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. 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.

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.