Asociación e interacciones de la apnea obstructiva del sueño (AOS) y del síndrome de hipoventilación obesidad (SHO) / Metabolic associations of the obstructive sleep apnea (AOS) and hypoventilation obesity syndrome

La apnea obstructiva del sueño (AOS) y el síndrome hipoventilación-obesidad (SHO) son patologías que se encuentran estrechamente asociadas a la obesidad como principal factor de riesgo, hasta un 70% de los pacientes con AOS son obesos. Ambas patologías comparten procesos fisiopatológicos comunes, donde destaca la inflamación sistémica, lo que, sumado a la hipoxia crónica intermitente y la fragmentación del sueño característicos de la AOS, aumenta considerablemente el riesgo de presentar comorbilidades metabólicas como síndrome metabólico, alteraciones en el metabolismo de la glucosa (resistencia a la insulina y diabetes mellitus tipo 2), y hígado graso metabólico. En esta revisión narrativa, se describirán los mecanismos identificados en estas asociaciones, así como la prevalencia y la evidencia sobre el tratamiento de la AOS y del SHO

Obstructive sleep apnea (OSA) and obesity-hypoventilation syndrome (OHS) are pathologies that are closely associated with obesity as the main risk factor, up to 70% of patients with OSA are obese. Both pathologies share common pathophysiological processes, where systemic inflammation stands out, which, added to the intermittent chronic hypoxia and sleep fragmentation characteristic of OSA, considerably increases the risk of presenting metabolic comorbidities such as metabolic syndrome, alterations in the metabolism of the glucose (insulin resistance and type 2 diabetes mellitus), and metabolic fatty liver. In this narrative review, the mechanisms identified in these associations will be described, as well as the prevalence and evidence on the treatment of OSA and OHS

Applicability of predictive equations for resting energy expenditure in obese patients with obstructive sleep apnea

ABSTRACT Objective To investigate the applicability of predictive equations for resting energy expenditure (REE) in obese individuals with obstructive sleep apnea (OSA) and the effects of OSA severity on REE. Materials and methods Twenty-nine obese men, 41.5 ± 7 years old, with moderate and severe OSA were recruited. All subjects were submitted to a clinical polysomnography, body composition, and indirect calorimetry measurements. REE was also predicted by three different equations: Harris and Benedict (1919), Cunningham (1990), and DRI (2002). Results No effects of OSA severity on REE were found. The measured REE (2416.0 ± 447.1 kcal/day) and the REE predicted by equations were different from each other (F = 2713.88; p < 0.05): Harris and Benedict (2128.0 ± 245.8 kcal/day), Cunningham (1789.1 ± 167.8 kcal/day) and DRI (2011.1 ± 181.4 kcal/day). Pearson correlations showed a moderate positive correlation between the REE measured and predicted by all equations. Conclusion Our findings suggest that predictive equations for REE underestimate the energy expenditure in obese patients with sleep apnea. Also, no effects of OSA severity on REE were found.

Imbalance in the diurnal salivary testosterone/cortisol ratio in men with severe obstructive sleep apnea: an observational study / Desequilíbrio na proporção salivar diurna de testosterona/cortisol em homens com apneia obstrutiva do sono grave: um estudo observacional

ABSTRACT INTRODUCTION: The complex relationship between sleep disorders and hormones could lead to alterations in the production of cortisol and testosterone in obstructive sleep apnea (OSA) patients. OBJECTIVE: The purpose of this study was to determine the diurnal trajectories of salivary free-testosterone, free-cortisol and their ratio (T/C). METHODS: Ten subjects newly diagnosed with OSA, based on nocturnal polysomnography evaluation and excessive daytime sleepiness, and seven matched controls were consecutively recruited. Cortisol and testosterone were measured in salivary samples collected upon awakening, at noon and in the evening. The psychometric evaluation of anxiety/depression and referred sexual function disturbances was performed to evaluate the presence of neuropsychological comorbidities. RESULTS AND CONCLUSION: The main finding was that OSA subjects displayed hypocortisolism upon awakening and a significant reduction in testosterone concentration in the evening in comparison with the control group, which has maintained the physiological testosterone and cortisol diurnal fluctuation, with higher hormone concentrations in the morning and lower concentrations in the evening. The use of data from multiple diurnal measurements rather than a single point allowed the detection of T/C ratio changes of opposite signs at the beginning and end of the day: the OSA subjects had a higher T/C ratio than the controls in the morning, while their T/C ratio was significantly lower than that of the controls in the evening. The imbalances in the anabolic-catabolic diurnal equilibrium suggest that OSA is associated with a dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, potentially an underlying cause of some of the neuropsychological comorbidities observed in OSA patients.

Resumo Introdução: A relação complexa entre os distúrbios do sono e os hormônios pode levar a alterações na produção de cortisol e testosterona em pacientes com Apneia obstrutiva do sono (AOS). Objetivo: O objetivo deste estudo foi determinar as curvas diurnas de testosterona e cortisol livres na saliva e sua proporção (razão T/C). Método: Dez indivíduos recém-diagnosticados com AOS com base na avaliação por polissonografia noturna e sonolência diurna excessiva e sete controles pareados foram recrutados, consecutivamente. Cortisol e testosterona foram medidos em amostras de saliva coletadas ao acordar, ao meio-dia e à noite. A avaliação psicométrica dos distúrbios de ansiedade/depressão e função sexual mencionados foi realizada para detectar a presença de comorbidades neuropsicológicas. Resultados: O achado principal foi que os indivíduos com AOS apresentam hipocortisolismo ao acordar e uma redução significante na concentração de testosterona à noite, em comparação com o grupo controle, que manteve a variação fisiológica diurna de testosterona e cortisol com concentrações hormonais mais elevadas pela manhã e concentrações mais baixas durante a noite. O uso de dados de várias mensurações diurnas, em vez de uma única mensuração, permitiu detectar as alterações na razão T/C de sinais opostos no início e no final do dia: os indivíduos com AOS apresentaram razão T/C maior que os controles na parte da manhã, enquanto que a razão T/C foi significantemente inferior à dos controles durante a noite. Conclusão: Os desequilíbrios no balanço anabólico-catabólico diurno sugerem que a AOS está associada a uma desregulação dos eixos hipotálamo-hipófise-adrenal e hipotálamo-hipófise-gonadal, potencialmente a causa subjacente de algumas das comorbidades neuropsicológicas observadas em pacientes com AOS.

Uncoupling protein-2 mRNA expression in mice subjected to intermittent hypoxia / Expressão do mRNA da uncoupling protein-2 em camundongos submetidos à hipóxia intermitente

Objective: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA)-on pancreatic expression of uncoupling protein-2 (UCP2), as well as on glycemic and lipid profiles, in C57BL mice. Methods: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group) or to a sham procedure (normoxia group). The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 ± 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period). Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. Results: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11). Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01). The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09) and 21% higher pancreatic β-cell function (p = 0.01). Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of α- and β-cell staining for insulin and glucagon. Conclusions: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted. .

Objetivo: Investigar o efeito da hipóxia intermitente com um modelo de apneia obstrutiva do sono (AOS) sobre a expressão de uncoupling protein-2 (UCP2), assim como sobre perfis glicêmicos e lipídicos, em camundongos C57BL. Métodos: Camundongos C57BL machos foram expostos a hipóxia intermitente ou hipóxia simulada (grupo controle) 8 h/dia durante 35 dias. A condição de hipóxia intermitente envolveu a exposição dos camundongos a uma atmosfera de 92% de N e 8% de CO2 por 30 s, com redução progressiva de fração de O2 inspirado até 8 ± 1%, seguida por exposição a ar ambiente por 30 s e repetições do ciclo (480 ciclos no período experimental de 8 h). Os pâncreas foram dissecados para isolar as ilhotas. Foi realizada PCR em tempo real utilizando o método TaqMan. Resultados: A expressão do mRNA da UCP2 nas ilhotas pancreáticas foi 20% maior no grupo controle que no grupo hipóxia (p = 0,11). A insulina sérica de jejum foi maior no grupo hipóxia do que no grupo controle (p = 0,01). O modelo de avaliação da homeostase de resistência à insulina indicou que, em comparação com os camundongos controle, aqueles expostos à hipóxia intermitente apresentaram 15% menor resistência à insulina (p = 0,09) e 21% maior função das células beta (p = 0,01). A coloração das ilhotas pancreáticas por imuno-histoquímica não mostrou diferenças significativas entre os grupos em termos da área ou da intensidade das células alfa e beta, marcadas por insulina e glucagon. Conclusões: Segundo nosso conhecimento, esta é a primeira descrição do efeito da hipóxia intermitente sobre a expressão da UCP2. Nossos achados sugerem que UCP2 regula a produção de insulina na AOS. Futuras investigações sobre o papel da UCP2 no controle glicêmico em pacientes com AOS são justificadas. .

Role of nitric oxide in the diuresis and natriuresis occurring in patients with obstructive sleep apnoea syndrome.

Objective. To determine whether nitric oxide (NO) has any role in the diuresis and natriuresis observed in patients with obstructive sleep apnoea syndrome (OSAS). Methods. We measured 12-hour urine volume in the day and in the night in patients with OSAS (n=20) and determined the concentrations of urinary sodium and nitrate. The frequency of urination in the night was also noted. The measurements were done again after two nights of continuous positive airway pressure (CPAP) therapy and after putting the patients on oral anti-oxidant treatment (vitamin C–100mg BD and vitamin E–400IU BD) for 45 days. Ten healthy normal subjects underwent the same protocol except the CPAP therapy. Results. In patients with OSAS, the night urine volume and sodium concentration were similar and the nitrate levels were higher compared to those in the day. After CPAP therapy, while the urine volume and sodium concentration decreased, the nitrate level became similar to that in the day. Such effects were not observed after anti-oxidant treatment. The frequency of urination was decreased in both the instances. The effects observed after CPAP therapy were similar to those observed in control subjects with or without anti-oxidant treatment. Conclusion. Renal NO promotes diuresis and natriuresis in patients with OSAS.

Proton magnetic resonance spectroscopy of brain in obstructive sleep apnoea in north Indian Asian subjects.

Background & objectives: Repeated apnoeic/hypoapnoeic episodes during sleep may produce cerebral damage in patients with obstructive sleep apnoea (OSA). The aim of this study was to determine the absolute concentration of cerebral metabolites in apnoeic and non-apnoeic subjects from different regions of the brain to monitor the regional variation of cerebral metabolites. Methods: Absolute concentration of cerebral metabolites was determined by using early morning proton magnetic resonance spectroscopy (1H MRS) in 18 apnoeic patients with OSA (apnoeics) having apnoea/hypopnoea index (AHI) >5/h, while 32 were non-apnoeic subjects with AHI< 5/h. Results: The absolute concentration of tNAA [(N-acetylaspartate (NAA)+N-acetylaspartylglutamate (NAAG)] was observed to be statistically significantly lower (P<0.05) in apnoeics in the left temporal and left frontal gray regions compared to non-apnoeics. The Glx (glutamine, Gln + glutamate, Glu) resonance showed higher concentration (but not statistically significant) in the left temporal and left frontal regions of the brain in apnoeics compared to non-apnoeics. The absolute concentration of myo-inositol (mI) was significantly high (P<0.03) in apnoeics in the occipital region compared to non-apnoeics. Interpretation & conclusions: Reduction in the absolute concentration of tNAA in apnoeics is suggestive of neuronal damage, probably caused by repeated apnoeic episodes in these patients. NAA showed negative correlation with AHI in the left frontal region, while Cho and mI were positively correlated in the occipital region and Glx showed positive correlation in the left temporal region of the brain. Overall, our results demonstrate that the variation in metabolites concentrations is not uniform across various regions of the brain studied in patients with OSA. Further studies with a large cohort of patients to substantiate these observations are required.

Consequências metabólicas na SAOS não tratada / Metabolic consequences of untreated obstructive sleep apnea syndrome

A associação entre SAOS e a síndrome metabólica é reconhecida, sendo denominada síndrome Z. Os critérios para a síndrome metabólica incluem pelo menos três dos seguintes fatores: obesidade central (circunferência da cintura > 102 cm em homens e > 88 cm em mulheres); triglicérides > 150 mg/dL; HDL colesterol < 40 mg/dL em homens e < 50 mg/dL em mulheres; pressão arterial > 130/85 mmHg; e glicemia de jejum > 100 mg/dL. A obesidade central esta associada a SAOS e síndrome metabólica, havendo evidências de que a apneia do sono seja um fator de risco independente da obesidade, intolerância à glicose e resistência insulínica. Embora a obesidade central seja um fator de risco para ambas as condições, há evidências de que a apneia do sono seja um fator de risco independente para a intolerância à glicose e a resistência à insulina. Os mecanismos implicados decorrem da ativação do sistema nervoso simpático e do eixo hipotálamo-hipófise-adrenal; da ativação de fatores pró-inflamatórios, como IL-6 e TNF-α; e da diminuição dos níveis de adiponectina mediados principalmente pela hipoxemia intermitente relacionada às apneias. Apesar dessas evidências, os resultados dos estudos são controversos em relação aos benefícios do tratamento da apneia do sono com CPAP nas alterações metabólicas. Adicionalmente, os poucos estudos que abordaram a apneia do sono obstrutiva como um fator de risco para as dislipidemias apresentaram resultados discordantes. Estudos controlados, populacionais e longitudinais são necessários para esclarecer a interação entre a apneia do sono e as consequências metabólicas no sentido de se tratar adequadamente esses indivíduos.

There is a recognized association between obstructive sleep apnea syndrome and metabolic syndrome, designated syndrome Z. The criteria for metabolic syndrome include at least three of the following factors: central obesity (waist circumference > 102 cm for males and > 88 cm for females); triglycerides > 150 mg/dL; HDL cholesterol < 40 mg/dL for males and < 50 mg/dL for females; arterial blood pressure > 130/85 mmHg; and fasting glucose > 100 mg/dL. Central obesity is associated with OSAS and metabolic syndrome, and there is evidence that obstructive sleep apnea is an independent risk factor for obesity, glucose intolerance and insulin resistance. The implied mechanisms result from the activation of the sympathetic nervous system and of the hypothalamus-hypophysis-adrenal axis; activation of pro-inflammatory markers, such as IL-6 and TNF-α; and the reduction in adiponectin levels, principally triggered by intermittent hypoxemia related to apnea. Despite such evidence, the results are controversial regarding the benefits of treating sleep apnea with CPAP in the presence of these metabolic alterations. In addition, the few studies that have addressed sleep apnea as a risk factor for dyslipidemia have presented conflicting results. Population-based, longitudinal controlled studies are necessary in order to elucidate the interaction between sleep apnea and metabolic consequences so that these individuals are properly treated.

The reciprocal interaction between sleep and type 2 diabetes mellitus: facts and perspectives

Type 2 diabetes mellitus is a systemic disease characterized by intolerance to glucose and peripheral resistance to insulin. This endocrine disease affects fundamental mechanisms of the central nervous system and jeopardizes the balance of vital functions such as the cardiovascular and circadian rhythm. The increased prevalence of metabolic disorders in our society is aggravated by endemic voluntary postponement of bedtime and by the current sedentary lifestyle, leading to epidemic proportions of obese people. Diabetes and chronic loss of sleep share the fact that both affect millions and one is detrimental to the other. Indeed, sleep deficits have marked modulatory effects on glucose metabolism and insulin sensitivity and foster metabolic syndrome that culminates in sleep disorders like restless syndrome and sleep apnea, which in turn lead to poor sleep quality. We examine the hypothesis that these two worldwide emerging disorders are due to two interlinked cycles. In our paradigm, we establish an intimate relationship between diabetes and sleep disturbances and postulate possible mechanisms that provide support for this conjecture. In addition, we propose some perspectives about the development of the reciprocal interaction between predictor components of metabolic syndrome and sleep disturbances that lead to poor sleep quality. The ability to predict the development and identify or associate a given mode of sleep disturbance to diabetes would be a valuable asset in the assessment of both. Furthermore, major advances in care coupled with healthy lifestyles can ensure a higher quality of life for people with diabetes.

Obstructive sleep apnea and insulin resistance: a role for microcirculation?

A apnéia obstrutiva do sono é um problema médico cujo reconhecimento tem aumentado. As últimas pesquisas mostrando sua freqüência na população em geral e seu importante papel metabólico, vascular e comportamental aumentou o número e a natureza das investigações revelando, assim, novos aspectos que abrem caminhos para estudos. Embora a apnéia obstrutiva do sono seja um fenômeno bem conhecido acompanhando diabetes e obesidade, novas descobertas sugerem que esta relação causal pode também ser verdadeira no sentido inverso. Na realidade, a apnéia obstrutiva do sono pode ser o marco inicial ou primário que induz ou agrava uma série de distúrbios vasculares e metabólicos que se aproximam da síndrome metabólica. Esta revisão discutirá mecanismos estabelecidos e potenciais responsáveis por estas mudanças. A apnéia obstrutiva do sono parece realmente juntar todos os elementos necessários para induzir resistência à insulina, hipertensão e possivelmente insuficiência cardíaca. Após análise cuidadosa destas modificações, considerando que as mesmas são interligadas, propomos que a microcirculação, como ocorre nos casos de síndrome metabólica e diabetes, poderia representar o denominador comum que mediaria a progressão desta patologia. Esta hipótese é discutida em detalhe e deve ser verificada em estudos pré-clínicos e clínicos apropriados que são atualmente possíveis usando técnicas não-invasivas em humanos.