ORIGINAL RESEARCH published: 01 November 2019 doi: 10.3389/fendo.2019.00752 Sympathetic Hyperactivity and Sleep Disorders in Individuals With Type 2 Diabetes Carolina López-Cano 1 , Liliana Gutiérrez-Carrasquilla 1 , Enric Sánchez 1 , Jessica González 2,3 , Andree Yeramian 1 , Raquel Martí 1 , Marta Hernández 1 , Gonzalo Cao 4 , Mercè Ribelles 5 , Xavier Gómez 6 , Silvia Barril 2,3 , Ferran Barbé 2,3 , Cristina Hernández 7,8 , Rafael Simó 7,8 and Albert Lecube 1,8* 1 Endocrinology and Nutrition Department, Institut de Recerca Biomèdica de Lleida (IRBLleida), Hospital Universitari Arnau de Vilanova, Obesity, Diabetes and Metabolism Research Group (ODIM), Universitat de Lleida (UdL), Lleida, Spain, 2 Respiratory Department, Institut de Recerca Biomèdica de Lleida (IRBLleida), Hospital Universitari Arnau de Vilanova-Santa María, Translational Research in Respiratory Medicine, Universitat de Lleida (UdL), Lleida, Spain, 3 Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain, 4 Section of Hormones, Clinic Laboratory, Hospital Universitari Arnau de Vilanova, Universitat de Lleida (UdL), Lleida, Spain, 5 Clinic Laboratory, Hospital Universitari Arnau de Vilanova, Universitat de Lleida (UdL), Lleida, Spain, 6 Clinic Laboratory, Department of Laboratory Medicine, Hospital Universitari Arnau de Vilanova, Universitat de Lleida (UdL), Lleida, Spain, 7 Diabetes and Metabolism Research Unit, Endocrinology and Nutrition Department, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain, 8 Centro de Investigación en Red en Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain Edited by: Gaetano Santulli, Introduction: Many studies on the impact of type 2 diabetes mellitus (T2DM) on Columbia University, United States sleep breathing have shown a higher prevalence and severity of sleep apnea-hypopnea Reviewed by: syndrome (SAHS) in those with T2DM. Moreover, an increased activity of the sympathetic Jan Brož, Charles University, Czechia nervous system has been described in both pathologies. This cross-sectional study Nirav Dhanesha, aimed to assess sympathetic activity in patients with T2DM, and to investigate the The University of Iowa, United States relationship between sympathetic activity and polysomnographic parameters. *Correspondence: Albert Lecube Materials and Methods: Thirty-six patients with T2DM without known clinical alecube@gmail.com macrovascular nor pulmonary disease and 11 controls underwent respiratory polygraphy, Specialty section: and their cardiac variability and 24-h urine total metanephrines were measured. This article was submitted to Results: SAHS was highly prevalent with a mean apnea-hypopnea index (AHI) in Clinical Diabetes, a section of the journal the range of moderate SAHS. In patients with T2DM, the nocturnal concentration of Frontiers in Endocrinology total metanephrines in urine were higher than diurnal levels [247.0 (120.0–1375.0) vs. Received: 05 August 2019 210.0 (92.0–670.0), p = 0.039]. The nocturnal total metanephrine concentration was Accepted: 17 October 2019 positively and significantly associatedwith the percentage of sleeping time spent with Published: 01 November 2019 oxygen saturation <90%(CT90). In the entire population and in subjects with T2DM, Citation: López-Cano C, the multivariate regression analysis showed a direct interaction between the nocturnal Gutiérrez-Carrasquilla L, Sánchez E, concentration of urine metanephrines and the CT90. González J, Yeramian A, Martí R, Hernández M, Cao G, Ribelles M, Conclusion: These findings suggest that the increase in sympathetic activity previously Gómez X, Barril S, Barbé F, described in patients with T2DM could be mediated through nocturnal breathing Hernández C, Simó R and Lecube A (2019) Sympathetic Hyperactivity and disturbances. The diagnosis and treatment of SAHS may influence sympathetic activity Sleep Disorders in Individuals With disorders and may contribute to an improvement in T2DM and cardiovascular risk. Type 2 Diabetes. Front. Endocrinol. 10:752. Keywords: type 2 diabetes, sympathetic hyperactivity, sleep apnea-hypopnea syndrome, sleep breathing, doi: 10.3389/fendo.2019.00752 cardiovascular risk Frontiers in Endocrinology | www.frontiersin.org 1 November 2019 | Volume 10 | Article 752 López-Cano et al. Sympathetic Hyperactivity and Sleep Disorders in Diabetes INTRODUCTION Endocrinology Department of the Arnau de Vilanova University Hospital. Willing participants were given detailed information A wealth of clinical and cross-sectional studies showed a higher about the objectives and procedures of the study. prevalence of sleep apnoea-hypopnea syndrome (SAHS) in Participants fulfilled the following inclusion criteria: T2DM patients with type 2 diabetes (T2DM). The data vary according to with more than 5 years of known evolution, men and women the population studied, but reach a prevalence of up to 85%, with aged 40 and 70 years without any history of vascular disease or 70% for the range of moderate SAHS (1–5). Despite the lack of lung disease and a BMI of less than 40 kg/m2 . The exclusion prospective studies to demonstrate the SAHS impact in patients criteria were presence of type 1 diabetes, chronic kidney disease, with T2D, it is well known that intermittent nocturnal hypoxia active neoplasia, neuromuscular diseases, active smoking or is associated with poorer glycaemic control and an increase in former smokers, history of alcohol abuse and treatment with cardiovascular risk (6–13). Alternatively, patients with T2D, in continuous positive airway pressure (CPAP). Patients who were comparison with the general population have a negative impact treated with drugs with activity on the central nervous system on breathing during sleep, creating greater sleep fragmentation, (e.g., hypnotics, antidepressants, sedatives, psycholeptics) were an increase in micro-awakenings and a higher prevalence of also excluded from the study. No pregnant women were included. nocturnal hypoxia episodes (14–18). However, there is little A control group of 11 healthy subjects without T2DM or lung evidence and some controversy on whether these alterations disease and well matched by age, body mass index (BMI), neck are responsible for hyperactivation of the sympathetic nervous and waist circumferences and blood pressure was also recruited system described in patients with T2DM. during the same period among the relatives of patients with Usually, the autonomic nervous system shows episodic diabetes, as well as the employees of our institution. oscillations of broad-spectrum activity during sleep with dynamic fluctuation of vital factors such as heart rate, blood pressure and ventilation (19, 20). Moreover, changes in sleep Measurement of Sleep-Disordered architecture are associated with increased sympathetic activity, Breathing leading to endothelial dysfunction and decreased nitric oxide The 36 recruited patients and the 11 controls underwent a concentration (21–23). In this way, episodes of nocturnal hypoxia non-attended respiratory polygraphic record with a portable also activate the sympathetic system, promoting alterations Sleep Diagnostic Alice PDx (Philips Respironics, Spain) which in cardiac variability and probably endothelial damage, records nasal airflow (nasal cannula), respiratory effort (chest which contributes to increased cardiovascular risk (24–27). and abdominal bands), snoring, body position and finger pulse Sympathetic overactivity has also been associated with metabolic oximetry. The same technician manually checked all sleep studies dysfunction such as insulin resistance, obesity, hypertension to reduce variability. Records with less than 5 h of correct and dyslipidaemia (28–30). Even genetic polymorphisms have signal were repeated. An apnea was defined as cessation of been identified the sympathetic nervous system of humans and airflow for more than 10 s. Hypopnea was defined as a reduction animals and seem to contribute to the development of obesity in respiratory signals for at least 10 s associated with oxygen and T2DM in certain populations (31–33). desaturation of 4% or more. The apnea-hypopnea index (AHI) Since the origin of sympathetic hyperactivation in patients was calculated as the total number of respiratory events (apneas with T2DM is not precisely known, we propose to analyse plus hypopneas) divided by the recording time in bed (per hour the relation between the presence of breathing disorders that of sleep). On this basis, SAHS was defined as an AHI >10 characterize their sleep with data related with sympathetic events/hour (e/h). The cumulative percentage of time spent with activity. We aimed to deepen this hypothesis by studying oxygen saturations below 90% (CT90) was also assessed (34–36). the polysomnographic record of 36 subjects with T2DM and its relationship with measurement of urine metanephrine Laboratory Assessment concentration, heart rate variability (HRV) and other serum After patients fasted overnight for 12 h, venous blood was markers of sympathetic activity. collected from the antecubital vein. Samples were separated by centrifugation (2,000 g at 4◦ C for 20 min) and analyzed MATERIALS AND METHODS in the clinical laboratory of our hospital using standard methods to obtain biochemical parameters. The measurement Ethic Statement of urine metanephrines was realized by high performance liquid The study was approved by the human ethics committee from chromatography. In order to compare the concentrations of the Arnau de Vilanova University Hospital and was conducted urine metanephrines between day and night, urine collection according to the ethical guidelines of the Helsinki Declaration. was carried out in two 12-h time periods [from 8:00 to Informed written consent was obtained from all participants 20:00 (day) and from 20:00 to 8:00 (night)]. The serum included in the study. concentration of hormones related with glucose metabolism [cortisol, insulin, glucagon, insulin-like growth factor-1 (IGF- Description of the Study Population 1) and growth hormone (GH)] were also determined through In this cross-sectional study, a total of 36 patients of Caucasian chemiluminescence enzyme immunoassay. All samples were origin with T2DM were prospectively recruited between collected in the absence of clinical evidence of active infection or September 2017 and July 2018 at the outpatient clinic in the inflammatory diseases. Frontiers in Endocrinology | www.frontiersin.org 2 November 2019 | Volume 10 | Article 752 López-Cano et al. Sympathetic Hyperactivity and Sleep Disorders in Diabetes Cardiac Variability Study: Heart Rate TABLE 1 | Baseline main clinical, metabolic and sleep-breathing characteristics of participants in the study. Variability Parameters Heart rate variability (HRV), defined as the measurement of Type 2 diabetes Control group p the variation in milliseconds between heart beats, was studied in its R-R intervals, through a QHRV device with DT-HW6c N 36 11 – hardware (QHRV, Santa Bárbara, CA, United States). The results Age (years) 56.3 ± 8.7 51.2 ± 8.8 0.101 were analyzed after measuring in four different stages: after a Women, n (%) 10 (27.7) 11 (100%) <0.001 15-min rest, breathing deeply, in Valsalva and in a standing BMI (Kg/m2 ) 31.9 ± 4.8 32.5 ± 5.8 0.745 position. In the time domain, we analyzed RR intervals, standard Neck circumference 41.9 ± 4.2 39.6 ± 2.8 0.095 deviations of RR intervals (SDNN), the square root of the mean (cm) squared difference of successive RR intervals (RMSSD), and the Waist circumference 113.0 ± 11.0 116.0 ± 10.8 0.431 (cm) percentage of adjacent NN intervals differing by more than 50 ms HbA1c (%) 8.0 ± 1.3 5.5 ± 0.5 (pNN50). This last measurement was referred to as “short-term” <0.001 LDL Cholesterol 2.8 ± 1.0 3.2 ± 1.1 0.337 HRV and reflects the parasympathetic influence on the heart rate. (mmol/l) In the frequency domain, we analyzed the low-frequency band Triglycerides (mmol/l) 1.7 (0.8–3.7) 1.1 (0.8–2.0) 0.089 (LF, an index of both sympathetic and parasympathetic activity), Systolic blood 131.6 ± 12.6 131.9 ± 10.5 0.902 high-frequency band (HF) and very low-frequency (VLF, that pressure (mm Hg) reflects thermoregulatory mechanisms, fluctuation in activity of Diastolic blood 77.6 ± 8.2 80.7 ± 5.3 0.260 the renin–angiotensin system, and the function of peripheral pressure (mm Hg) chemoreceptors) (37). Patients were advised not to consume AHI (events/hour) 23.5 (3.0–78.0) 14.0 (0.0–67.0) 0.227 food, coffee or nicotine 3 h before the test and to not receive CT90 (%) 7.5 (0.0–64.0) 6.5 (0.0–44.0) 0.355 treatment with anticholinergics, fludrocortisone, antihistamines, alpha or beta antagonists, or anxiolytics during 48 h before Data are mean ± SD, median (range) or n (percentage). BMI, body mass index; HbA1c, the test. glycated hemoglobin; LDL, low density lipoprotein; AHI, apnea-hypopnea index; CT90, percentage of time spent with oxygen saturations below 90%. Statistical Analysis TABLE 2 | Hormones values and heart variability parameters of participants in the Normal distribution of the variables was assessed using the study. Kolmogorov-Smirnov test. Data were expressed as the mean ± standard deviation or percentage. Given their skewed Type 2 diabetes Control group p distribution, AHI, CT90 and serum triglycerides are shown as median (range) and were logarithmically transformed to achieve Cortisol (nmol/L) 330.0 (41.0–616.2) 452 (211.3–798.3) 0.094 a normal distribution. The relationship between the continuous Insulin (mIU/L) 100.3 (24.0–523.8) 128.5 (40.1–188.0) 0.899 variables was examined by the Pearson linear correlation test. IGF-1 (ng/mL) 135.1 (55.3–273.2) 149.9 (85.0–215.9) 0.461 Univariate and multivariate logistic regression models were Glucagon 136.0 (61.0–304.0) 112.0 (63.0–183.0) 0.348 (pg/mL) computed. A stepwise multivariate regression analysis was GH (ng/mL) 0.1 (0.0–2.1) 0.1 (0.0–1.2) 0.800 performed to explore the variables independently related to LFa/RFa resting 0.9 (0.3–2.0) 0.7 (0.2–1.8) 0.299 nocturnal urine metanephrines. Variables significantly associated with changes in urine metanephrines in the bivariate analysis LFa/RFa 0.6 (0.2–1.7) 0.4 (0.3–0.7) 0.099 respiratory (i.e., CT90 and serum glucagon concentration), together with LFa/RFa valsalva 1.7 (0.8–3.0) 1.7 (0.6–3.5) 0.591 heart rate variability parameters and clinically relevant variables LFa/RFa 1.1 (0.3–2.8) 0.7 (0.5–2.2) 0.022 (i.e., gender, BMI, age, smoking habit, blood pressure, AHI, neck standing circumference and HbA1c) were included in the analysis. All p- SDNN 21.5 (7.1–85.3) 39.5 (17.4–76.7) 0.013 values were based on a two-sided test of statistical significance. Significance was accepted at the level of p < 0.05. Statistical Data are median (range). IGF-1, insulin-like growth factor-1; GH, growth hormone; LFa, analyses were performed using the SPSS statistical package (IBM low frequency component; RFa, high frequency component; SDNN, standard deviation SPSS, Statistics for Windows, Version 20.0. Armonk, NY, USA). of beat to beat or NN intervals. RESULTS with a median CT90 of 7.5 (0–64)%. Finally, hormone values and HRV parameters were within the normal range (Table 2). The main clinical features and metabolic data of the study Urine concentrations of total metanephrines were statistically population are presented in Table 1. Briefly, patients with T2DM higher during the night compared with the concentrations during were 56.3 ± 8.7 years old, mainly female (27.7%) and obese (BMI the day period in the group of subjects with T2DM [247.0 31.9 ± 4.8 kg/m2 ) and showed a poor metabolic control (HbA1c (120.0.1375.0) vs. 210.0 (92.0–670.0), p = 0.039]. However, no 8.0 ± 1.3%). Regarding measurements from the non-attended differences between day and night were observed in the control polygraphy, they exhibited a median AHI of 23.5 (3.0–78.0) e/h, group [243.0 (104.0–560.0) vs. 250.5 (94.0–485.0), p = 0.674). Frontiers in Endocrinology | www.frontiersin.org 3 November 2019 | Volume 10 | Article 752 López-Cano et al. Sympathetic Hyperactivity and Sleep Disorders in Diabetes Linear correlations between day and night metanephrines night and the percentage of time spent with oxygen saturation and serum hormones and heart rate variability parameters are <90% (p = 0.001) [together with serum glucagon concentration shown in Table 3. Whereas the nocturnal concentration of urine (p = 0.001), LFa/RFa resting (p = 0.009) and diastolic blood metanephrines were positively associated with values of CT90 pressure (p = 0.047), R2 = 0.741]. This indicated that the increase (r = 0.617, p < 0.001), this association disappeared with the in the secretion of metanephrines at night could be related with metanephrines collected during the day (r = 0.093, p = 0.644) the severity of nocturnal hypoxia (Table 4). When subjects with (Figure 1). In addition, nocturnal and daily urine metanephrines T2DM were assessed alone, serum glucagon concentrations (p were negatively associated with serum glucagon concentrations = 0.011) and CT90 (p = 0.016) still independently predicted (r = −0.427, p = 0.008). In the multivariate regression analysis nocturnal urine metanephrines (R2 = 0.549). However, in the including the entire population we found a significant direct control group, only diastolic blood pressure and serum glucagon interaction between the concentration of urine metanephrines at concentrations but not CT90 were significantly related with nocturnal total metanephrines. DISCUSSION TABLE 3 | Linear correlations between day and night metanephrines and serum hormones and heart rate variability parameters. The main findings in this study were that a subgroup of patients Night metanephrines Day metanephrines with T2DM exhibited an increase in urine metanephrines at night associated with nocturnal hypoxia and with a decrease in serum r p r p glucagon concentrations, specifically for the parasympathetic CT90 (log) 0.617 <0.001 0.093 0.644 tone. This autonomic disturbance can be explained by the AHI (log) 0.146 0.356 0.426 0.146 deleterious effects of diabetes during night-time sleep, leading to an important nocturnal hypoxia. Cortisol (mmol/L) 0.069 0.677 −0.102 0.522 It is well known that T2DM patients exhibit a hyperactivation Insulin (mIU/L) 0.235 0.145 0.050 0.752 of the sympathetic nervous system (SNS) that amplifies the IGF-1 (ng/mL) 0.045 0.784 0.039 0.802 effect of hyperglycaemia, increasing both cardiovascular risk and Glucagon (pg/mL) −0.427 0.008 −0.452 0.003 microangiopathic diabetic complications (38). The origin of this GH (ng/mL) 0.231 0.151 0.101 0.519 sympathetic hyperactivation has not been precisely described. LFa/RFa respiratory −0.163 0.335 −0.176 0.271 We propose that, both intermittent hypoxia and the greater LFa/RFa valsalva 0.085 0.612 0.236 0.132 number of micro-awakenings that characterize the sleep of LFa/RFa standing 0.127 0.448 0.035 0.828 T2DM patients could explain the increase in SNS activity. LFa/RFa resting −0.161 0.334 −0.137 0.386 While the evidence is controversial, previous studies have IGF-1, insulin-like growth factor-1; GH, growth hormone; LFa, low frequency component; demonstrated that apnea and hypopnea events are accompanied RFa, high frequency component. by concomitant cyclic variations in heart rate and changes in both FIGURE 1 | Linear correlation between concentration of urine metanephrines and percentage of time with oxygen saturations below 90%. Frontiers in Endocrinology | www.frontiersin.org 4 November 2019 | Volume 10 | Article 752 López-Cano et al. Sympathetic Hyperactivity and Sleep Disorders in Diabetes TABLE 4 | Variables independently related to nocturnal urine total metanephrines women in comparison with premenopausal women (48). In our in the multiple regression analysis (stepwise method) in the entire population. study, the LFa/RFa respiratory parameter was the only parameter β Beta (95% IC) p related with heart rate variability that was significantly decreased in women when compared to men [0.7 (0.2–1.7) vs. 0.4 (0.2– CT90 (log) 0.520 191.2 (93.9 to 288.6) 0.001 0.8), p = 0.002], and it was also the only parameter that was Glucagon (pg/mL) −0.505 −1.3 (−2.0 to −0.6) 0.001 positively associated with age in the bivariate analysis (r = 0.318, LFa/RFa resting −0.379 −148.9 (−255.4 to −42.5) 0.009 p = 0.038). The other heart rate variability parameters and Systolic blood 0.277 6.0 (0.0 to 12.0) 0.047 serum hormone concentrations showed no differences between pressure (mm Hg) genders nor correlations with age. In addition, gender and age AHI (events/hour) −0.212 – 0.095 were not independently associated with total nocturnal urine Smoking status * −0.240 – 0.114 metanephrines in the multivariate analysis. GH (ng/mL) −0.260 – 0.172 The present study does not have sufficient power to exhibit LFa/RFa standing −0.218 – 0.196 endothelial damage or cardiovascular risk caused by this Age (years) −0.148 – 0.289 hyperactivity, but some previous studies have described the IGF-1 (ng/mL) 0.138 – 0.356 relationship between variability in autonomic function and an Insulin (mIU/L) 0.132 – 0.370 increase in insulin resistance, oxidative stress and inflammatory Systolic blood −0.246 – 0.371 response that cause endothelial celldamage, development of pressure (mmHg) atherosclerosis and increased cardiovascular risk (49–51). Along Cortisol (mmol/L) −0.115 – 0.434 the same lines, it has been described that cardiovascular LFa/RFa respiratory −0.100 – 0.436 autonomic neuropathy contributes to a poorer prognosis in HbA1c (%) 0.120 – 0.443 ischemic heart disease and heart failure (52). Also, the decrease BMI (kg/m2 ) 0.074 – 0.596 in HRV can predict the progression of atherosclerosis in T2DM Gender −0.047 – 0.742 patients (53). (men/women) Our study has some limitations. First, this is a cross sectional LFa/RFa respiratory −0.041 – 0.763 whereby causality cannot be determined. The size of the study LFa/RFa Valsalva 0.026 – 0.866 might have been inadequate, and a prospective study with a Neck circumference −0.016 – 0.914 higher number of patients could yield better results. In addition, (cms) it should be noted that the control group in our study was Constant – −58.1 (−540.7 to 424.3) 0.802 composed only of women. As previously mentioned, women R2 = 0.741 have a lower sympathetic nerve activity than men, so this data could influence our results. However, in the multivariate CT90, percentage of time spent with oxygen saturation below 90%; LFa, low frequency regression analysis, gender was not related to the concentration component; RFa, high frequency component; AHI, apnea-hypopnea index; GH, growth hormone; IGF-1, insulin-like growth factor-1; HbA1c, glycated hemoglobin; BMI, body of urine metanephrines at night. Second, the HRV study might mass index. have been influenced by differences in baseline physical condition or cardiac status. We did not perform any cardiac evaluation although all participants were asked for cardiovascular diseases sympathetic and parasympathetic activity without differences in and arrhythmias and neither of them were athletic. Third, the subjects with diabetes (39, 40). As far as we know, hyperactivation effects of the antidiabetics (insulin, SGLT2, incretins) could not of the autonomic system has been described in patients with be excluded. T2DM but with involvement of both patterns (sympathetic and parasympathetic) and it was related to male sex and the presence of neuropathy (41–43). None of our patients had clinical CONCLUSION neuropathy, and the test group was predominantly female. We suggest that the increased sympathetic activity previously Although we cannot elucidate whether the effects of hypoxia described in patients with T2DM is mediated through the and diabetes overlap with the effects of obesity, some recent deleterious effect of diabetes in nocturnal breathing. In studies have shown an increased SAHS prevalence in non- addition, sympathetic activity is associated with disorders of overweight patients with Type 1 diabetes, suggesting that autonomic tone at resting, suggesting a new pathological pathway nocturnal hypoxia might be more related to autonomic between T2DM and cardiovascular risk. More studies are disturbances rather than obesity (44, 45). needed to clarify whether treatment of SAHS will improve Our study combined data from men and women in the sympathetic hyperactivity, T2DM and cardiovascular outcomes analyses, but differences regarding sex and menopausal status in these patients. have been previously described. In this way, some findings suggest that men have a higher sympathetic nerve activity than women after the development of essential hypertension, and that DATA AVAILABILITY STATEMENT this could have implications for gender-specific management of hypertension (46, 47). Similarly, muscle sympathetic nerve The datasets generated for this study are available on request to activity has been described to be greater in postmenopausal the corresponding author. Frontiers in Endocrinology | www.frontiersin.org 5 November 2019 | Volume 10 | Article 752 López-Cano et al. Sympathetic Hyperactivity and Sleep Disorders in Diabetes AUTHOR CONTRIBUTIONS publication. CL-C and AL designed the study, supervised the research, analyzed and interpreted data, and wrote CL-C, LG-C, and ES recruited patients, collected and analyzed the manuscript. data, wrote the first draft of the manuscript, and had final approval of the version for publication. FB supervised FUNDING the research, interpreted data, and critically reviewed the draft of the article. JG, SB, ES, MR, and RM collected This study was supported by grants from the Instituto de Salud and analyzed data, and critically reviewed the draft of the Carlos III (Fondo de Investigación Sanitaria, PI12/00803 and article. LG-C, MH, and XG recruited patients, collected PI15/00260), European Union (European Regional Development data, and contributed to the discussion. GC, MR, and Fund, Fondo Europeo de Desarrollo Regional, Una manera de AY collected and analyzed data, and contributed to the hacer Europa), the Fundación Sociedad Española Endocrinología discussion. CH and RS designed the study, supervised the y Nutrición, and Menarini Spain S.A. The funders had no role in statistical analysis, interpreted data, critically revised draft the study design, data collection and analysis, decision to publish, of the article, and had final approval of the version for or preparation of the manuscript. REFERENCES 14. Engeda J, Mezuk B, Ratliff S, Ning Y. Association between duration and quality of sleep and the risk of pre-diabetes: evidence from NHANES. Diabet Med. 1. Foster GD, Sanders MH, Millman R, Zammit G, Borradaile KE, Newman (2013) 30:676–80. doi: 10.1111/dme.12165 AB, et al. Obstructive sleep apnea among obese patients with type 2 diabetes. 15. Grandner MA, Seixas A, Shetty S, Shenoy S. Sleep duration and diabetes risk: Diabetes Care. (2009) 32:1017–19. doi: 10.2337/dc08-1776 population trends and potential mechanisms. Curr Diab Rep. (2016) 16:106. 2. West SD, Nicoll DJ, Stradling JR. 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Laitinen T, Lindström J, Eriksson J, Ilanne-Parikka P, Aunola, Keinänen- Kiukaanniemi S, et al. Cardiovascular autonomic dysfunction is associated Copyright © 2019 López-Cano, Gutiérrez-Carrasquilla, Sánchez, González, with central obesity in persons with impaired glucose tolerance. Diabet Med. Yeramian, Martí, Hernández, Cao, Ribelles, Gómez, Barril, Barbé, Hernández, Simó (2011) 28:699–704. doi: 10.1111/j.1464-5491.2011.03278.x and Lecube. This is an open-access article distributed under the terms of the Creative 42. Subbalakshmi NK, Adhikari PM, Rajeev A, Asha K, Jeganathan PS. Commons Attribution License (CC BY). The use, distribution or reproduction in Independent predictors of cardiac parasympathetic dysfunction in type 2 other forums is permitted, provided the original author(s) and the copyright owner(s) diabetes mellitus. Singapore Med J. (2008) 49:121–8. are credited and that the original publication in this journal is cited, in accordance 43. Jyotsna VP, Ambekar S, Singla R, Joshi A, Dhawan A, Kumar N, et al. with accepted academic practice. No use, distribution or reproduction is permitted Cardiac autonomic function in patients with diabetes improves with practice which does not comply with these terms. Frontiers in Endocrinology | www.frontiersin.org 7 November 2019 | Volume 10 | Article 752