Sleep Effectiveness and Insulin and Glucose Homeostasis

Evidence from experimental studies supports the hypothesis that fragmented or insufficient
sleep contributes to impaired glucose and insulin homeostasis. The sleep spectrogram, an
EEG-independent measure of sleep effectiveness, maps coupled oscillations of heart rate
variability and ECG-derived respiration. In a sample of non-diabetic subjects with and
without sleep apnea, we previously explored the association between ECG-spectrogram derived
biomarkers and glucose metabolism and found that the marker of effective sleep, High
Frequency Coupling (HFC), is associated with reduced diabetes risk (increased Disposition
Index). HFC is also enhanced by sedative medications (unpublished data). In this study we
will 1.) explore the relationship between sleep effectiveness and insulin sensitivity across
the sleep period, by frequently sampling glucose and insulin during nocturnal polysomnography
in healthy and prediabetic subjects; and 2.) evaluate the impact of pharmacologic enhancement
of effective sleep with nightly eszopiclone (1 week, home environment) on glycemic profiles
(continuous glucose monitoring, 72 hrs) in prediabetics and diabetics compared to
pretreatment baseline. We expect that desirable glycemic profiles will correlate with the
spectrographic marker of effective sleep while undesirable glucose profiles will correlate
with the marker of ineffective sleep. Using pharmacologic enhancement of effective sleep, we
expect to demonstrate improvement in glycemic profiles in prediabetic and diabetic subjects
compared to pre-treatment baseline.

Inclusion Criteria:

- Healthy volunteers, men and women 18-64 years of age.

- Fluent English speakers.

- Health status as per criteria listed for prediabetes and diabetes (based on 2003
American Diabetes Association criteria and 2009 International Expert Committee Report:
Prediabetics will have impaired glucose tolerance with fasting plasma glucose (FPG)
100-125 mg/dL, Hemoglobin A1C 5.7-6.4%, or 2-hour plasma glucose (PG) 140-199 mg/dL
after 75-g oral glucose tolerance test (OGTT). Diabetics will have FPG ≥ 126 mg/dL,
Hemoglobin A1C ≥ 6.5%, or 2-hour PG ≥ 200 mg/dL on OGTT.

Exclusion Criteria:

- Primary psychiatric disease or conditions which may independently contribute to sleep
fragmentation or may hinder the subject's ability to complete the proposed testing:

- Respiratory, liver, or clotting disorders

- History of sleep disordered breathing, Restless legs syndrome or Periodic limb
movement disorder or high clinical suspicion of sleep disordered breathing or other
sleep disorder (e.g., snoring, excessive daytime sleepiness, frequent napping,
excessive motor activity)

- Shift worker or circadian phase disorder

- Abnormal resting ECG, pacemaker, atrial fibrillation or other arrhythmia

- Seizure disorder

- History of depression, bipolar disorder, anxiety disorder, schizophrenia or use of
psychiatric medication

- Narcolepsy

- Tobacco or recreational drug use

- Pregnancy or lactation

- Regular use of stimulants or hypnotic medication

- Evidence of sleep apnea (Apnea-Hypopnea Index > 10 on screening sleep study)