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Tissue-specific Insulin Resistance in Obstructive Sleep Apnea: Role of Hypoxia

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ClinicalTrials.gov Identifier: NCT03695315
Recruitment Status : Recruiting
First Posted : October 4, 2018
Last Update Posted : February 28, 2019
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
Obstructive sleep apnea (OSA) is a common condition associated with significant adverse health outcomes. Our overarching hypothesis is that patients with OSA and hypoxia (H-OSA) have greater degrees of insulin resistance in both liver and adipose tissue when compared to those without hypoxia (NH-OSA) thus leading to increased risk for the development of diabetes in the former group.

Condition or disease Intervention/treatment
Obstructive Sleep Apnea Hypoxia Insulin Resistance Device: Continuous Positive Airway Pressure

Detailed Description:

Obstructive sleep apnea (OSA) is a common condition associated with significant adverse health outcomes. An estimated 25% of men and 10% of women will have OSA during their lifetime. OSA is associated with an increased prevalence of insulin resistance and type 2 diabetes and, with severe degrees of OSA, non-alcoholic fatty liver disease (NAFLD) as well. The mechanisms accounting for the association between insulin resistance and OSA are not fully understood. The investigators have previously demonstrated that experimentally-induced sleep restriction in healthy volunteers led to a reduction in whole-body insulin sensitivity and increased rates of lipolysis and gluconeogenesis, accompanied by an increase in stress hormone levels. Studies by others suggest that, in animal models studied under hypoxic conditions, hepatic carbohydrate and lipid homeostasis are perturbed leading to hepatic steatosis and inflammation. Taken together, these observations form the basis of our overarching hypothesis that patients with OSA and hypoxia (H-OSA) have greater degrees of insulin resistance in both liver and adipose tissue when compared to those without hypoxia (NH-OSA) thus leading to increased risk for the development of diabetes in the former group.

In Aim 1: The investigators will test the hypothesis that, although individuals with OSA have been shown to have insulin resistance in multiple target tissues (adipose, muscle, liver, beta cell), these abnormalities will be significantly greater in patients with OSA that is accompanied by hypoxia (H-OSA,) in comparison to those without hypoxia (NH-OSA). The investigators will compare tissue-specific insulin sensitivity in 30 subjects with H-OSA and 30 with NH-OSA matched for sex, age, BMI, and apnea-hypopnea index. Hepatic and extra-hepatic insulin sensitivity will be measured using hyperinsulinemic-euglycemic clamps and stable isotope tracer studies of endogenous glucose production, gluconeogenesis, de novo lipogenesis (DNL), and lipolysis. Beta cell function and insulin kinetics will be assessed from insulin and C-peptide concentrations during an oral glucose tolerance test. Liver fat will be measured by magnetic resonance and total lean and fat mass by dual-energy X-ray absorptiometry. In Aim 2: The investigators will test the hypothesis that treatment with continuous positive airway pressure (CPAP) will improve insulin sensitivity in all of the target tissues and that these improvements will be greater in those with hypoxia at baseline. After stabilization on CPAP therapy and maintenance for six weeks, each of the individuals studied in Aim 1 will undergo a repeat sleep study and metabolic assessments identical to those described above in Aim 1. The investigators hypothesize that in NH-OSA insulin resistance is primarily triggered by increased levels of stress hormones due to fragmented sleep and this is manifested largely in extra-hepatic tissues (muscle and adipose), whereas in H-OSA there is additional stimulation of hepatic DNL, leading to liver fat accumulation and hepatic insulin resistance.


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Study Type : Observational
Estimated Enrollment : 60 participants
Observational Model: Case-Crossover
Time Perspective: Prospective
Official Title: Tissue-specific Insulin Resistance in Obstructive Sleep Apnea: Role of Hypoxia
Actual Study Start Date : October 31, 2018
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : August 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sleep Apnea
Drug Information available for: Insulin

Group/Cohort Intervention/treatment
OSA with hypoxia
People with obstructive sleep apnea and hypoxia before and after treatment with continuous positive airway pressure
Device: Continuous Positive Airway Pressure
CPAP is a noninvasive treatment for sleep apnea

OSA without hypoxia
People with obstructive sleep apnea and without hypoxia before and after treatment with continuous positive airway pressure
Device: Continuous Positive Airway Pressure
CPAP is a noninvasive treatment for sleep apnea




Primary Outcome Measures :
  1. Insulin sensitivity [ Time Frame: 8 weeks ]
    Stable isotope will be used to determine the changes in hepatic and extra hepatic insulin sensitivity

  2. Liver fat [ Time Frame: 8 weeks ]
    Magnetic resonance will be used to measure changes in liver fat fraction


Secondary Outcome Measures :
  1. Oral Glucose Tolerance Test [ Time Frame: 8 weeks ]
    To measure insulin kinetics

  2. Dual energy x-ray absorptiometry [ Time Frame: 8 weeks ]
    To determine changes in total fat mass


Biospecimen Retention:   Samples With DNA
Participation for genetic material retention is optional. Genetic information may be shared broadly in a coded form for future genetic research or analysis. This genetic information will NOT be used for genomic data sharing with genome-wide association studies. The genetic analysis which will be limited to the set of participants recruited to this study. The specimens may be used by our UCSF research team for studies on diabetes, cardiovascular disease, liver disease, and other aspects of metabolism.


Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Participants will be recruited from the UCSF Clinical Sleep Medicine Laboratory. Patients seen by UCSF sleep medicine physicians (including Dr. Krystal [Lab Co-Director]) in sleep clinic and those who are referred for polysomnography (PSG) for OSA and for whom the physician has provided approval to be approached, will be contacted by the study coordinator and offered the opportunity to be screened to participate in the study. The study coordinator will review the consent form with the prospective volunteers and will ask for their approval to have their PSG data reviewed by Dr. Krystal, who will determine if the participants meet PSG entry criteria for participation in the study and if found to qualify, to be contacted by phone.
Criteria

Sixty nondiabetic men and women

Inclusion Criteria:

  • Ages 40-70,
  • BMI 25 to 35 kg/m2
  • Participants newly diagnosed obstructive sleep apnea (OSA) must meet the criteria for one of the two following groups:

    • OSA with hypoxia (H-OSA) defined as those with an H-AHI≥15 so as to match the NH-OSA subjects in event frequency and because this is the range defined as more than mild OSA such that we would be likely to see pathology associated with OSA; or,
    • OSA without hypoxia (NH-OSA) defined as having a rate of non-hypoxic respiratory events ≥ 15 per hour (NH-AHI≥15) and having a rate of hypoxic events of less than 5 per hour (H-AHI<5,(52)).

Exclusion Criteria:

  • Type 1 or 2 diabetes mellitus (fasting glucose ≥126 mg/dL or 2-h glucose ≥200 mg/dL or Hgb A1c ≥6.5%);
  • History of chronic obstructive pulmonary disease (COPD) or parenchymal lung disease;
  • Unstable hypertension;
  • Treatment for asthma;
  • Current tobacco use;
  • Current alcohol consumption exceeding 1 drink/day in women and 2 in men;
  • HIV infection or infectious hepatitis;
  • Pregnancy or lactation within the past six months;
  • Use of any hypolipidemic agent;
  • History of surgery for obesity;
  • Hgb below the lower limit of normal;
  • Aspartate transaminase (AST) or alanine transaminase (ALT) greater than 3 X the upper limit of normal;
  • Change in body weight >5% within preceding 6 months (by self-report).
  • Patients diagnosed with OSA but who do not meet the study-specified criteria for either the H-OSA or NH-OSA groups will also be excluded;
  • Claustrophobia;
  • Implants such as pacemakers, spinal nerve stimulators, or implants or metals that preclude magnetic resonance (MR) scanning;
  • Shoulder-to-shoulder width of greater than 68 cm;
  • Girth greater than 170 cm;
  • Weight greater than 205 kg.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03695315


Contacts
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Contact: Jean-Marc Schwarz, PhD 415-206-5533 jean-marc.schwarz@ucsf.edu
Contact: Andrew Krystal, MD 415-476-7702 Andrew.Krystal@ucsf.edu

Locations
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United States, California
University of California San Francisco Recruiting
San Francisco, California, United States, 94110
Principal Investigator: Jean-Marc Schwarz, PhD         
Sponsors and Collaborators
University of California, San Francisco
Investigators
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Principal Investigator: Jean-Marc Schwarz, PhD University of California, San Francisco
Principal Investigator: Andrew Krystal, MD University of California, San Francisco

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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03695315     History of Changes
Other Study ID Numbers: 1R01DK117953 ( U.S. NIH Grant/Contract )
First Posted: October 4, 2018    Key Record Dates
Last Update Posted: February 28, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of California, San Francisco:
Obstructive Sleep Apnea
Hypoxia
Insulin Resistance
Additional relevant MeSH terms:
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Apnea
Sleep Apnea Syndromes
Sleep Apnea, Obstructive
Insulin Resistance
Hypoxia
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Wake Disorders
Nervous System Diseases
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs