Plasma Concentration of Caspase-8 Is Associated With Short Sleep Duration and the Risk of Incident Diabetes Mellitus

The Journal of Clinical Endocrinology & Metabolism, Apr 2018

The biological mechanism for the association between sleep duration and incident diabetes mellitus (DM) is unclear. Sleep duration and caspase-8, a marker of apoptotic activity, have both been implicated in β-cell function.

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Plasma Concentration of Caspase-8 Is Associated With Short Sleep Duration and the Risk of Incident Diabetes Mellitus

J Clin Endocrinol Metab, April Plasma Concentration of Caspase-8 Is Associated With Short Sleep Duration and the Risk of Incident Diabetes Mellitus Thomas Svensson 0 1 2 Akiko Kishi Svensson 0 3 4 Mariusz Kitlinski 5 Peter Almgren 0 Gunnar Engstro? m 0 Jan Nilsson 0 Marju Orho-Melander 0 Peter M. Nilsson 0 Olle Melander 0 6 Main Outcomes: Incident DM. 0 Department of Clinical Sciences, Lund University, Sk a ?ne University Hospital , 20502 Malm o ? , Sweden 1 Center of Innovation, University of Tokyo , Tokyo 113-8656 , Japan 2 Department of Neuropsychiatry, Keio University School of Medicine , Tokyo 160-8582 , Japan 3 Department of Diabetes and Metabolic Diseases, University of Tokyo , Tokyo 113-0033 , Japan 4 Clinical Research Support Center, University of Tokyo Hospital , Tokyo 113-0033 , Japan 5 Department of Cardiology, Sk a ?ne University Hospital , 20502 Malm o ? , Sweden 6 Department of Internal Medicine, Sk a ?ne University Hospital , 20502 Malm o ? , Sweden Context: The biological mechanism for the association between sleep duration and incident diabetes mellitus (DM) is unclear. Sleep duration and caspase-8, a marker of apoptotic activity, have both been implicated in b-cell function. Objective: To investigate the associations between sleep duration and plasma caspase-8 and incident DM, respectively. Setting: The Malmo? Diet and Cancer (MDC) Study is a population-based, prospective study run in the city of Malmo? , Sweden. Participants: A total of 4023 individuals from the MDC Study aged 45 to 68 years at baseline without a history of prevalent DM and with information on habitual sleep duration. Results: Mean follow-up time was 17.8 years. Sleep duration was the only behavioral variable significantly associated with plasma caspase-8. Plasma caspase-8 was significantly associated with incident DM per standard deviation of its transformed continuous form [hazard ratio (HR) = 1.24; 95% confidence interval (CI), 1.13 to 1.36] and when dichotomized into high (quartile 4) (HR = 1.44; 95% CI, 1.19 to 1.74) compared with low (quartiles 1 to 3) concentrations. Caspase-8 interacted with sleep duration; compared with individuals who had 7 to 8 hours of sleep and low plasma caspase-8, those with high plasma caspase-8 and sleep duration ,6 hours (HR = 3.54; 95% CI, 2.12 to 5.90), 6 to 7 hours (HR = 1.81; 95% CI, 1.24 to 2.65), and 8 to 9 hours (HR = 1.54; 95% CI, 1.09 to 2.18) were at significantly increased risks of incident DM. Conclusions: Sleep duration is associated with plasma caspase-8. Caspase-8 independently predicts DM years before disease onset and modifies the effect of sleep duration on incident DM. Future studies should investigate if change of sleep duration modifies plasma concentrations of caspase-8. (J Clin Endocrinol Metab 103: 1592-1600, 2018) - *These authors contributed equally to this study. Abbreviations: BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; HDL, high-density lipoprotein; HR, hazard ratio; LDL, low-density lipoprotein; MDC, Malmo? Diet and Cancer; MDC-CC, Malmo? Diet and Cancer Cardiovascular Cohort; SD, standard deviation; TG, triglyceride. Sfactor for incident diabetes mellitus (DM), with leep duration is a suggested novel behavioral risk prospective studies reporting that both short ( 1?8 ) and long sleep duration ( 5?8 ) are associated with incident DM. The explanatory mechanism for the found associations is yet to be established. Aberrant sleeping times may lead to or be an indicator of circadian misalignment, which in turn results in significantly decreased plasma insulin secretion ( 9 ). Disrupted circadian rhythms have therefore been suggested to possibly result in deficient pancreatic b-cell function and increased susceptibility to type 2 DM ( 10 ). Sleep duration is suggested to regulate tumor necrosis factor a ( 11 ), and b-cell apoptosis may be a consequence of activated cysteinyl aspartic acid?protease-8 (caspase-8) ( 12 ), a key enzyme in the tumor necrosis factor receptor pathway ( 13, 14 ). The current body of knowledge as outlined above thus proposes a potential pathway between aberrant sleeping times, including too short and too long sleep duration, activation of caspase-8, and subsequent incident DM. It also indicates a potential for caspase-8 to be used in the context of DM prognosis and diagnosis. Anti?caspase-8 antibodies are found in patients with type 1 DM and are associated with ketoacidosis ( 15 ). Moreover, concentrations of caspase-8 can be measured in human plasma using validated methods ( 16, 17 ), and circulating plasma levels of caspase-8 are a marker of apoptotic activity (18). This allows not only for the investigation of a potential novel biomarker of incident DM but also may provide an explanatory mechanism for the yet unexplained association between short/long sleep duration and incident DM. The primary objective of this study is thus to elucidate ( 1 ) whether sleep duration is associated with plasma concentrations of caspase-8, ( 2 ) whether measured plasma concentrations of caspase-8 are associated with incident DM, and ( 3 ) whether caspase-8 modifies the known association between sleep duration and incident DM. We hypothesize, based on the evidence available to date, that short sleep duration will be associated with increased plasma levels of caspase-8, which in turn will be associated with incident DM and act as an effect modifier for the association between sleep duration and incident DM. Materials and Methods The Malm o? Diet and Cancer (MDC) Study is a population-based, prospective study in the city of Malmo? , Sweden. Details of the study are described elsewhere ( 19 ); in brief, between 1991 and 1996, men and women aged 45 to 73 years were randomly selected and recruited for a baseline examination. Participants answered a detailed questionnaire on heredity, socioeconomic variables, social network, occupation, physical activity, alcohol consumption, smoking, diseases, and medication and provided anthropometric data and blood samples. From the MDC Study, 6103 individuals were randomly selected between 1991 and 1994 to participate in the MDC Cardiovascular Cohort (MDC-CC) with the purpose of studying the epidemiology of carotid artery disease ( 20 ). Of the 6103 MDC-CC participants, 4685 had measured plasma levels of caspase-8. Those with prevalent DM (n = 183) or a fasting blood glucose concentration $6.1 mmol/L (n = 211) at baseline, as well as those who had provided incomplete information on sleep duration (n = 25), were excluded from the current study. Moreover, participants were excluded if their measured level of caspase-8 (n = 2) and their sleep duration (n = 11) represented outlier values of more than three interquartile ranges below or above the first and fourth quartiles, respectively. In addition, individuals who did not have data on kidney function, as measured by cystatin C (n = 230), were also excluded. A total of 4023 individuals were included in the analyses. All participants were followed from starting point until 31 December 2012, with person-years calculated from the starting point to incident DM, date of death, or end of follow-up period, whichever came first. The MDC Study was approved by the ethics committee at Lund University, and all participants provided written informed consent. Caspase-8 Caspase-8 was measured in stored fasting plasma specimens immediately frozen to 280?C at the MDC-CC baseline examination. Plasma concentrations of caspase-8 were quantified using a validated high-specificity immunoassay, the proximity extension assay, which has been described in detail elsewhere ( 16, 17 ). Concentrations of caspase-8 were provided on a logarithmic (log2) scale. The distribution of log2 caspase-8 was positively skewed and transformed with the square root throughout. Hazard ratios (HRs) of transformed continuous caspase-8 are expressed per 1 standard deviation (SD) in the Cox proportional hazards models. To allow for the creation of a categorical variable, the transformed caspase-8 was divided into quartiles with incidence rates of DM calculated for each quartile. A subsequent binary cutoff at quartile 4 was chosen on the basis of higher DM incidence rates in this particular group compared with quartiles 1 to 3, a result that was confirmed by KaplanMeier survival curves, which demonstrated similar survival probability for individuals in quartiles 1 to 3 but much lower probability for those in quartile 4 (data not shown). Sleep duration Habitual sleep duration was assessed through two open questions asking participants how long they slept on weekdays and weekends, respectively. The two questions were formulated as follows: ( 1 ) ?How many hours do you usually sleep per night during a typical week (Monday to Friday)?? and ( 2 ) ?How many hours do you usually sleep per night during a typical weekend (Saturday to Sunday)?? A weighted average sleep duration [((weekday 3 5) + (weekend 3 2))/7] was calculated for all participants, thereby allowing the subsequent construction of a categorical variable representing five sleep duration groups (,6 hours, 6 to 7 hours, 7 to 8 hours, 8 to 9 hours, and $9 hours). Short and long sleep duration were defined as ,6 hours and $9 hours, respectively. The reference category (7 to 8 hours) was chosen on the basis of the lowest incidence rate of DM in this particular group. Incident DM The process of DM end-point retrieval has been described in detail elsewhere ( 21 ). In brief, individuals with incident DM were identified through linkage of a 10-digit national personal identification number with six local and national registers: the Malm o? HbA1c register, the Regional Diabetes 2000 register of the Scania region ( 22 ), the Swedish National Diabetes Register ( 23 ), the Swedish National Inpatient Register ( 24 ), the Swedish Cause of Death Register ( 25 ), and the Swedish Prescribed Drug Register ( 26 ). In addition to the mentioned registers, individuals with incident DM could also be captured by having a fasting plasma glucose concentration $7 mmol/L or a 120-minute plasma glucose value of .11.0 mmol/L in subpopulations of the MDC participating in a MDC reexamination ( 27 ) or the Malmo? Preventive Project reexamination ( 28 ). Incident DM was defined as new-onset DM in individuals without prevalent DM at the MDC baseline examination. Prevalent DM was defined as having a measured fasting blood glucose $6.1 mmol/L (corresponding to fasting plasma glucose concentration $7 mmol/L) at the MDC baseline examination, a self-reported history of physician-diagnosed DM, the use of DM medication according to the MDC baseline questionnaire, or being diagnosed and registered in any of the local or national diabetes registries as previously described ( 29 ). Statistical analyses Multilinear regression with stepwise backward elimination using the likelihood ratio test (retention: P , 0.05) was used to determine significant predictors of caspase-8. Each model was tested against the preceding model with the following variables entered into the first model: age, sex, cystatin C, education, physical activity, smoking, alcohol intake, shift work, waist circumference, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TGs), fasting blood glucose, hypertension, sleep quality, and sleep duration. Kaplan-Meier survival curves were created for incident DM according to the plasma concentrations (low and high, respectively) of caspase-8. Cox proportional hazards regression was used to determine HRs and confidence intervals (CIs) for the association between sleep duration, caspase-8, and incident DM. All statistical models were stratified by categories of body mass index (BMI) (,18.5 kg/m2, 18.5 to 24.9 kg/m2, 25.0 to 29.9 kg/m2, or $30.0 kg/m2) using the Stata option ?strata()? to account for different baseline hazards across BMI categories. The minimally adjusted model (model 1) was adjusted for age (continuous), sex, cystatin C (continuous in mg/L), and education (elementary school or higher than elementary school) at the starting point; model 2 was also adjusted for physical activity, smoking (never, past, and current smoker: ,20 cigarettes/d or $20 cigarettes/d), alcohol consumption (none, 0.1 to 1.4, 1.5 to 6.5, 6.6 to 14.1, or $14.2 g ethanol/d), and shift work (yes/no); model 3 was also adjusted for waist circumference (continuous in centimeters), LDL, HDL, TGs, fasting blood glucose, and hypertension. Sleep quality was added as a covariate in the final model (model 4). No sexspecific stratification was done as there were no significant interactions between sex and caspase-8 or sleep duration, respectively. The HR of caspase-8 in analyses of the continuous variable is expressed in terms of incremental increases per SD of the transformed variable. Physical activity was defined as leisure time physical activity based on 18 items adapted from the Minnesota Leisure Time Physical Activity instrument and has been described in detail elsewhere ( 30 ). Hypertension was defined as systolic blood pressure $140 mm Hg, diastolic blood pressure $90 mm Hg, or use of antihypertensive medication. LDL, HDL, TGs, and fasting blood glucose were all treated as binary variables with cutoff points at the median. Missing values for any covariate were addressed through the construction of dummy variables. The P value for the interaction between sleep duration and caspase-8 was determined using the likelihood ratio test where the final multivariable model (model 4), which included an interaction term between sleep duration and caspase-8, was compared with a model without this term. Global tests for proportionality were conducted for the final multivariable models and did not reveal any significant deviation from the proportional hazards assumption. All statistical analyses were performed using Stata version 13.1 SE (StataCorp LP, College Station, TX). The significance level was set as P , 0.05. Data-sharing statement Due to ethical and legal restrictions related to the Swedish Biobanks in Medical Care Act (2002:297) and the Personal Data Act (1998:204), data are available upon request from the data access group of MDC Study by contacting Anders Dahlin (). Role of the funding source The sponsors had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Results Table 1 shows baseline characteristics of participants according to low and high levels of plasma concentrations of caspase-8. Individuals with high levels of caspase8 were significantly older, were more likely to be men, had higher plasma concentrations of cystatin C, and had a larger waist circumference, a higher prevalence of overweight/obesity, hypertension, and higher LDL, TGs, and fasting blood glucose. They also had lower education, lower HDL, and both lower and higher physical activity levels, in addition to both shorter (,6 hours) and longer ($9 hours) sleep duration. The multilinear regression with stepwise backward elimination showed that age, male sex, cystatin C, waist circumference, LDL, fasting blood glucose, and short sleep duration were significantly associated with plasma concentrations of caspase-8 (Table 2). There were a total of 494 cases of incident DM during 71,692 person-years of follow-up. Mean follow-up time was 17.8 years. Kaplan-Meier survival probability curves for the association between dichotomized caspase8 (high and low plasma concentrations) and incident DM are depicted in Fig. 1. In the final multivariable model (model 4), high plasma concentrations of caspase-8 were Baseline Characteristics According to Plasma Concentrations of Caspase-8 (Dichotomized at Caspase-8 Abbreviation: NS, nonsignificant. ax2 test for categorical variables, analysis of variance for continuous variables. significantly associated with incident DM when considering the per 1 SD increase of caspase-8 (HR = 1.24; 95% CI, 1.13 to 1.36) and as a binary variable (HR = 1.44; 95% CI, 1.19 to 1.74) (Table 3). The interaction between sleep duration and caspase-8 significantly improved prediction of incident DM (P for interaction = 0.007) with the effect of short sleep duration on incident DM modified by level of caspase-8 (Table 4 and Fig. 2). Compared with a reference category of individuals who had 7 to 8 hours of sleep with a low plasma concentration of caspase-8, those with high plasma concentrations of caspase-8 and a sleep duration of ,6 hours (HR = 3.54; 95% CI, 2.12 to 5.90), 6 to 7 hours (HR = 1.81; 95% CI, 1.24 to 2.65), and 8 to 9 hours (HR = 1.54; 95% CI, 1.09 to 2.18) were at significantly increased risk of incident DM. Discussion This study presents three major, and to the best of our knowledge, novel findings: first, short sleep duration is directly associated with apoptotic activity, as quantified through elevated plasma levels of caspase-8; second, high plasma concentrations of caspase-8 as well as incremental increases per SD of caspase-8 are significantly associated with incident DM; and third, a high plasma concentration of caspase-8 significantly interacts with sleep duration, thus acting as an effect modifier for the association between sleep duration and incident DM. Taken together, our results indicate that caspase-8 could be a novel biomarker for incident DM and a possible explanatory biological mechanism for the association between sleep duration and incident DM. Caspase-8 initiates the dissemination of apoptotic signals ( 31 ) and is a key enzyme in the Fas-mediated apoptotic pathway ( 13 ). Moreover, caspase-8 has the potential to be used as a clinical biomarker; it can be readily quantified in plasma using a high-specificity proximity extension assay ( 16, 17 ), and circulating plasma levels of caspase-8 are a marker of apoptotic activity and significantly associated with coronary events (18). In our study we demonstrated that seven variables were predictive of elevated levels of plasma caspase-8: higher age, male sex, reduced kidney function (measured through cystatin C), high LDL cholesterol, high fasting blood glucose, increased waist circumference, and short sleep duration. In addition to their cross-sectional association with caspase-8, each of these variables acts as an independent risk factor not only for DM but also for cardiovascular disease. However, when including the mentioned covariates in our multivariable adjusted Cox model, the variables account for merely 7% of the risk for the association between high plasma concentrations of caspase-8 and incident DM. This indicates that the association between caspase-8 and DM is independent from conventional DM risk factors and highlights the possibility that caspase-8 could be a marker specific to the pathogenesis of DM. Although the exact mechanism through which this occurs is still unclear, experimental studies to date have discussed caspase-8 in the context of maintaining b-cell mass, regulating insulin secretion, and sustaining b-cell apoptosis ( 32 ). This is compatible with the finding that plasma levels of caspase-8 may represent an increased rate of apoptosis ( 18 ). It further suggests that caspase-8 could potentially be related to b-cell dysfunction years before disease onset and subsequently be indicative of DM susceptibility. Moreover, it offers an explanatory mechanism to the association between caspase-8 and coronary events ( 18 ). Sleep duration is a DM risk factor that has garnered increased attention over the past years, with several prospective studies showing that both short ( 1?8 ) and long ( 5?8 ) sleep duration are associated with incident DM. The biological mechanism responsible for these associations is unclear, although it has been suggested that reduced sleep duration may lead to decreased leptin and increased ghrelin ( 33 ), which in turn may stimulate appetite and lead to increased BMI. In our study, the adjustment for waist circumference, HDL, LDL, TGs, fasting blood glucose, and hypertension attenuated the significant association between short sleep duration (,6 hours) and incident DM, indicating that they may in fact mediate the association between short sleep duration and disease development. Conversely, the association between long sleep duration and DM has been considered due to reverse causation bias ( 2 ), as well as comorbidity and residual confounding ( 5 ). Our findings, however, indicate that sleep duration is a risk factor for incident DM only in Bold values denote statistically significant results. ?No.? is the number of participants in the respective groups. ?Events? is the number of individuals who developed diabetes. aThe continuous variable is expressed as the HR and 95% CI for the incremental increase per SD of the square root?transformed variable. bModel 1 is stratified by BMI category and adjusted for sex, age, cystatin C, and education. cP , 0.001. dP , 0.05. eModel 2 is also adjusted for physical activity, smoking, alcohol consumption, and shift work. fModel 3 is also adjusted for waist circumference, LDL levels, HDL levels, TG levels, fasting blood glucose levels, and hypertension. gModel 4 is also adjusted for sleep quality. Bold values denote statistically significant results. aThe multivariable models are stratified by BMI category and adjusted for age, sex, cystatin C, education, physical activity, smoking, alcohol consumption, shift work, waist circumference, LDL, HDL, TGs, fasting blood glucose, hypertension, and sleep quality. bP , 0.001. cP , 0.01. dP , 0.05. individuals with high plasma concentrations of caspase8. Individuals with short sleep duration and high plasma concentrations of caspase-8 had a 3.5-fold increased risk of incident DM, an effect size greater than that of elevated fasting blood glucose (HR = 3.1) in this study. We are thus prompted to suggest that caspase-8 should be considered an effect modifier and a biomarker that could offer the unique potential to be used for DM risk assessment in the context of a specific modifiable behavioral risk factor. Moreover, short sleep duration was the only behavioral risk factor associated with elevated plasma concentrations of caspase-8, and when considering sleep duration as a continuous variable, there was a highly significant inverse linear association between sleep duration and caspase-8. It is therefore possible that behavioral interventions aiming to normalize sleep duration could be important in those with high plasma concentrations of caspase-8. Additional studies that would allow for replication of our results are thus highly warranted, and an important question for future studies to address is whether elevated plasma concentrations of caspase-8 can be reduced through sleep interventions. This study has a few limitations: first, sleep was assessed through self-reported questionnaires. However, given the nature and size of our study, this is the only feasible way of gathering data. In addition, self-reported sleep duration may lead to an overestimation of sleep duration with any nondifferential misclassification resulting in a subsequent underestimation of our study findings. Second, generalizability of results to other populations may be limited, especially in the context of using a novel biomarker such as caspase-8. Third, it is possible that caspase-8 is a marker of the consequences of obstructive sleep apnea. Direct information on obstructive sleep apnea is not available in the MDC Study, but we have tried to account for this by adjusting for sleep quality and by stratifying our analyses on BMI to consider different baseline hazards across BMI categories. Finally, although it cannot be established how or why caspase-8, an intracellular enzyme, would be found in plasma, it is conceivable that caspase-8 is suspended in plasma following its release from blood cells, thus allowing quantification using the validated method described. Despite such limitations, this study has a number of strengths. First, incident DM was established using nationwide registers with very high accuracy. Second, the MDC questionnaire asks about habitual sleep duration, which would be the question of choice if sleep duration was assessed by health care professionals. Finally, we have used a population highly representative of the Swedish general population and adjusted for a large number of covariates associated with incident DM. In summary, we have demonstrated for the first time, to our knowledge, that ( 1 ) short sleep duration is associated with increased apoptotic activity as measured through plasma concentrations of caspase-8, ( 2 ) plasma caspase-8 is independently associated with a significantly increased risk of incident DM many years before disease onset, and ( 3 ) this effect is amplified in combination with short sleep duration, a modifiable risk behavior for DM. Acknowledgments Financial Support: O.M. was supported by the European Research Council (StG-282255), the Swedish Heart and Lung Foundation, Swedish Research Council, Novo Nordisk Foundation, Knut and Alice Wallenberg Foundation, G o?ran Gustafsson Foundation, Sk a?ne University Hospital donation funds, Medical Faculty at Lund University, governmental funding of clinical research within the national health services, Albert Pa? hlsson Research Foundation, and Region Sk a?ne. Author Contributions: T.S. and A.K.S. conceived and designed the study, analyzed and interpreted data, drafted the manuscript, and gave final approval of the submitted manuscript. O.M. conceived and designed the study, interpreted data, critically revised the manuscript for important intellectual content, and gave final approval of the submitted manuscript. M.K., P.A., G.E., J.N., M.O.-M., and P.M.N. interpreted data, critically revised the manuscript for important intellectual content, and gave final approval of the submitted manuscript. T.S. and O.M. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Correspondence and Reprint Requests: Thomas Svensson, MD, PhD, Department of Clinical Sciences, Lund University, Sk a?ne University Hospital, CRC, Jan Waldenstro? ms gata 35, 20502 Malm o?, Sweden. E-mail: . Disclosure Summary: The authors have nothing to disclose. Svensson et al 1. Mallon L , Broman JE , Hetta J . High incidence of diabetes in men with sleep complaints or short sleep duration: a 12-year follow-up study of a middle-aged population . Diabetes Care . 2005 ; 28 ( 11 ): 2762 - 2767 . 2. Beihl DA , Liese AD , Haffner SM . 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Svensson, Thomas, Svensson, Akiko Kishi, Kitlinski, Mariusz, Almgren, Peter, Engström, Gunnar, Nilsson, Jan, Orho-Melander, Marju, Nilsson, Peter M, Melander, Olle. Plasma Concentration of Caspase-8 Is Associated With Short Sleep Duration and the Risk of Incident Diabetes Mellitus, The Journal of Clinical Endocrinology & Metabolism, 2018, 1592-1600, DOI: 10.1210/jc.2017-02374