Oguz Kokturk

Leptin and Ghrelin Levels in Patients with Obstructive Sleep Apnea Syndrome

Background: Leptin is a hormone with well-investigated functions concerning body composition, energy homeostasis and feeding behavior in humans. The obstructive sleep apnea syndrome (OSAS) is strongly associated with obesity, which is known to be closely associated with hyperleptinemia. More recently, ghrelin, a hormone that also influences appetite and energy homeostasis, has been discovered. Objectives: The aim of this study was to investigate serum leptin and ghrelin levels in obese patients with OSAS in comparison with equally obese controls without OSAS. Methods: Thirty untreated obese patients with moderate-severe OSAS (apnea-hypopnea index: AHI ≧15) and 22 obese controls (AHI <5) were studied. To confirm the diagnosis, all patients underwent standard polysomnography in our sleep disorders center. Serum samples were taken at 08:00 h in the morning after overnight fasting. Results: Significantly higher serum leptin levels were found in OSAS patients compared to controls (p = 0.012), but there was no significant difference in serum ghrelin levels between OSAS patients and controls. Serum leptin levels were significantly correlated with body mass index in both OSAS patients (r = 0.55, p = 0.002) and controls (r = 0.46, p = 0.028), but only in OSAS patients was the leptin level significantly correlated with AHI (r = 0.38, p = 0.036). Conclusion: These data support findings suggesting that leptin is a hormonal factor affected by OSAS and not determined by obesity alone. Further studies are needed to investigate the relationship between serum ghrelin and OSAS.

Association of serotonin transporter gene polymorphism with obstructive sleep apnea syndrome

Background and Objective: Obstructive sleep apnea syndrome (OSAS) is a common condition characterized by repetitive pharyngeal collapse during sleep and daytime sleepiness. There is genetic predisposition to sleep disorders. Serotonin is involved in the regulation of sleep. The synaptic 5‐hydroxytryptamine (HT) is inactivated by presynaptic reuptake, which is mediated by the serotonin transporter. Blockage of the serotonin transporter leads to increased extracellular 5‐HT. Polymorphism of the serotonin transporter gene (STG) leads to alterations in serotonin level and may be important in OSAS. In this study, we aimed to assess the role of STG polymorphism in OSAS.

Comparison of Serum Adiponectin and Tumor Necrosis Factor-Alpha Levels between Patients with and without Obstructive Sleep Apnea Syndrome

Background: The obstructive sleep apnea syndrome (OSAS) is closely associated with cardiovascular and metabolic disorders. Objectives: The aim of this study was to evaluate the influence of OSAS on plasma adiponectin levels independent of obesity in our study group. We also investigated the association between plasma adiponectin, plasma tumor necrosis factor-α (TNF-α), obesity, cardiovascular disease (CVD) and OSAS. Methods: The patients were classified into controls or OSAS patients according to the apnea-hypopnea index (AHI): patients with an AHI <5 constituted the control group (n = 32) and patients with an AHI ≧5 constituted the OSAS group (n = 106). Plasma TNF-α and adiponectin levels were measured in both groups. Results: Plasma adiponectin levels were negatively correlated with AHI, body mass index (BMI) and SpO2 <90% and positively correlated with minimum oxygen saturation. The plasma levels of TNF-α were positively correlated with SpO2 <90%, BMI and fasting plasma glucose levels. In addition, there was a significant negative correlation between plasma TNF-α and adiponectin levels in theOSAS group. Compared with thenon-obese OSAS group, subjects with obesity and OSAS had lower adiponectin levels and SpO2 <90%, and higher TNF-α levels. Obese OSAS patients had higher rates of CVD with lower plasma adiponectin levels when compared with obese control subjects. Conclusion: Serum adiponectin is significantly lower in patients with OSAS and it is independent of obesity. This might explain the high incidence of CVD and metabolic syndrome in patients with OSAS.

Association of the -1438G/A polymorphism of the 5-HT2A receptor gene with obstructive sleep apnea syndrome

Objective: Serotonergic neurons innervating motoneurons increase their firing rates in response to respiratory challenges, and long-term facilitation of respiratory activity in response to hypoxia is serotonin (5-HT) dependent. Polymorphism of the genes which code for 5-HT receptors may affect functions of the serotonergic system, and may be associated with obstructive sleep apnea syndrome (OSAS). The objective in this study was to assess the significance of T102C and –1438G/A polymorphisms of the 5-HT2A receptor gene in OSAS. Methods: Fifty-five patients with OSAS and 102 healthy volun teers were included for genetic analyses of T102C and –1438G/A polymorphisms of the 5-HT2A receptor gene. Results: For the T102C polymorphism, there was no significant difference between the patients and controls and both genders (p > 0.05). For the –1438G/A polymorphism, the A/A and G/A genotypes were overrepresented in the patients and controls, respectively (p = 0.045). In the control group, the genotypes of both genders were not significantly different (p > 0.05). In the patients, the A/A and G/A genotypes were overrepresented in males and females, respectively (p = 0.035). Concerning males, the A/A genotype was overrepresented in patients (p = 0.007). Conclusion: Serotonergic mechanisms appear to be related to OSAS. The T102C polymorphism of the 5-HT2A receptor gene is not associated with OSAS. However, the –1438G/A polymorphism is associated with OSAS occurrence, especially in male patients. This polymorphism may also be associated with different OSAS incidences of both genders.

Relationship between sleep complaints and proinflammatory cytokines in haemodialysis patients

Background:  Sleep complaints are common in end‐stage renal disease. We aimed to investigate the relationship between sleep‐related complaints and inflammatory cytokines in haemodialysis (HD) patients, and also the effects of HD on sleep patterns and cytokine levels.

Apnea-hypopnea indexes calculated using different hypopnea definitions and their relation to major symptoms

A major problem in the discussion of sleep-disordered breathing is caused by the use of different criteria to define its terms. Hypopnea is a good example of this: there is no consensus about its definition yet. In our study, the diagnosis value of apnea-hypopnea indexes (AHIs) determined by different hypopnea definitions was evaluated. The 90 patients who had an AHI> 5, scored according to the hypopnea definition of the American Academy of Sleep Medicine (AASM), participated in our study. The records of these patients were scored three times more according to different hypopnea definitions (hypopnea-arousal, hypopnea-desaturation, hypopnea-effort). AHIAASM, AHIarousal, AHIdesat, and AHIeffortwere determined via new scorings. Patients’ daytime sleepiness was evaluated by the Epworth Sleepiness Scale (> 10). When all of three major symptoms (snoring, observed apnea, and daytime sleepiness) were found in a patient’s history, the term “clinical OSAS” was applied. The Epworth value correlated with all of the indexes. In the scope of both the determination of daytime sleepiness and the verification of “clinical OSAS” diagnosis, the value AHIAASM= 5 had the highest sensitivity (100%) and specificity (94%).

Consequences of hypoxia-reoxygenation phenomena in patients with obstructive sleep apnea syndrome.

Background and Objectives : Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by numerous episodes of absence of respiratory flow during sleep, which can be followed by a decrease in SaO2 , which is rapidly normalized when ventilation resumes. We hypothesize that this hypoxia-reoxygenation phenomena may affect the generation of vascular endothelial growth factor (VEGF), erythropoietin (EPO), endothelin-1 (ENDO-1), and inducible nitric oxide synthase (iNOS). Design and Setting : Prospective, patients referred to sleep disorders center. Patients and Methods : The presence and severity of OSAS were determined using the standard overnight polysomnography. Diagnosis of OSAS was made when the apnea-hypopnea index (AHI) was ≥15, independent of the appearance of symptoms. Serum levels of VEGF, EPO, ENDO-1, and nitrite-nitrate were measured after overnight fasting in 69 patients with OSAS and in 17 healthy control subjects. Serum levels of VEGF and nitrite-nitrate were measured again after 12 weeks of treatment with continuous positive airway pressure (CPAP) in OSAS patients. Results : Serum VEGF levels were found to be significantly higher and nitrite-nitrate levels were found to be significantly lower in OSAS patients than in controls (P=.003, .008, respectively), but no differences in EPO and ENDO-1 levels were found between the groups. We demonstrated that in OSAS patients, the serum VEGF levels were decreased and nitrate levels were increased after 12 weeks of CPAP treatment (P=.001, .002, respectively). Conclusion : According to our data, it is likely that hypoxia-reoxygenation phenomena affect the VEGF and nitrite-nitrate levels, which may be pathogenic factors in generating cardiovascular complications in OSAS.

Insulin receptor substrate gene polymorphism is associated with obstructive sleep apnea syndrome in men.

Objective: The objective of this study was to assess significance of insulin receptor substrate (IRS) ‐1 gene polymorphism (Gly972Arg) at codon 972 in obstructive sleep apnea syndrome (OSAS).

Association of GABABR1 Receptor Gene Polymorphism with Obstructive Sleep Apnea Syndrome

Objective: GABABR (gamma-amino butyric acid B receptor)-mediated neurotransmission has been implicated in the pathophysiology of a variety of neuropsychiatric disorders. GABABR1 gene variants were identified by single-strand conformation analysis. The nucleotide exchanges cause a substitution of alanine to valine in exon 1a1 (Ala20Val), a substitution of glycine to serine in exon 7 (Gly489Ser) and a silent C to G nucleotide exchange encoding the amino acid phenylalanine in exon 11 (Phe658Phe). The significance of GABABR1a gene polymorphism in obstructive sleep apnea syndrome (OSAS) as well as the association of these polymorphisms with the polysomnography findings in OSAS patients are not known. In this study, we aimed to assess the significance of 3 different GABABR1 gene polymorphisms (Ala20Val, Gly489Ser and Phe658Phe) in OSAS. Methods: Seventy-five patients (23 female and 52 male) with OSAS and 99 healthy volunteers (51 female, 48 male) were included in the study to assess Ala20Val, Gly489Ser and Phe658Phe polymorphisms of the GABABR1 gene. Results: For the Ala20Val variants, there was no significant difference between the genotypes and allele frequencies of the patients and controls, nor between both genders (p > 0.05). For Phe658Phe polymorphism, there was no significant difference between genotypes and allele frequencies of the patients and controls (p > 0.05). However, the C/C genotype was overrepresented and the T/C genotype was less frequent in male than female patients (p = 0.03). The C/C genotype was overrepresented and the T/C genotype was less frequent in male patients than male controls (p = 0.01). For GABABR1-Gly489Ser polymorphism, all of the patients and controls had G/G genotype. The apnea arousal index scores of the male patients with C/C genotype were significantly higher than in the patients with C/T genotype (p = 0.01). The percent total sleep time in non-REM 1 scores of the male patients with T/T genotype were significantly higher than in the patients with T/C genotype (p = 0.021). The percent total sleep time in non-REM 2 scores of the female patients with C/C genotype were significantly higher than in the patients with C/T genotype (p = 0.006). Conclusion: The Ala20Val polymorphism of the GABABR1 gene may be associated with OSAS, whereas Gly489Ser polymorphism does not seem to be involved in OSAS. The C/C variant of the Phe658Phe polymorphism GABABR1 gene seems associated with the occurrence of OSAS and is also associated with some sleep related parameters (apnea arousal index and percent total sleep time in non-REM) recorded by polysomnography.

Tryptophan Metabolism and Sleep

Sleep and sleep medicine are in the limelight of the researchers for thousands of years. The definition of sleep started to change in the light of scientific experiments performed in the twentieth century, and the number of investigations on sleep medicine increased tremendously. Effects of nutritional factors on the regulation of the sleep-wake cycle and central nervous system triggered new developments in sleep medicine. Tryptophan is an essential amino acid and a precursor of serotonin, melatonin, and nicotinamide. More recently, the role of tryptophan played in the sleep-wake rhythm of newborns has been an interest of research. High levels of tryptophan are associated with the improvement in the total hours and the efficiency of sleep and increase in the duration of nocturnal immobility and decrease in both the number of nocturnal awakenings and the sleep latency of newborns. Serotonin is named as “neurohormone of sleep” after understanding the key role of serotonin in the mechanisms of the sleep-wake cycle. Inhibition of tryptophan hydroxylase enzyme decreases both the synthesis of serotonin from tryptophan and serotonin levels significantly leading to insomnia. The serotonergic system has a crucial impact on sleep and airway stabilization. Majority of investigations on serotonin have shown that serotonergic system is related to obstructive sleep apnea syndrome (OSAS). Melatonin is secreted by the pineal gland. It is synthesized from 5-HT by pinealocytes and then released into the blood and cerebrospinal fluid. It is well known that melatonin affects sleep, circadian rhythm, puberty, antioxidant status, aging, and blood pressure. Contrary to other sleep disorders, scarce data on the involvement of melatonin in OSAS are available. Investigators have shown that plasma melatonin levels are low in patients with newly diagnosed OSAS. Elaborate prospective studies should be conducted while bearing in mind the drawbacks of aforementioned studies to better delineate the role of tryptophan and its products in the pathogenesis, adverse outcome of sleep disorders and to answer whether consumption of tryptophan-rich foods and its products might be a novel pharmacological treatment or not in sleep medicine.