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

Obstructive sleep apnoea (OSA) is associated with type 2 diabetes mellitus (T2DM). However, mechanisms mediating association between these two conditions remain unclear. This study investigated, whether the OSA-associated changes in adipose tissue lipolysis might contribute to impaired glucose homeostasis in patient with T2DM. Thirty-five matched subjects were recruited into three groups: T2DM + severe OSA (T2DM + OSA, n = 11), T2DM with mild/no OSA (T2DM, n = 10) and healthy controls (n = 14). Subcutaneous abdominal adipose tissue microdialysis assessed spontaneous, epinephrine- and isoprenaline-stimulated lipolysis. Glucose metabolism was assessed by intravenous glucose tolerance test. Spontaneous lipolysis was higher in the T2DM + OSA compared with the T2DM (60.34 ± 23.40 vs. 42.53 ± 10.16 μmol/L, p = 0.013), as well as epinephrine-stimulated lipolysis (236.84 ± 103.90 vs. 167.39 ± 52.17 µmol/L, p < 0.001). Isoprenaline-stimulated lipolysis was unaffected by the presence of OSA (p = 0.750). The α2 anti-lipolytic effect was decreased in T2DM + OSA by 59% and 315% compared with T2DM and controls (p = 0.045 and p = 0.007, respectively). The severity of OSA (AHI) was positively associated with spontaneous (p = 0.037) and epinephrine-stimulated (p = 0.026) lipolysis. The α2-adrenergic anti-lipolytic effect (p = 0.043) decreased with increasing AHI. Spontaneous lipolysis was positively associated with Insulin resistance (r = 0.50, p = 0.002). Epinephrine-stimulated lipolysis was negatively associated with the Disposition index (r = - 0.34, p = 0.048). AHI was positively associated with Insulin resistance (p = 0.017) and negatively with the Disposition index (p = 0.038). Severe OSA in patients with T2DM increased adipose tissue lipolysis, probably due to inhibition of the α2-adrenergic anti-lipolytic effect. We suggest that dysregulated lipolysis might contribute to OSA-associated impairments in insulin secretion and sensitivity.

• MeSH
• adrenalin aplikace a dávkování   MeSH
• diabetes mellitus 2. typu komplikace   epidemiologie   metabolismus   patologie   MeSH
• glukosa metabolismus   MeSH
• homeostáza fyziologie   MeSH
• inzulin metabolismus   MeSH
• inzulinová rezistence fyziologie   MeSH
• isoprenalin aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipolýza účinky léků   genetika   MeSH
• obstrukční spánková apnoe komplikace   epidemiologie   metabolismus   patologie   MeSH
• senioři MeSH
• tuková tkáň účinky léků   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adrenalin MeSH
• glukosa MeSH
• inzulin MeSH
• isoprenalin MeSH

Obstructive sleep apnea (OSA) has been demonstrated to be implicated in disorder of insulin secretion and diabetes mellitus. In this study, we aimed to evaluate the protective role of tempol, a powerful antioxidant, in chronic intermittent hypoxia (IH)-induced pancreatic injury. The rat model of OSA was established by IH exposure. The pathological changes, increased blood-glucose level, and raised proinsulin/insulin ratio in pancreatic tissues of rats received IH were effectively relieved by tempol delivery. In addition, the enhanced levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta, IL-6, and inflammatory mediators, PGE2, cyclooxygenase-2 (COX-2), NO, and inducible nitric oxide synthase (iNOS) in pancreatic tissue were suppressed by tempol. Moreover, tempol inhibited IH-induced apoptosis in pancreatic tissue as evidenced by upregulated Bcl-2 level, and downregulated Bax and cleaved caspase-3 levels. Finally, the abnormal activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling pathways induced by IH was restrained by tempol administration. In summary, our study demonstrates that tempol relieves IH-induced pancreatic injury by inhibiting inflammatory response and apoptosis, which provides theoretical basis for tempol as an effective treatment for OSA-induced pancreatic injury.

• MeSH
• antioxidancia farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   fyziologie   MeSH
• cyklické N-oxidy farmakologie   terapeutické užití   MeSH
• hypoxie farmakoterapie   metabolismus   patologie   MeSH
• krysa rodu Rattus MeSH
• mediátory zánětu antagonisté a inhibitory   metabolismus   MeSH
• obstrukční spánková apnoe farmakoterapie   metabolismus   patologie   MeSH
• pankreas účinky léků   metabolismus   patologie   MeSH
• potkani Wistar MeSH
• spinové značení MeSH
• zánět farmakoterapie   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antioxidancia MeSH
• cyklické N-oxidy MeSH
• mediátory zánětu MeSH
• spinové značení MeSH
• tempol MeSH Prohlížeč

Performing hypoxia-reoxygenation cycles in cell culture with a cycle duration accurately reflecting what occurs in obstructive sleep apnea (OSA) patients is a difficult but crucial technical challenge. Our goal was to develop a novel device to expose multiple cell culture dishes to intermittent hypoxia (IH) cycles relevant to OSA with limited gas consumption. With gas flows as low as 200 ml/min, our combination of plate holders with gas-permeable cultureware generates rapid normoxia-hypoxia cycles. Cycles alternating 1 min at 20% O2 followed by 1 min at 2% O2 resulted in Po2 values ranging from 124 to 44 mmHg. Extending hypoxic and normoxic phases to 10 min allowed Po2 variations from 120 to 25 mmHg. The volume of culture medium or the presence of cells only modestly affected the Po2 variations. In contrast, the nadir of the hypoxia phase increased when measured at different heights above the membrane. We validated the physiological relevance of this model by showing that hypoxia inducible factor-1α expression was significantly increased by IH exposure in human aortic endothelial cells, murine breast carcinoma (4T1) cells as well as in a blood-brain barrier model (2.5-, 1.5-, and 6-fold increases, respectively). In conclusion, we have established a new device to perform rapid intermittent hypoxia cycles in cell cultures, with minimal gas consumption and the possibility to expose several culture dishes simultaneously. This device will allow functional studies of the consequences of IH and deciphering of the molecular biology of IH at the cellular level using oxygen cycles that are clinically relevant to OSA.

• Klíčová slova
• cell hypertrophy, diabetic nephropathy, fibrosis, mTOR complex 1, microRNAs,
• MeSH
• buněčné kultury * přístrojové vybavení   MeSH
• časové faktory MeSH
• design vybavení MeSH
• endoteliální buňky metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• hypoxie buňky MeSH
• hypoxie metabolismus   MeSH
• kultivační média metabolismus   MeSH
• kyslík metabolismus   MeSH
• lidé MeSH
• nádorová hypoxie MeSH
• nádorové buněčné linie MeSH
• nádory prsu metabolismus   MeSH
• obstrukční spánková apnoe metabolismus   MeSH
• plyny MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• HIF1A protein, human MeSH Prohlížeč
• kultivační média MeSH
• kyslík MeSH
• plyny MeSH

Obstructive sleep apnoea (OSA) has been associated with disturbances in energy metabolism and insulin resistance, nevertheless, the links between OSA severity, resting energy expenditure (REE) and insulin resistance (homeostasis model assessment, HOMA-IR) remained unexplored. Therefore, we investigated the effects of OSA severity on REE, and relationships between REE and HOMA-IR in patients with OSA. Forty men [mean (SD) age 49.4 (11.4) years] underwent overnight polysomnography; REE was assessed using indirect calorimetry. REE adjusted for fat-free mass (FFM) was higher in patients with moderate-to severe OSA [n=24; body mass index (BMI) 31.1 (2.7) kg.m(-2); apnoea-hypopnoea index (AHI)>/=15 episodes.h(-1)] compared to participants with no clinically significant OSA (n=16; BMI 30.3 (2.2) kg.m(-2); AHI<15 episodes.h(-1)) [median (interquartile range) 30.4 (26.1-31.3) versus 25.8 (24.6-27.3) kcal.kg(-1).24 h(-1), p=0.005)]. AHI and oxygen desaturation index (ODI) were directly related to REE/FFM (p=0.001; p<0.001, respectively) and to HOMA-IR (p<0.001 for both). In stepwise multiple linear models, REE/FFM was independently predicted by ODI (p<0.001) and age (p=0.028) (R(2)=0.346); HOMA-IR was independently predicted by ODI only (p<0.001, R(2)=0.457). In conclusion, male patients with moderate-to severe OSA have increased REE paralleled by impaired insulin sensitivity. Severity of nocturnal intermittent hypoxia reflected by ODI is an independent predictor of REE/FFM and HOMA-IR.

• MeSH
• adipokiny krev   MeSH
• dospělí MeSH
• energetický metabolismus * MeSH
• glukosa metabolismus   MeSH
• index tělesné hmotnosti MeSH
• inzulinová rezistence * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nepřímá kalorimetrie MeSH
• obezita komplikace   patofyziologie   MeSH
• obstrukční spánková apnoe metabolismus   patofyziologie   MeSH
• odpočinek MeSH
• polysomnografie MeSH
• senioři MeSH
• složení těla MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adipokiny MeSH
• glukosa MeSH

OBJECTIVES: Obstructive sleep apnea is associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Although several studies have suggested that intermittent hypoxia in obstructive sleep apnea may induce abnormalities in glucose homeostasis, it remains to be determined whether these abnormalities improve after discontinuation of the exposure. The objective of this study was to delineate the effects of intermittent hypoxia on glucose homeostasis, beta cell function, and liver glucose metabolism and to investigate whether the impairments improve after the hypoxic exposure is discontinued. INTERVENTIONS: C57BL6/J mice were exposed to 14 days of intermittent hypoxia, 14 days of intermittent air, or 7 days of intermittent hypoxia followed by 7 days of intermittent air (recovery paradigm). Glucose and insulin tolerance tests were performed to estimate whole-body insulin sensitivity and calculate measures of beta cell function. Oxidative stress in pancreatic tissue and glucose output from isolated hepatocytes were also assessed. RESULTS: Intermittent hypoxia increased fasting glucose levels and worsened glucose tolerance by 67% and 27%, respectively. Furthermore, intermittent hypoxia exposure was associated with impairments in insulin sensitivity and beta cell function, an increase in liver glycogen, higher hepatocyte glucose output, and an increase in oxidative stress in the pancreas. While fasting glucose levels and hepatic glucose output normalized after discontinuation of the hypoxic exposure, glucose intolerance, insulin resistance, and impairments in beta cell function persisted. CONCLUSIONS: Intermittent hypoxia induces insulin resistance, impairs beta cell function, enhances hepatocyte glucose output, and increases oxidative stress in the pancreas. Cessation of the hypoxic exposure does not fully reverse the observed changes in glucose metabolism.

• Klíčová slova
• Glucose intolerance, insulin resistance, intermittent hypoxia, obstructive sleep apnea,
• MeSH
• beta-buňky metabolismus   fyziologie   MeSH
• glukosa metabolismus   fyziologie   MeSH
• glukózový toleranční test MeSH
• homeostáza fyziologie   MeSH
• hypoxie metabolismus   patofyziologie   MeSH
• inzulinová rezistence fyziologie   MeSH
• krevní glukóza analýza   fyziologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obstrukční spánková apnoe metabolismus   patofyziologie   MeSH
• oxidační stres fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glukosa MeSH
• krevní glukóza MeSH