Chenjuan Gu’s research while affiliated with Johns Hopkins University and other places

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.

Background Obesity and its associated metabolic complications are leading causes of morbidity and mortality worldwide. Recent studies suggest that the timing of meals may be critically important for weight control and metabolic health. Consuming calories later in the day is associated with greater risks of obesity and metabolic syndrome. Interventional diet studies show more weight loss with early, rather than later, eating. Our team conducted a randomized, crossover study ("Dinner Time Study") that compared the metabolic effects of routine dinner (6pm) vs late dinner (10pm) with a fixed sleep period (11pm-7am) in young, healthy adults. We found that late dinner caused an 18% increase in post-prandial glucose and a 10% decrease in dietary fat oxidation. These metabolic consequences in the long term may lead to the development of obesity and type 2 diabetes. However, it remains unclear whether the adverse metabolic effects of late dinner are mediated by circadian misalignment (eating at the "wrong" time relative to the body's central circadian clock) or mediated by sleep (eating too close to bedtime, coinciding with the fall in metabolic rate induced by sleep). To address this question, we aim to examine the metabolic effects of early dinner, late dinner, and late dinner followed by delayed sleep, in healthy adults. Methods Dinner Time 2 Study is a randomized crossover trial with 3 treatment arms with a 3-4-week washout period: (1) early dinner + routine sleep; (2) late dinner + routine sleep; (3) late dinner + late sleep. Dinner times and bedtimes will be customized to each participant's central circadian rhythm (assessed by dim light melatonin onset, DLMO). The primary objectives of this study are to (1) examine the metabolic effects of early dinner (DLMO-3h) vs late dinner (DLMO+1h) with a fixed routine bedtime (DLMO+2h); (2) examine the metabolic effects of routine bedtime (DLMO+2h) vs delayed bedtime (DLMO+6h) with a fixed late dinner time (DLMO+1h). We will examine 24-h profiles of glucose, insulin, free fatty acids, triglycerides, and dietary fat oxidation using serial blood sampling and an ingested stable isotope ([2H31] palmitate) tracer. We aim to recruit 20 healthy adults, age 18-30 years old, with a BMI 18-29.9 kg/m2. Participants who perform night shift work or have any sleep disorders or metabolic diseases including diabetes are ineligible. Each participant will have 4 overnight admissions to our Clinical Research Unit (1 DLMO visit and 3 metabolic visits). A total of 3 participants have successfully completed the protocol since recruitment started in 2021. Conclusion Dinner Time 2 will greatly advance our understanding of the interactions between meal timing, sleep timing, and metabolism, which could inform the design and implementation of future studies that leverage chronobiology to combat diabetes and obesity. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Introduction Obstructive sleep apnea (OSA) has been associated with Alzheimer’s disease (AD) progression but a causal relationship is unclear. We hypothesized that OSA can influence (AD) biomarkers including beta-amyloid (Aβ) and tau, as well as neural filament light chain (NfL). Methods To test this hypothesis, we examined plasma tau, NfL, Aβ42, and Aβ40 in a randomized crossover study of OSA vs. 3-night CPAP withdrawal in 30 subjects with severe OSA adherent to CPAP. We compared the overnight change in evening to morning plasma samples across the untreated night (off) versus CPAP treated night (on). Paired t-tests were used to compare measures across sleep conditions while hierarchical linear regression with difference in the overnight change of each biomarker between conditions were set as dependent variables with age and sex as covariates. Results Of the 30 subjects, mean age was 52 years and 27% were women. As expected, CPAP withdrawal caused sleep disruption and recurrence of underlying OSA. Sleep architecture measures including %N3 (Off: 6.1% [3.7-8.5], On: 15.1% [10.6-19.6], p<0.001), %REM (Off: 11.8% [8.8-14.7], On: 20.6% [18.3-22.9], p<0.001), and measures of breathing such as AHI4% (Off: 63/hr [54-72], On: 3/hr [2-4], p<0.001), SpO2 below 90% (Off: 20 min [14-26], On: 1 min [0-3], p<0.001), and SpO2 min (Off: 77% [74-80], On: 88% [86-90], p<0.001) were all significantly different in the untreated versus CPAP treated nights. Compared to CPAP treatment, the overnight change in NfL was increased relative to CPAP withdrawal while the overnight change in Aβ40 was decreased relative to CPAP withdrawal. No change was observed with tau or Aβ42. We found that difference in %N3 between the on- and off-CPAP conditions significantly explained an additional 15.7% of the variance beyond a base model including age and sex alone. No other difference in sleep architecture or apnea severity/hypoxemic burden metric significantly contributed to the variance in overnight change in Aβ40 between conditions, and we identified no significant predictors for variance in overnight change in NfL. Conclusion This study presents some of the first evidence for an effect of acute CPAP withdrawal on neurodegenerative and amyloid plasma biomarkers and implicates a role for N3 sleep in this effect. Support (If Any) AASMF Focus award, NIDDK P30DK072488, R01AG066870, K24HL109156

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.

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.

Obesity increases levels of an adipocyte-produced hormone leptin, which activates the sympathetic nervous system leading to hypertension. We have recently reported that acute leptin infusion induces hypertension acting via the TRPM7 (transient receptor potential cation channel subfamily M member 7) cation channel in the carotid bodies. We hypothesize that this mechanism causes hypertension when leptin levels are elevated chronically as observed in diet-induced obesity. We have developed a novel extended release preparation, hydrogel, of a TRPM7 inhibitor FTY720, which was administered to the carotid body area bilaterally and compared with control hydrogel in (1) male lean C57BL/6J mice treated with subcutaneous infusions of leptin; (2) diet-induced obese male C57BL/6J with hyperleptinemia at baseline. In the experiment (3), diet-induced obese C57BL/6J mice, in which Trpm7 was silenced in the carotid body areas by transfection with Ad-Trpm7 shRNA, were compared with control mice transfected with Ad-CON-shRNA . All mice were implanted in the left femoral artery with telemetry before the experiments for continuous blood pressure monitoring. In lean mice, leptin increased 24 hours mean arterial pressure from 101.2±1.2 to 112±1.5 mm Hg; Trpm7 inhibitor abolished leptin-induced hypertension. Obese mice had elevated mean arterial pressure of 115.3±1.7 mm Hg, which was lowered by 8.7±1.0 mm Hg on week 2 after Trpm7 inhibitor treatment ( P <0.001), and this effect persisted by week 3. Trpm7 shRNA decreased blood pressure from 119.0±2.2 to 109.6±1.4 mm Hg ( P <0.01), whereas scrambled shRNA had no effect. In conclusion, our study has shown that inhibition of TRPM7 in carotid bodies abolished leptin-induced hypertension in obese mice.

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.