Tissue-specific Insulin Resistance in Obstructive Sleep Apnea: Role of Hypoxia
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.
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.
Obstructive Sleep Apnea Hypoxia Insulin Resistance Apnea Sleep Apnea Syndromes Sleep Apnea, Obstructive Insulin Continuous Positive Airway Pressure
For people ages 40-70
Sixty nondiabetic men and women
- 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)).
- 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;
- 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.
- University of California San Francisco not yet accepting patients
San Francisco California 94110 United States
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