STUDY OBJECTIVES: Sleep-disordered breathing and diabetes mellitus (DM) are often concomitant; however, data on the impact of sleep-disordered breathing on mortality in the population with diabetes remain scarce. METHODS: The population from the Sleep Heart Health Study, a multicenter prospective observational study representing 5,780 patients with polysomnography and mortality data, including 453 patients with DM, was analyzed to assess the impact of sleep-disordered breathing variables and the presence of DM on all-cause, cardiovascular disease, and noncardiovascular disease associated mortality. Survival analysis and proportional hazard regression models were used to calculate the adjusted hazard ratios (aHRs) for mortality. RESULTS: Patients with DM and the average oxygen saturation > 91.4% had significantly lower all-cause (aHR 0.52, confidence interval [CI] 0.34-0.80) and cardiovascular disease mortality risk (aHR 0.44, CI 0.22-0.87) as compared with patients with oxygen saturation below this value. Apnea-hypopnea index > 31 (aHR 1.58, CI 1.10-2.28) and oxygen desaturation index > 13.3 (aHR 1.58, CI 1.10-2.25) were associated with increased all-cause mortality in participants with DM on treatment. Sleep efficiency and proportion of rapid eye movement sleep did not have any impact on mortality in patients with DM and thus differed significantly from individuals without DM, where increased all-cause mortality was observed in those with sleep efficiency < 81.4% (aHR 0.77, CI 0.68-0.87) or rapid eye movement sleep < 14.9% (aHR 0.78, CI 0.68-0.89). CONCLUSIONS: Patients with diabetes on treatment and moderate to severe sleep-disordered breathing experience increased all-cause mortality. Reduced average oxygen saturation predicted both all-cause and cardiovascular death in the population with diabetes. CITATION: Vichova T, Petras M, Waldauf P, Westlake K, Vimmerova-Lattova Z, Polak J. Sleep-disordered breathing increases mortality in patients with diabetes. J Clin Sleep Med. 2025;21(1):89-99.

• Klíčová slova
• cardiovascular disease, diabetes mellitus, mortality, oxygen saturation, sleep-disordered breathing,
• MeSH
• diabetes mellitus * mortalita   epidemiologie   MeSH
• kardiovaskulární nemoci mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• polysomnografie * statistika a číselné údaje   MeSH
• prospektivní studie MeSH
• senioři MeSH
• syndromy spánkové apnoe * mortalita   komplikace   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH

The molecular mechanisms linking obstructive sleep apnea (OSA) with type 2 diabetes mellitus (T2DM) remain unclear. This study investigated the effect of OSA on skeletal muscle lipid oxidation in nondiabetic controls and in type 2 diabetes (T2DM) patients. Forty-four participants matched for age and adiposity were enrolled: nondiabetic controls (control, n = 14), nondiabetic patients with severe OSA (OSA, n = 9), T2DM patients with no OSA (T2DM, n = 10), and T2DM patients with severe OSA (T2DM + OSA, n = 11). A skeletal muscle biopsy was performed; gene and protein expressions were determined and lipid oxidation was analyzed. An intravenous glucose tolerance test was performed to investigate glucose homeostasis. No differences in lipid oxidation (178.2 ± 57.1, 161.7 ± 22.4, 169.3 ± 50.9, and 140.0 ± 24.1 pmol/min/mg for control, OSA, T2DM, and T2DM+OSA, respectively; p > 0.05) or gene and protein expressions were observed between the groups. The disposition index, acute insulin response to glucose, insulin resistance, plasma insulin, glucose, and HBA1C progressively worsened in the following order: control, OSA, T2DM, and T2DM + OSA (p for trend <0.05). No association was observed between the muscle lipid oxidation and the glucose metabolism variables. We conclude that severe OSA is not associated with reduced muscle lipid oxidation and that metabolic derangements in OSA are not mediated through impaired muscle lipid oxidation.

• Klíčová slova
• IVGTT, free fatty acids, glucose intolerance, hypoxia, lipid utilization, muscle metabolism, obstructive sleep apnea, type 2 diabetes mellitus,
• MeSH
• diabetes mellitus 2. typu * komplikace   metabolismus   MeSH
• glukosa metabolismus   MeSH
• inzulinová rezistence * MeSH
• inzuliny * MeSH
• lidé MeSH
• lipidy MeSH
• obstrukční spánková apnoe * metabolismus   MeSH
• polysomnografie MeSH
• svaly metabolismus   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glukosa MeSH
• inzuliny * MeSH
• lipidy MeSH

INTRODUCTION: The European Sleep Apnea Database was used to identify distinguishable obstructive sleep apnoea (OSA) phenotypes and to investigate the clinical outcome during positive airway pressure (PAP) treatment. METHOD: Prospective OSA patient data were recruited from 35 sleep clinics in 21 European countries. Unsupervised cluster analysis (anthropometrics, clinical variables) was performed in a random sample (n=5000). Subsequently, all patients were assigned to the clusters using a conditional inference tree classifier. Responses to PAP treatment change in apnoea severity and Epworth sleepiness scale (ESS) were assessed in relation to baseline patient clusters and at short- and long-term follow-up. RESULTS: At baseline, 20 164 patients were assigned (mean age 54.1±12.2 years, 73% male, median apnoea-hypopnoea index (AHI) 27.3 (interquartile range (IQR) 14.1-49.3) events·h-1, and ESS 9.8±5.3) to seven distinct clusters based on anthropometrics, comorbidities and symptoms. At PAP follow-up (median 210 [IQR 134-465] days), the observed AHI reduction (n=1075) was similar, whereas the ESS response (n=3938) varied: largest reduction in cluster 3 (young healthy symptomatic males) and 6 (symptomatic males with psychiatric disorders, -5.0 and -5.1 units, respectively (all p<0.01), limited reduction in clusters 2 (obese males with systemic hypertension) and 5 (elderly multimorbid obese males, -4.2 (p<0.05) and -3.7 (p<0.001), respectively). Residual sleepiness in cluster 5 was particularly evident at long-term follow-up (p<0.05). CONCLUSION: OSA patients can be classified into clusters based on clinically identifiable features. Importantly, these clusters may be useful for prediction of both short- and long-term responses to PAP intervention.

• Publikační typ
• časopisecké články MeSH

Obstructive sleep apnea (OSA) is a common disorder in Type 2 diabetes (T2D) patients further increasing their already high cardiovascular risk. As T2D patients typically not report OSA symptoms, systematic screening for OSA in this population is warranted. We aimed to determine the readiness of T2D patients to undergo screening and to compare their adherence to continuous positive airway pressure (CPAP) therapy with "regular" sleep clinic patients who typically seek medical advice on their own initiative. We therefore recruited 494 consecutive T2D patients and offered them OSA screening using home sleep monitoring (type IV device). All participants in high risk of moderate-to-severe OSA were recommended home sleep apnea testing (HSAT) followed by CPAP therapy. Patients were followed-up for 12 months and outcomes compared to 228 consecutive sleep clinic patients undergoing HSAT. Among 307 screened T2D patients, 94 (31%) were identified at high risk of moderate-to-severe OSA. Subsequently, 54 patients underwent HSAT, 51 were recommended, and 38 patients initiated CPAP (acceptance 75%). Among 228 sleep clinic patients, 92 (40%) were recommended and 74 patients initiated CPAP (acceptance 80%). After 1 year, 15 (39%) T2D and 29 (39%) sleep clinic patients showed good CPAP adherence (use ≥ 4 h/night ≥ 70% nights). In conclusion, 20 T2D patients needed to be screened in order to obtain one successfully treated patient. OSA screening in T2D patients identified 31% with moderate-to-severe OSA. Once diagnosed, their CPAP acceptance and adherence did not differ from sleep clinic patients. However, the reasons for the high dropout during the screening-diagnostic process impacting the overall success of the screening program need to be identified and addressed.

• Klíčová slova
• CPAP acceptance, CPAP adherence, diabetes, screening, sleep apnea,
• Publikační typ
• časopisecké články MeSH

Metabolic impairments associated with obstructive sleep apnea syndrome (OSA) are linked to tissue hypoxia, however, the explanatory molecular and endocrine mechanisms remain unknown. Using gas-permeable cultureware, we studied the chronic effects of mild and severe hypoxia on free fatty acid (FFA) uptake, storage, and oxidation in L6 myotubes under 20, 4, or 1% O2. Additionally, the impact of metformin and the peroxisome proliferator-activated receptor (PPAR) β/δ agonist, called GW501516, were investigated. Exposure to mild and severe hypoxia reduced FFA uptake by 37 and 32%, respectively, while metformin treatment increased FFA uptake by 39% under mild hypoxia. GW501516 reduced FFA uptake under all conditions. Protein expressions of CD36 (cluster of differentiation 36) and SCL27A4 (solute carrier family 27 fatty acid transporter, member 4) were reduced by 17 and 23% under severe hypoxia. Gene expression of UCP2 (uncoupling protein 2) was reduced by severe hypoxia by 81%. Metformin increased CD36 protein levels by 28% under control conditions and SCL27A4 levels by 56% under mild hypoxia. Intracellular lipids were reduced by mild hypoxia by 18%, while in controls only, metformin administration further reduced intracellular lipids (20% O2) by 36%. Finally, palmitate oxidation was reduced by severe hypoxia, while metformin treatment reduced non-mitochondrial O2 consumption, palmitate oxidation, and proton leak at all O2 levels. Hypoxia directly reduced FFA uptake and intracellular lipids uptake in myotubes, at least partially, due to the reduction in CD36 transporters. Metformin, but not GW501516, can increase FFA uptake and SCL27A4 expression under mild hypoxia. Described effects might contribute to elevated plasma FFA levels and metabolic derangements in OSA.

• Klíčová slova
• CD36 receptor, FFA oxidation, FFA uptake, GW501516, free fatty acids, hypoxia, metformin, myotubes,
• Publikační typ
• časopisecké články MeSH

Obstructive sleep apnea (OSA) is associated with insulin resistance (IR) and glucose intolerance. Elevated endothelin-1 (ET-1) levels have been observed in OSA patients and in mice exposed to intermittent hypoxia (IH). We examined whether pharmacological blockade of type A and type B ET-1 receptors (ETA and ETB) would ameliorate glucose intolerance and IR in mice exposed to IH. Subcutaneously implanted pumps delivered BQ-123 (ETA antagonist; 200 nmol/kg/day), BQ-788 (ETB antagonist; 200 nmol/kg/day) or vehicle (saline or propyleneglycol [PG]) for 14 days in C57BL6/J mice (10/group). During treatment, mice were exposed to IH (decreasing the FiO2 from 20.9% to 6%, 60/h) or intermittent air (IA). After IH or IA exposure, insulin (0.5 IU/kg) or glucose (1 mg/kg) was injected intraperitoneally and plasma glucose determined after injection and area under glucose curve (AUC) was calculated. Fourteen-day IH increased fasting glucose levels (122 ± 7 vs. 157 ± 8 mg/dL, PG: 118 ± 6 vs. 139 ± 8; both p < 0.05) and impaired glucose tolerance (AUCglucose: 19,249 ± 1105 vs. 29,124 ± 1444, PG AUCglucose: 18,066 ± 947 vs. 25,135 ± 797; both p < 0.05) in vehicle-treated animals. IH-induced impairments in glucose tolerance were partially ameliorated with BQ-788 treatment (AUCglucose: 21,969 ± 662; p < 0.05). Fourteen-day IH also induced IR (AUCglucose: 7185 ± 401 vs. 8699 ± 401; p < 0.05). Treatment with BQ-788 decreased IR under IA (AUCglucose: 5281 ± 401, p < 0.05) and reduced worsening of IR with IH (AUCglucose: 7302 ± 401, p < 0.05). There was no effect of BQ-123 on IH-induced impairments in glucose tolerance or IR. Our results suggest that ET-1 plays a role in IH-induced impairments in glucose homeostasis.

• Klíčová slova
• bosentan, diabetes, endothelin, endothelin receptor, obstructive sleep apnea,
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• Berlin questionnaire, STOP Bang questionnaire, cardiovascular risk factor, home sleep monitor, screening, sleep apnea, type 2 diabetes,
• Publikační typ
• časopisecké články MeSH

Obstructive sleep apnea (OSA) is associated with insulin resistance, glucose intolerance, and type 2 diabetes. Causal mechanisms mediating this association are not well defined; however, augmented lipolysis in adipose might be involved. Here, we investigated the effect of acipimox treatment (lipolysis inhibitor) on glucose tolerance and insulin sensitivity in mice exposed to intermittent hypoxia (IH). C57BL6/J mice were exposed for 14 days to IH or control conditions. IH was created by decreasing the fraction of inspired oxygen from 20.9 to 6.5%, 60 times/h. Control exposure was air (fraction of inspired oxygen, 20.9%) delivered at an identical flow rate. Acipimox was provided in drinking water (0.5 g/ml) during exposures. After exposures, intraperitoneal insulin (0.5 IU/kg) and glucose (1 g/kg) tolerance tests were performed, and primary adipocytes were isolated for lipolysis experiments. IH elevated fasting glucose by 51% and worsened glucose tolerance and insulin sensitivity by 33 and 102%, respectively. In parallel, IH increased spontaneous lipolysis by 264%, and reduced epididymal fat mass by 15% and adipocyte size by 8%. Acipimox treatment prevented IH-induced lipolysis and increased epididymal fat mass and adipocyte size by 19 and 10%, respectively. Acipimox fully prevented IH-induced impairments in fasting glycemia, glucose tolerance, and insulin sensitivity. For all reported results, P less than 0.05 was considered significant. Augmented lipolysis contributes to insulin resistance and glucose intolerance observed in mice exposed to IH. Acipimox treatment ameliorated the metabolic consequences of IH and might represent a novel treatment option for patients with obstructive sleep apnea.

• Klíčová slova
• diabetes, insulin resistance, intermittent hypoxia, lipolysis, obstructive sleep apnea,
• MeSH
• adipozita účinky léků   MeSH
• experimentální diabetes mellitus krev   komplikace   genetika   patologie   MeSH
• fenotyp MeSH
• glukosa metabolismus   MeSH
• hypoxie komplikace   metabolismus   MeSH
• inzulin metabolismus   MeSH
• lipolýza * účinky léků   MeSH
• mastné kyseliny krev   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• obstrukční spánková apnoe krev   komplikace   genetika   patologie   MeSH
• pyraziny farmakologie   MeSH
• regulace genové exprese účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• tukové buňky účinky léků   patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• acipimox MeSH Prohlížeč
• glukosa MeSH
• inzulin MeSH
• mastné kyseliny MeSH
• pyraziny MeSH

OBJECTIVE: Many cases of obstructive sleep apnea (OSA) involve collapse of the tongue base and soft palate during sleep, causing occlusion of the upper airway and leading to oxygen desaturation. Existing therapies can be effective, but they are plagued by patient adherence issues and the invasiveness of surgical approaches. A new, minimally invasive implant for OSA has been developed, which is elastic and contracts a few weeks after deployment, stabilizing the surrounding soft tissue. The device has had good outcomes in preclinical testing; this report describes the preliminary feasibility and safety of its implementation in humans. PATIENTS AND METHODS: A prospective, multicenter, single-arm feasibility study was conducted. Subjects were adults with moderate-to-severe OSA who had previously failed or refused conventional continuous positive airway pressure treatment. Intraoperative feasibility data, postoperative pain, and safety information were collected for a 30-day postoperative period. RESULTS: Forty subjects participated (37 men, three women; average age of 46.1 years); each received two tongue-base implants and two soft-palate implants. Surgical procedure time averaged 43 minutes. Postsurgical pain resolved readily in most cases; at 30 days post implantation, <20% of subjects reported pain, which averaged less than two out of ten. Adverse events were generally the mild and expected sequelae of a surgical procedure with general anesthesia and intraoral manipulation. The device was well tolerated. Implant extrusions were reported with soft-palate implants (n=12), while tongue-base implants required few revisions (n=2). Quantitative and qualitative sleep effectiveness outcomes (including full-night polysomnographic and quality-of-life measures) will be presented in a subsequent report. CONCLUSION: Implantation of the device was feasible. Although a relatively high rate of extrusions occurred in the now-discontinued palate implants, tongue-base implants were largely stable and well tolerated. The minimally invasive and maintenance-free implant may provide a new alternative to higher morbidity surgical procedures.

• Klíčová slova
• breathing, implantable device, obstructive sleep apnea, sleep, surgical treatment, tongue base,
• Publikační typ
• časopisecké články MeSH

Modern lifestyle has profoundly modified human sleep habits. Sleep duration has shortened over recent decades from 8 to 6.5 hours resulting in chronic sleep deprivation. Additionally, irregular sleep, shift work and travelling across time zones lead to disruption of circadian rhythms and asynchrony between the master hypothalamic clock and pacemakers in peripheral tissues. Furthermore, obstructive sleep apnea syndrome (OSA), which affects 4 - 15% of the population, is not only characterized by impaired sleep architecture but also by repetitive hemoglobin desaturations during sleep. Epidemiological studies have identified impaired sleep as an independent risk factor for all cause of-, as well as for cardiovascular, mortality/morbidity. More recently, sleep abnormalities were causally linked to impairments in glucose homeostasis, metabolic syndrome and Type 2 Diabetes Mellitus (T2DM). This review summarized current knowledge on the metabolic alterations associated with the most prevalent sleep disturbances, i.e. short sleep duration, shift work and OSA. We have focused on various endocrine and molecular mechanisms underlying the associations between inadequate sleep quality, quantity and timing with impaired glucose tolerance, insulin resistance and pancreatic β-cell dysfunction. Of these mechanisms, the role of the hypothalamic-pituitary-adrenal axis, circadian pacemakers in peripheral tissues, adipose tissue metabolism, sympathetic nervous system activation, oxidative stress and whole-body inflammation are discussed. Additionally, the impact of intermittent hypoxia and sleep fragmentation (key components of OSA) on intracellular signaling and metabolism in muscle, liver, fat and pancreas are also examined. In summary, this review provides endocrine and molecular explanations for the associations between common sleep disturbances and the pathogenesis of T2DM.

• Klíčová slova
• Diabetes, Insulin resistance, Intermittent hypoxia, Metabolic syndrome, Obesity, Obstructive sleep apnea, Shift working, Sleep,
• Publikační typ
• časopisecké články MeSH