Effects of sex, age, and body mass index on serum bicarbonate.

Rationale: Obesity hypoventilation syndrome (OHS) is often underdiagnosed, with significant morbidity and mortality. Bicarbonate, as a surrogate of arterial carbon dioxide, has been proposed as a screening tool for OHS. Understanding the predictors of serum bicarbonate could provide insights into risk factors for OHS. We hypothesized that the bicarbonate levels would increase with an increase in body mass index (BMI), since the prevalence of OHS increases with obesity. Methods: We used the TriNetX Research Network, an electronic health record database with de-identified clinical data from participating healthcare organizations across the United States, to identify 93,320 adults without pulmonary or advanced renal diseases who had serum bicarbonate and BMI measurements within 6 months of each other between 2017 and 2022. We used linear regression analysis to examine the associations between bicarbonate and BMI, age, and their interactions for the entire cohort and stratified by sex. We also applied a non-linear machine learning algorithm (XGBoost) to examine the relative importance of age, BMI, sex, race/ethnicity, and obstructive sleep apnea (OSA) status on bicarbonate. Results: This cohort population was 56% women and 72% white and 80% non-Hispanic individuals, with an average (SD) age of 49.4 (17.9) years and a BMI of 29.1 (6.1) kg/m2. The mean bicarbonate was 24.8 (2.8) mmol/L, with higher levels in men (mean 25.2 mmol/L) than in women (mean 24.4 mmol/L). We found a small negative association between bicarbonate and BMI, with an expected change of -0.03 mmol/L in bicarbonate for each 1 kg/m2 increase in BMI (p < 0.001), in the entire cohort and both sexes. We found sex differences in the bicarbonate trajectory with age, with women exhibiting lower bicarbonate values than men until age 50, after which the bicarbonate levels were modestly higher. The non-linear machine learning algorithm similarly revealed that age and sex played larger roles in determining bicarbonate levels than the BMI or OSA status. Conclusion: Contrary to our hypothesis, BMI is not associated with elevated bicarbonate levels, and age modifies the impact of sex on bicarbonate.

Ketogenic diet acutely improves gas exchange and sleep apnoea in obesity hypoventilation syndrome: A non-randomized crossover study.

BACKGROUND AND OBJECTIVE: Obesity hypoventilation syndrome (OHS) causes hypercapnia which is often refractory to current therapies. We examine whether hypercapnia in OHS can be improved by a ketogenic dietary intervention. METHODS: We conducted a single-arm crossover clinical trial to examine the impact of a ketogenic diet on CO2 levels in patients with OHS. Patients were instructed to adhere to 1 week of regular diet, 2 weeks of ketogenic diet, followed by 1 week of regular diet in an ambulatory setting. Adherence was assessed with capillary ketone levels and continuous glucose monitors. At weekly visits, we measured blood gases, calorimetry, body composition, metabolic profiles, and sleep studies. Outcomes were assessed with linear mixed models. RESULTS: A total of 20 subjects completed the study. Blood ketones increased from 0.14 ± 0.08 during regular diet to 1.99 ± 1.11 mmol/L (p < 0.001) after 2 weeks of ketogenic diet. Ketogenic diet decreased venous CO2 by 3.0 mm Hg (p = 0.008), bicarbonate by 1.8 mmol/L (p = 0.001), and weight by 3.4 kg (p < 0.001). Sleep apnoea severity and nocturnal oxygen levels significantly improved. Ketogenic diet lowered respiratory quotient, fat mass, body water, glucose, insulin, triglycerides, leptin, and insulin-like growth factor 1. Rebound hypercapnia was observed after resuming regular diet. CO2 lowering was dependent on baseline hypercapnia, and associated with circulating ketone levels and respiratory quotient. The ketogenic diet was well tolerated. CONCLUSION: This study demonstrates for the first time that a ketogenic diet may be useful for control of hypercapnia and sleep apnoea in patients with obesity hypoventilation syndrome.

Connecting insufficient sleep and insomnia with metabolic dysfunction.

The global epidemic of obesity and type 2 diabetes parallels the rampant state of sleep deprivation in our society. Epidemiological studies consistently show an association between insufficient sleep and metabolic dysfunction. Mechanistically, sleep and circadian rhythm exert considerable influences on hormones involved in appetite regulation and energy metabolism. As such, data from experimental sleep deprivation in humans demonstrate that insufficient sleep induces a positive energy balance with resultant weight gain, due to increased energy intake that far exceeds the additional energy expenditure of nocturnal wakefulness, and adversely impacts glucose metabolism. Conversely, animal models have found that sleep loss-induced energy expenditure exceeds caloric intake resulting in net weight loss. However, animal models have significant limitations, which may diminish the clinical relevance of their metabolic findings. Clinically, insomnia disorder and insomnia symptoms are associated with adverse glucose outcomes, though it remains challenging to isolate the effects of insomnia on metabolic outcomes independent of comorbidities and insufficient sleep durations. Furthermore, both pharmacological and behavioral interventions for insomnia may have direct metabolic effects. The goal of this review is to establish an updated framework for the causal links between insufficient sleep and insomnia and risks for type 2 diabetes and obesity.

Time-Restricted Eating in Metabolic Syndrome-Focus on Blood Pressure Outcomes.

PURPOSE OF THE REVIEW: Time-restricted eating (TRE) is a promising dietary intervention for weight loss and improvement of cardiometabolic risk factors. We aim to provide a critical review of blood pressure outcomes reported in clinical TRE studies in adults with metabolic syndrome, in the context of the proposed mechanisms that underlie the relationship between timing of eating and blood pressure. RECENT FINDINGS: Clinical TRE studies report mixed results pertaining to blood pressure outcomes, likely due to significant heterogeneity in study design and TRE protocols. Mechanistically, TRE's metabolic benefits have been speculated to be mediated by alignment of meal timing with circadian regulation of metabolic processes and/or enhancement of catabolism as a result of prolonging the fasting period. TRE protocols that start and end earlier appear to have more pronounced blood pressure lowering effects. Blood pressure also tends to be lower with narrower eating windows. Concurrent weight loss is not consistently linked to blood pressure reduction, while lower insulin levels may be an important factor for blood pressure reduction. Notably, no published studies have reported 24-h blood pressure profiles or data on blood pressure variability. Blood pressure has only been examined in limited TRE studies, measured at a single time point. Given the clinical relevance of blood pressure's diurnal variability and the mechanistic evidence underlying timing of eating and blood pressure effects, more studies are needed to investigate TRE's effects on the diurnal variability of blood pressure.

Metformin Alleviates Airway Hyperresponsiveness in a Mouse Model of Diet-Induced Obesity.

Obese asthma is a unique phenotype of asthma characterized by non-allergic airway hyperresponsiveness (AHR) and inflammation which responds poorly to standard asthma therapy. Metformin is an oral hypoglycemic drug with insulin-sensitizing and anti-inflammatory properties. The objective of the current study was to test the effect of metformin on AHR in a mouse model of diet-induced obesity (DIO). We fed 12-week-old C57BL/6J DIO mice with a high fat diet for 8 weeks and treated them with either placebo (control, n = 10) or metformin (n = 10) added in drinking water (300 mg/kg/day) during the last 2 weeks of the experiment. We assessed AHR, metabolic profiles, and inflammatory markers after treatments. Metformin did not affect body weight or fasting blood glucose, but significantly reduced serum insulin (p = 0.0117). Metformin reduced AHR at 30 mg/ml of methacholine challenge (p = 0.0052) without affecting baseline airway resistance. Metformin did not affect circulating white blood cell counts or lung cytokine mRNA expression, but modestly decreased circulating platelet count. We conclude that metformin alleviated AHR in DIO mice. This finding suggests metformin has the potential to become an adjuvant pharmacological therapy in obese asthma.

ATS Core Curriculum 2021. Adult Sleep Medicine: Sleep Apnea.

The American Thoracic Society Sleep Core Curriculum updates clinicians on important sleep topics, presented during the annual meeting, and appearing in summary here. This year's sleep core theme is sleep-disordered breathing and its management. Topics range from pathophysiological mechanisms for the association of obstructive sleep apnea (OSA) and metabolic syndrome, surgical modalities of OSA treatment, comorbid insomnia and OSA, central sleep apnea, and sleep practices during a pandemic. OSA has been associated with metabolic syndrome, independent of the role of obesity, and the pathophysiology suggests a role for sleep fragmentation and intermittent hypoxia in observed metabolic outcomes. In specific patient populations, surgical treatment modalities for OSA have demonstrated large reductions in objective disease severity compared with no treatment and may facilitate adherence to positive airway pressure treatment. Patient-centered approaches to comorbid insomnia and sleep apnea include evaluating for both OSA and insomnia simultaneously and using shared-decision making to determine the order and timing of positive airway pressure therapy and cognitive behavioral therapy for insomnia. The pathophysiology of central sleep apnea is complex and may be due to the loss of drive to breathe or instability in the regulatory pathways that control ventilation. Pandemic-era sleep practices have evolved rapidly to balance safety and sustainability of care for patients with sleep-disordered breathing.

Effects of Dinner Timing on Sleep Stage Distribution and EEG Power Spectrum in Healthy Volunteers.

PURPOSE: Eating time and sleep habits are important modifiable behaviors that affect metabolic health, but the relationship between food intake and sleep remains incompletely understood. Observational data suggest that late food intake is associated with impaired sleep quality. We examined the effect of routine dinner (RD, 5 hours before bedtime) vs late dinner (LD, 1 hour before bedtime) on sleep architecture in healthy volunteers. PARTICIPANTS AND METHODS: This was a post hoc analysis of a randomized crossover study of RD vs LD with a fixed sleep opportunity in a laboratory setting. On each of the two visits, 20 healthy adult volunteers (10 women) received an isocaloric meal followed by overnight polysomnography. Sleep architecture over the course of the night was assessed using visual sleep staging and EEG spectral power analysis and was compared between RD and LD. We modeled the proportions of spectral power in alpha, beta, delta, and theta bands as functions of dinner timing, time of night, and their interaction with mixed-effect spline regression. RESULTS: Conventional sleep stages were similar between the 2 visits. LD caused a 2.5% initial increase in delta power and a reciprocal 2.7% decrease in combined alpha and beta power (p<0.0001). These effects diminished as sleep continued with a reversal of these patterns in the latter part of the night. CONCLUSION: Contrary to the existing literature, shifting dinner timing from 5 hours before sleep to 1 hour before sleep in healthy volunteers did not result in significant adverse changes in overnight sleep architecture. In fact, LD was associated with deeper sleep in the beginning of the night and lighter sleep in the latter part of the night in healthy volunteers. This novel manifestation of postprandial hypersomnia may have therapeutic potential in patients with sleep disorders.

Leptin receptor expression in the dorsomedial hypothalamus stimulates breathing during NREM sleep in db/db mice.

STUDY OBJECTIVES: Obesity leads to obstructive sleep apnea (OSA), which is recurrent upper airway obstruction during sleep, and obesity hypoventilation syndrome (OHS), hypoventilation during sleep resulting in daytime hypercapnia. Impaired leptin signaling in the brain was implicated in both conditions, but mechanisms are unknown. We have previously shown that leptin stimulates breathing and treats OSA and OHS in leptin-deficient ob/ob mice and leptin-resistant diet-induced obese mice and that leptin's respiratory effects may occur in the dorsomedial hypothalamus (DMH). We hypothesized that leptin receptor LepRb-deficient db/db mice have obesity hypoventilation and that restoration of leptin signaling in the DMH will increase ventilation during sleep in these animals. METHODS: We measured arterial blood gas in unanesthetized awake db/db mice. We subsequently infected these animals with Ad-LepRb or control Ad-mCherry virus into the DMH and measured ventilation during sleep as well as CO2 production after intracerebroventricular (ICV) infusions of phosphate-buffered saline or leptin. RESULTS: Awake db/db mice had elevated CO2 levels in the arterial blood. Ad-LepRb infection resulted in LepRb expression in the DMH neurons in a similar fashion to wildtype mice. In LepRb-DMH db/db mice, ICV leptin shortened REM sleep and increased inspiratory flow, tidal volume, and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in these animals. CONCLUSION: Leptin stimulates breathing and treats obesity hypoventilation acting on LepRb-positive neurons in the DMH.

Metabolic Effects of Late Dinner in Healthy Volunteers-A Randomized Crossover Clinical Trial.

CONTEXT: Consuming calories later in the day is associated with obesity and metabolic syndrome. We hypothesized that eating a late dinner alters substrate metabolism during sleep in a manner that promotes obesity. OBJECTIVE: The objective of this work is to examine the impact of late dinner on nocturnal metabolism in healthy volunteers. DESIGN AND SETTING: This is a randomized crossover trial of late dinner (LD, 22:00) vs routine dinner (RD, 18:00), with a fixed sleep period (23:00-07:00) in a laboratory setting. PARTICIPANTS: Participants comprised 20 healthy volunteers (10 male, 10 female), age 26.0 ± 0.6 years, body mass index 23.2 ±â€…0.7 kg/m2, accustomed to a bedtime between 22:00 and 01:00. INTERVENTIONS: An isocaloric macronutrient diet was administered on both visits. Dinner (35% daily kcal, 50% carbohydrate, 35% fat) with an oral lipid tracer ([2H31] palmitate, 15 mg/kg) was given at 18:00 with RD and 22:00 with LD. MAIN OUTCOME MEASURES: Measurements included nocturnal and next-morning hourly plasma glucose, insulin, triglycerides, free fatty acids (FFAs), cortisol, dietary fatty acid oxidation, and overnight polysomnography. RESULTS: LD caused a 4-hour shift in the postprandial period, overlapping with the sleep phase. Independent of this shift, the postprandial period following LD was characterized by higher glucose, a triglyceride peak delay, and lower FFA and dietary fatty acid oxidation. LD did not affect sleep architecture, but increased plasma cortisol. These metabolic changes were most pronounced in habitual earlier sleepers determined by actigraphy monitoring. CONCLUSION: LD induces nocturnal glucose intolerance, and reduces fatty acid oxidation and mobilization, particularly in earlier sleepers. These effects might promote obesity if they recur chronically.

Understanding the pathophysiological mechanisms of cardiometabolic complications in obstructive sleep apnoea: towards personalised treatment approaches.

In January 2019, a European Respiratory Society research seminar entitled "Targeting the detrimental effects of sleep disturbances and disorders" was held in Dublin, Ireland. It provided the opportunity to critically review the current evidence of pathophysiological responses of sleep disturbances, such as sleep deprivation, sleep fragmentation or circadian misalignment and of abnormalities in physiological gases such as oxygen and carbon dioxide, which occur frequently in respiratory conditions during sleep. A specific emphasis of the seminar was placed on the evaluation of the current state of knowledge of the pathophysiology of cardiovascular and metabolic diseases in obstructive sleep apnoea (OSA). Identification of the detailed mechanisms of these processes is of major importance to the field and this seminar offered an ideal platform to exchange knowledge, and to discuss pitfalls of current models and the design of future collaborative studies. In addition, we debated the limitations of current treatment strategies for cardiometabolic complications in OSA and discussed potentially valuable alternative approaches.

The Role of Animal Models in Developing Pharmacotherapy for Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is a highly prevalent disease characterized by recurrent closure of the upper airway during sleep. It has a complex pathophysiology involving four main phenotypes. An abnormal upper airway anatomy is the key factor that predisposes to sleep-related collapse of the pharynx, but it may not be sufficient for OSA development. Non-anatomical traits, including (1) a compromised neuromuscular response of the upper airway to obstruction, (2) an unstable respiratory control (high loop gain), and (3) a low arousal threshold, predict the development of OSA in association with anatomical abnormalities. Current therapies for OSA, such as continuous positive airway pressure (CPAP) and oral appliances, have poor adherence or variable efficacy among patients. The search for novel therapeutic approaches for OSA, including pharmacological agents, has been pursued over the past years. New insights into OSA pharmacotherapy have been provided by preclinical studies, which highlight the importance of appropriate use of animal models of OSA, their applicability, and limitations. In the present review, we discuss potential pharmacological targets for OSA discovered using animal models.