Fat Metabolism in OSA and COPD

Study Overview
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Brief Summary
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Obstructive sleep apnea (OSA) is the most common type of sleep apnea and is caused by an obstruction of the upper airways. The obstruction results in periods of intermittent hypoxia and re-oxygenation, which lead to increased oxidative stress, increased inflammation, endothelial dysfunction, and insulin resistance. Chronic obstructive pulmonary disease (COPD) is a lung disease that leads to poor airflow. This disease leads to systemic hypoxia, reduced oxidative capacity, and increased inflammation. The direct cause of OSA and COPD is unclear, but OSA and COPD may be linked to other comorbid conditions such as obesity and type II diabetes. Upon onset of OSA and COPD, metabolic disturbances associated with obesity and type II diabetes can be exacerbated. Obesity is a condition characterized by an increase in visceral fat, elevated plasma levels of free fatty acids, inflammation, and insulin resistance. Although the effects of body fat distribution have not been studied in these patients, an increase in both subcutaneous and abdominal fat mass in non-OSA older women was shown to increase morbidity and mortality. Fat/adipose tissue is an active tissue capable of secreting proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, reactive oxygen species and adipokines. Particularly, abdominal fat is a prominent source of pro-inflammatory cytokines, which contributes to a low grade, chronic inflammatory state in these patients. Additionally, an increased inflammatory state is associated with reduced lean body mass, and together with elevated circulating free fatty acids may increase the occurrence of lipotoxicity and insulin resistance. Thus, increased fat deposition is associated with a poor prognosis in OSA and COPD patients and therefore it is of clinical and scientific importance to understand the changes in fat metabolism and digestion as a result of OSA and COPD. It is therefore our hypothesis that fat synthesis and insulin resistance is increased and whole body protein synthesis is decreased in OSA and COPD patients, leading to a poor prognosis.

Detailed Description
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This research study involves 3 visits for subjects and healthy controls. The first visit is the screening visit and includes review of the informed consent and a DXA scan and the second and third visit for the study days. For the first test day, 3 hours of the subjects time will be for urine and blood sample collection, and to stable isotope administration (deuterated water, isotopically labeled amino acids). Subjects are allowed to go home after and eat normally. On the second study day, subjects will arrive early that morning. For the duration of the study, subjects have to lie in the bed (except for bathroom privileges). They can watch tv or bring and use a book/tablet. The research nurse or study staff will be present in the human subject area to assist the subject if necessary. Subjects are not allowed to eat or drink during the second test day, except for the test drink (meal) and water. One IV catheter will be placed in a vein of the arm/hand for blood draws. The hand will be placed in a hot box during blood collection. Another IV catheter will be placed in the contra-lateral forearm for a primed and continuous infusion of isotopes (isotopically labeled amino acids and glycerol). Each day, a total of 80-100 ml of blood will be obtained. Stable isotopes will be ingested and infused on the first test day and added to the test drinks and infused on the second day. On the second test day, subjects will fill out questionnaires. After completion of the study, we will provide the subject with a meal.

Official Title
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Fat Metabolism and Digestion in Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease

Conditions
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Obstructive Sleep Apnea, Chronic Obstructive Pulmonary Disease, Obesity

Participation Criteria
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Eligibility Criteria
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Inclusion criteria subjects: Established diagnosis of OSA or COPD Ability to sign informed consent Ability to walk, sit down and stand up independently Age 30 years and older Ability to lie in supine position for up to 8 hours Clinically stable condition and not suffering from a respiratory tract infection or exacerbation of their disease Willingness and ability to comply with the protocol Inclusion criteria healthy normal weight and obese subjects: Healthy male & female according to the investigator's or appointed staff's judgment Ability to walk, sit down and stand up independently Age 30 years or older Ability to lay in supine or elevated position for 8 hours No diagnosis of OSA or COPD Willingness and ability to comply with the protocol Exclusion Criteria Established diagnosis of malignancy Untreated metabolic diseases including hepatic or renal disorder Presence of acute illness or metabolically unstable chronic illness Presence of fever within the last 3 days Any other condition according to the PI or study physician that would interfere with proper conduct of the study / safety of the patient Use of long-term oral corticosteroids or short course of oral corticosteroids in the preceding month before enrollment Use of protein or amino acid containing nutritional supplements within 5 days of first study day 5 days of first study day Failure to give informed consent or Investigator's uncertainty about the willingness or ability of the subject to comply with the protocol requirements History of hypo- or hyper-coagulation disorders, including use of a Coumadin derivative, history of deep venous thrombosis (DVT), or pulmonary embolism (PE) at any point in lifetime Currently taking anti-thrombotics and cannot stop for 7 days (i.e. medical indication) Recent myocardial infarction ( < 1 year ago) Current alcohol or drug abuse (Possible) pregnancy

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| COPD and OSA<br>Subjects with diagnosis of COPD and OSA | |
| COPD<br>Subjects with diagnosis of COPD | |
| OSA<br>Subjects with diagnosis of OSA | |
| controls<br>Gender, age, BMI matched controls | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic triglyceride synthesis | changes in hepatic triglyceride synthesis before and after a meal | Pre meal ingestion and 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, 240, 270, and 300 min post meal ingestion | 
| Hepatic de novo lipogenesis | changes in hepatic de novo lipogenesis before and after a meal | Pre meal ingestion and 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, 240, 270, and 300 min post meal ingestion | 
| Adipose tissue triglyceride synthesis | changes in adipose tissue triglyceride synthesis before and after a meal | pre and 4 hours post meal | 
| Adipose tissue de novo lipogenesis | changes in adipose tissue de novo lipogenesis before and after a meal | pre and 4 hours post meal | 
| Adipose tissue lipolysis - glycerol rate of appearance | changes in adipose tissue lipolysis before and after a meal. plasma enrichment of glycerol. | Pre meal ingestion and 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, 240, 270, and 300 min post meal ingestion | 
| Rate of appearance of ingested glucose | determine changes in appearance of glucose rate in subjects | Pre meal ingestion and 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, 240, 270, and 300 min post meal ingestion | 
| Endogenous Glucose Production | Determine whole body glucose production in subjects | Pre meal ingestion and 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, 240, 270, and 300 min post meal ingestion | 
| Glucose disposal | Determine whole body glucose uptake in subjects | Pre meal ingestion and 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, 240, 270, and 300 min post meal ingestion | 
| Net whole-body protein synthesis | change in whole-body protein synthesis rate after intake of meal | 0, 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210 min post-meal | 
| Citrulline Rate of appearance | plasma enrichment of citrulline | Postabsorptive state during 2 hours | 
| Arginine turnover rate | Arginine enrichment in plasma | postabsorptive state during 3 hours | 
| Whole body collagen breakdown rate | Hydroxyproline enrichment in plasma | Postabsorptive state during 3 hours | 
| Tryptophan turnover rate | Tryptophan enrichment in plasma | Postabsorptive state during 3 hours | 
| Myofibrillar protein breakdown rate | 3methylhistidine enrichment in plasma | 0,15,30,45,60,75,90,105,120,150,180,210 min post-meal | 
| Glycine rate of appearance | glycine enrichment in plasma | Postabsorptive state during 3 hours | 
| Taurine turnover rate | enrichment of taurine in | postabsorptive state during 3 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fat digestion and absorption | defining fat digestion and absorption after a meal. Enrichment in palmitic acid and tripalmitin fatty acids in plasma | Pre meal ingestion and 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, 240, 270, and 300 min post meal ingestion | 
| Insulin response to feeding | acute changes from postabsorptive state to postprandial state | pre and up to 5 hours post meal | 
| Body composition | body composition will be determined by dual-energy X-ray absorptiometry and by deuterated water dilution technique. Plasma deuterium enrichments will be determined. | 1 day | 
| Physical activity questionnaire | Outcome of physical activity assessment in breast cancer patients and healthy controls in relation to the fat metabolism | 1 day | 
| Protein digestion after feeding | Ratio enrichment free phenylalanine vs phenylalanine from protein spirulina | 0,15,30,45,60,75,90,105,120,150,180,210, min post-meal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obstructive Sleep Apnea, Chronic Obstructive Pulmonary Disease, Obesity, Hepatic fat metabolism, fat digestion, whole body protein synthesis, protein digestion, amino acid metabolism, adipose tissue fat metabolism, lipolysis