Obstructive Sleep Apnea and Glucose Metabolism (OSAGM)

Many adults who are overweight have obstructive sleep apnea (OSA) which disrupts sleep and makes it difficult to breath during the night. OSA increases the risk for a person to become insulin resistant and diabetic. It is not known why OSA causes this problem, i.e., whether it is disrupted sleep or lack of oxygen., which can change how the body handles glucose in adipose tissue, muscle tissue and liver.

The purpose of this research study is to determine the key issues and mechanisms responsible for dysregulated glucose metabolism in people with OSA. The investigators will do this by comparing glucose metabolism in people who have OSA, and those who do not, and by evaluating the effect of treating OSA by providing continuous positive airway pressure (CPAP) or simply oxygen during the night.

The proposed study will evaluate the primary causes(s) (hypoxia, sleep fragmentation, or both) and pathophysiological mechanisms responsible for the OSA-associated metabolic abnormalities. Knowing the primary cause of Obstructive Sleep Apnea and pathophysiological mechanisms responsible for the OSA-associated metabolic abnormalities could help develop potentially novel therapeutic strategies to provide treatment for adults in improving OSA and associated comorbidities.

Study Overview

• Status: Suspended
• Conditions: Glucose Metabolism Disorders; Sleep Apnea
• Intervention / Treatment: Procedure: Positive Airway Pressure; Procedure: Supplemental Oxygen; Procedure: Sham

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Bettina Mittendorfer, PhD; Phone Number: 3143628450; Email: mittendb@wustl.edu

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

General Inclusion Criteria (for all subjects):

• Age: ≥30 and ≤70 years,
• BMI: ≥30 and ≤45 kg/m2 or body fat ≥ 30 % for women and ≥ 25 % for men,
• Maximum body circumference <170 cm
• Weight stable (≤2% change)
• Untrained (≤1 h of structured exercise/wk) for at least 3 months before entering the study
• No diabetes (fasting blood glucose <126 mg/dl, 2h oral glucose tolerance test (OGTT) glucose <200 mg/dl, HbA1c ≤6.5%)

Sleep-related inclusion criteria:

Subjects without OSA:

• AHI <5/h of sleep;
• Oxygen desaturation index <3/h
• No known sleep disorders and periodic limb movement arousal index <15/h during polysomnography
• Reported sleep duration ≥6 h per night
• Regular sleep schedules (i.e. bedtime between 8 pm and 12 am and wake-time between 4 am and 8 am on all days of the week)

Subjects with OSA

• AHI ≥10/h of sleep (i.e., moderate to severe OSA)
• Oxygen desaturation index ≥4/h;
• No polysomnogram finding that would trigger immediate PAP treatment as per standard operating protocol in our sleep medicine center (a single SaO2 <50%, SaO2 <70% for >2 minutes, electrocardiogram pause >5 sec, or ventricular tachycardia >30 sec), because of the risk of a potentially adverse outcome if they are not randomized to the PAP group
• Periodic limb movement arousal index <15/h during polysomnography,
• Reported sleep duration ≥6 h per night,
• Regular night-time sleep schedules, defined as bedtime between 8 pm and 12 am and wake-time between 4 am and 8 am on all days of the week.

General Exclusion Criteria (for all subjects):

• Current treatment for previously diagnosed OSA;
• Self-reported severe difficulty sleeping in unfamiliar environments;
• Metal implants that are incompatible with magnetic resonance imaging;
• Controlled substances, tobacco products, dietary supplements, or medications known or suspected to affect sleep, breathing, upper airway muscle physiology, or glucose metabolism
• Evidence of disease (e.g., diabetes, congestive heart failure; chronic obstructive pulmonary disease; hypoventilation, defined as daytime partial pressure of carbon dioxide (pCO2) >45 mm Hg; major neurological or neuromuscular disorders; cancer; uncontrolled hypertension; etc.);
• Contraindications to supplemental oxygen or PAP (e.g., recent trans-sphenoidal surgery).
• Unwillingness or inability to provide informed consent
• Study physician considers subject to be unable to safely complete the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Positive Airway Pressure (PAP); A registered polysomnographic technologist will perform a titration starting at 4 cm water (H2O) and adjust this value as needed to identify the optimal pressure to achieve an Apnea Hypopnea Index (AHI) <5 (including rapid eye movement sleep in the supine position). After PAP titration, subjects will be instructed to use the machine at the optimal pressure every night for 3 months. Compliance will be defined as: ≥4 hours use on 70% of nights and average use ≥6 hours per night.	Procedure: Positive Airway Pressure; See arm/group description
Experimental: Supplemental Oxygen (O2); Subjects randomized to night-time supplemental oxygen will complete an overnight oxygen titration protocol in the clinical research unit. Initially, subjects will receive 0.5 liters oxygen (O2)/min; the delivery rate will then be increased by 0.5 l/min until oxygen saturation (SaO2) is ≥88%. The optimal O2 delivery rate determined during this study will be used for the intervention. The oxygen concentrators used at home will record cumulative hours of use to provide an objective measure of adherence (monitored weekly). Compliance will be defined as ≥6 h average use per night..	Procedure: Supplemental Oxygen; See arm/group description
Sham Comparator: Sham; Subjects in the sham treatment group will complete the oxygen titration protocol described for the night-time supplemental oxygen group, except that their oxygen concentrator will have been covertly modified to deliver room air at a rate of 0.5 l/min.	Procedure: Sham; See arm/group description
No Intervention: Controls; Subjects without OSA will be recruited and complete all testing for primary outcome measures, but will not undergo any intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin mediated glucose disposal	The hyperinsulinemic-euglycemic clamp technique combined with isotope-labelled tracer infusions will be used to assess insulin mediated glucose rate of disappearance before and after treatment of OSA with three months of night-time supplemental oxygen, PAP, or sham.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
β-cell function	β-cell responsivity to glucose and the disposition index will be determined to characterize the insulin secretory response to glucose infusion and the relationship between insulin secretion and insulin sensitivity. This outcome will be determined by using an insulin-modified intravenous glucose tolerance test in conjunction with mathematical modelling and insulin sensitivity data from the hyperinsulinemic clamp.	3 months
Tissue oxygenation	Adipose and muscle tissue oxygenation, expressed as mmHg, will be evaluated in situ during the hyperinsulinemic-euglycemic clamp studies.	3 months
Body composition analysis	Detailed body composition analysis using dual energy x-ray absorptiometry (DXA) will provide the researchers with total and appendicular lean body and fat mass, expressed in grams of participants.	3 months

Collaborators and Investigators

• Sponsor: University of Missouri-Columbia
• Investigators: Principal Investigator: Bettina Mittendorfer, PhD, Washington University School of Medicine

Publications and helpful links

General Publications

• Cao C, Koh HE, Van Vliet S, Patterson BW, Reeds DN, Laforest R, Gropler RJ, Mittendorfer B. Increased plasma fatty acid clearance, not fatty acid concentration, is associated with muscle insulin resistance in people with obesity. Metabolism. 2022 Jul;132:155216. doi: 10.1016/j.metabol.2022.155216. Epub 2022 May 13.
• van Vliet S, Koh HE, Patterson BW, Yoshino M, LaForest R, Gropler RJ, Klein S, Mittendorfer B. Obesity Is Associated With Increased Basal and Postprandial beta-Cell Insulin Secretion Even in the Absence of Insulin Resistance. Diabetes. 2020 Oct;69(10):2112-2119. doi: 10.2337/db20-0377. Epub 2020 Jul 10.

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2018
• Primary Completion (Estimated): February 1, 2024
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: December 1, 2017
• First Submitted That Met QC Criteria: January 22, 2018
• First Posted (Actual): January 24, 2018

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 2, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Obstructive Sleep Apnea; Glucose Metabolism
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Apnea; Metabolic Diseases; Glucose Metabolism Disorders
• Other Study ID Numbers: 201710015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No