have insomnia symptoms or daytime ceptualized and designed the study, analyzed Newman AB, Borhani NO. Recruitment of adults sleepiness, as individuals vary substan- the data, interpreted the results, and wrote the 65 years and older as participants in the Cardio- tially in the duration of sleep that is article. M.C., M.L.B., L.D., R.C.K., D.S.S., J.A.R., vascular Health Study. Ann Epidemiol 1993;3: needed for restoration (39). S.R., S.R.P., and I.J. interpreted the data and 358–366 Observational studies inherently limit reviewed and edited the article. L.B.S. is the 16. Geffken DF, Cushman M, Burke GL, Polak JF, guarantor of this work and, as such, had full Sakkinen PA, Tracy RP. Association between causal inference. Although we adjusted access to all the data in the study and takes physical activity and markers of inflammation for several potential confounders in our responsibilityfortheintegrityof the dataandthe in a healthy elderly population. Am J Epidemiol multivariable analyses, we cannot ex- accuracy of the data analysis. 2001;153:242–250 clude the possibility of uncontrolled 17. Radloff LS. The CES-D scale: a self-report confounding behind the observed associ- References depression scale for research in the general population. Appl Psychol Meas 1977;1:385–401 ations. However, any remaining con- 1. Strohl KP, Novak RD, Singer W, et al. Insulin levels, blood pressure and sleep apnea. Sleep 18. Mittelmark MB, Psaty BM, Rautaharju PM, founder that is potentially able to – et al. Prevalence of cardiovascular diseases fl 1994;17:614 618 in uence our results would need to be 2. Tiihonen M, Partinen M, Narv¨ anen¨ S. The se- among older adults. The Cardiovascular Health – strongly associated with both sleep symp- verity of obstructive sleep apnoea is associated Study. Am J Epidemiol 1993;137:311 317 toms and glucose metabolism, and gen- with insulin resistance. J Sleep Res 1993;2:56–61 19. Wisniewski JV. Geriatric impairment and 3. Seicean S, Kirchner HL, Gottlieb DJ, et al. disability: the Cardiovascular Health Study. J erally be unrelated to the factors included Am Geriatr Soc 2011;59:554–555 in our models. Several small interven- Sleep-disordered breathing and impaired glucose metabolism in normal-weight and 20. Psaty BM, Lee M, Savage PJ, Rutan GH, tional studies (26,40) suggest that sleep overweight/obese individuals: the Sleep German PS, Lyles M; The Cardiovascular Health apnea therapy may improve insulin resis- Heart Health Study. Diabetes Care 2008;31: Study Collaborative Research Group. Assessing tance, supporting a causal relationship 1001–1006 the use of medications in the elderly: methods 4. American Psychiatric Association. Diagnostic and initial experience in the Cardiovascular Health between SDB and insulin resistance. Of – and Statistical Manual of Mental Disorders, fifth Study. J Clin Epidemiol 1992;45:683 692 note, these interventional studies have ed (DSM-5). Washington, DC, American Psychi- 21. Quan SF, Howard BV, Iber C, et al. The Sleep in general excluded older individuals. atric Association, 2013. Heart Health Study: design, rationale, and 5. Keckeis M, Lattova Z, Maurovich-Horvat E, methods. Sleep 1997;20:1077–1085 Summary et al. Impaired glucose tolerance in sleep disor- 22. Cushman M, Cornell ES, Howard PR, Bovill In this population-based study of older ders. PLoS One 2010;5:e9444 EG, Tracy RP. Laboratory methods and quality adults, having observed apnea, bother- 6. Knutson KL, Van Cauter E, Zee P, Liu K, assurance in the Cardiovascular Health Study. – some snoring, and daytime sleepiness Lauderdale DS. Cross-sectional associations be- Clin Chem 1995;41:264 270 23. Arnold AM, Kronmal RA. Multiple imputa- were associated with impaired glucose tween measures of sleep and markers of glucose metabolism among subjects with and tion of baseline data in the Cardiovascular metabolism, insulin resistance, and without diabetes: the Coronary Artery Risk De- Health Study. Am J Epidemiol 2003;157:74–84 risk of incident type 2 diabetes. For ob- velopment in Young Adults (CARDIA) Sleep 24. Janiszewski PM, Janssen I, Ross R. Does served apnea, more recent exposure Study. Diabetes Care 2011;34:1171–1176 waist circumference predict diabetes and car- tended to be more strongly associated 7. Punjabi NM, Shahar E, Redline S, Gottlieb DJ, diovascular disease beyond commonly evaluated cardiometabolic risk factors? Diabetes with subsequent risk of type 2 diabe- Givelber R, Resnick HE; Sleep Heart Health Study Investigators. Sleep-disordered breathing, glu- Care 2007;30:3105–3109 tes than chronic exposure. The associa- cose intolerance, and insulin resistance: the 25. Pallayova M, Steele KE, Magnuson TH, et al. tions persisted after adjustment for Sleep Heart Health Study. Am J Epidemiol Sleep apnea predicts distinct alterations in glu- total and central adiposity, suggesting 2004;160:521–530 cose homeostasis and biomarkers in obese that SDB may impair glucose metabo- 8. Gutt M, Davis CL, Spitzer SB, et al. Validation adults with normal and impaired glucose me- of the insulin sensitivity index (ISI(0,120)): com- tabolism. Cardiovasc Diabetol 2010;9:83 lism independent of body fat. In con- parison with other measures. Diabetes Res Clin 26.WeinstockTG,WangX,RueschmanM, trast to previous studies, we found no Pract 2000;47:177–184 et al. A controlled trial of CPAP therapy on met- consistent association between the 9. Stumvoll M, Mitrakou A, Pimenta W, et al. abolic control in individuals with impaired glu- insomnia symptoms and glucose me- Use of the oral glucose tolerance test to assess cose tolerance and sleep apnea. Sleep 2012;35: – tabolism or incident type 2 diabetes. insulin release and insulin sensitivity. Diabetes 617 625B Care 2000;23:295–301 27. Wang X, Bi Y, Zhang Q, Pan F. Obstructive Further studies are needed to deter- 10. West SD, Nicoll DJ, Stradling JR. Prevalence sleep apnoea and the risk of type 2 diabetes: mine whether insomnia symptoms of obstructive sleep apnoea in men with type 2 a meta-analysis of prospective cohort studies. affect the risk of incident type 2 diabe- diabetes. Thorax 2006;61:945–950 Respirology 2013;18:140–146 tes differently in older adults than in 11. Vgontzas AN, Liao D, Pejovic S, Calhoun S, 28. Muraki I, Tanigawa T, Yamagishi K, et al. younger adults. Karataraki M, Bixler EO. Insomnia with objective Nocturnal intermittent hypoxia and the devel- short sleep duration is associated with type 2 opment of type 2 diabetes: the Circulatory Risk diabetes: a population-based study. Diabetes in Communities Study (CIRCS). Diabetologia Care 2009;32:1980–1985 2010;53:481–488 Funding. This research was supported by Na- 12. Plantinga L, Rao MN, Schillinger D. Preva- 29. Bixler EO, Vgontzas AN, Lin H-M, Calhoun tional Heart, Lung, and Blood Institute contracts lence of self-reported sleep problems among SL, Vela-Bueno A, Kales A. Excessive daytime HHSN-268201200036C, HHSN-268200800007C, people with diabetes in the United States, sleepiness in a general population sample: the N01-HC-55222, N01-HC-85079, N01-HC-85080, 2005-2008. Prev Chronic Dis 2012;9:E76 role of sleep apnea, age, obesity, diabetes, and 2058 Sleep and Glucose Metabolism Diabetes Care Volume 38, November 2015

depression. J Clin Endocrinol Metab 2005;90: Catecholamines and blood pressure in obstructive duration and insomnia. Arch Gen Psychiatry 4510–4515 sleep apnea syndrome. Chest 1993;103:722–727 2002;59:131–136 30. Lindberg E, Taube A, Janson C, Gislason T, 34. Vgontzas AN, Tan TL, Bixler EO, Martin LF, 38. Vgontzas AN, Liao D, Bixler EO, Chrousos Svardsudd¨ K, Boman G. A 10-year follow-up Shubert D, Kales A. Sleep apnea and sleep dis- GP, Vela-Bueno A. Insomnia with objective of snoring in men. Chest 1998;114:1048– ruption in obese patients. Arch Intern Med short sleep duration is associated with a 1055 1994;154:1705–1711 high risk for hypertension. Sleep 2009;32: 31. Spiegel K, Knutson K, Leproult R, Tasali E, 35. Jennum P, Sjøl A. Epidemiology of snoring 491–497 Van Cauter E. Sleep loss: a novel risk factor for and obstructive sleep apnoea in a Danish pop- 39. Van Dongen HP, Vitellaro KM, Dinges DF. insulin resistance and Type 2 diabetes. J Appl ulation, age 30-60. J Sleep Res 1992;1:240–244 Individual differences in adult human sleep Physiol (1985) 2005;99:2008–2019 36. Littner M, Hirshkowitz M, Kramer M, et al.; and wakefulness: leitmotif for a research 32. Knutson KL, Van Cauter E. Associations be- American Academy of Sleep Medicine; Stand- agenda. Sleep 2005;28:479–496 tween sleep loss and increased risk of obesity ards of Practice Committe. Practice parameters 40. Lam JCM, Lam B, Yao TJ, et al. A random- and diabetes. Ann N Y Acad Sci 2008;1129:287– for using polysomnography to evaluate insom- ised controlled trial of nasal continuous posi- 304 nia: an update. Sleep 2003;26:754–760 tive airway pressure on insulin sensitivity in 33. Marrone O, Riccobono L, Salvaggio A, 37. Kripke DF, Garﬁnkel L, Wingard DL, Klauber obstructive sleep apnoea. Eur Respir J 2010; Mirabella A, Bonanno A, Bonsignore MR. MR, Marler MR. Mortality associated with sleep 35:138–145