Sleep and Metabolism

The goal of this study is to uncover sleep and circadian mechanisms contributing to adverse metabolic health. The protocol is a 21 day (7 outpatient days, 14 inpatient days) mechanistic randomized-crossover study designed to identify the impact of chronic sleep restriction and circadian timing, independently and in combination on energy metabolism and identify the independent and combined effects on glucose tolerance.

Nearly half of all Americans are obese and/or have been diagnosed with diabetes, accounting for over 327 billion dollars in health care costs in the United States each year. Increasing evidence suggests that chronic short-sleep durations contribute to these diseases, but the specific mechanisms as to how short-sleep durations results in weight gain and diabetes are debated.

Reports of weight gain due to sleep restriction do not comply with the energy balance hypothesis, which would predict that with an increased amount of wakefulness and an associated increase in energy expenditure, there would be a negative shift in energy balance and resulting weight loss over time. Restricting sleep in the laboratory, however, pushes participants towards a positive energy balance via increased daily energy intake when access to food is ad libitum.

The goals of this study are to uncover the impact of chronic sleep restriction, circadian timing, and their combination on energy intake patterns, determine the influence of chronic sleep restriction on food choice when there is equal opportunity to eat at all circadian times, and discover the impact of chronic sleep restriction, circadian timing, and their combination, on glucose tolerance.

1. Ambulatory monitoring: Participants will maintain a consistent 7-day at home 8h sleep schedule at habitual times before both laboratory visits to ensure 1) subjects are not sleep restricted and 2) that they are obtaining the same light-dark schedule prior to each laboratory visit for stable entrainment; verified by actigraphy, sleep logs, and call-ins to a time stamped recorder. Drugs, medications, caffeine, alcohol, and nicotine will be prohibited to use during this time and toxicology analysis will be performed upon admission.
2. Outpatient diet: For 3-days prior to each protocol, participants will consume an outpatient isocaloric diet designed to meet individual daily energy requirements. The diet will consists of a breakfast, lunch, dinner, and snack and participants will be trained by staff in how to prepare the meals. Participants will be instructed to only consume the food provided during these 3-days and be asked by staff to confirm this is all they ate via daily check-ins to ensure adherence.
3. Inpatient protocols: Participants will be admitted to an individual room free of external time cues (e.g. clocks, radios, computers, visits and sunlight). Room temperature is maintained at 21 - 22.2 degrees Celsius and light intensity set at ≤5 lux during forced desynchrony procedures and 0 lux (darkness) during scheduled sleep opportunities. Participants will be instrumented for full polysomnography (PSG) and given a telemetry pill for continuous core body temperature measurement. An 18-gauge IV catheter will also be inserted into the forearm and connected to a triple-stopcock manifold via an IV loop with a 12-foot small-lumen extension cable through which blood sampling can continue in the next room without disturbing leisure activity or sleep.

After instrumentation, participants will be given an 8h sleep opportunity at habitual timing (determined via actigraphy) and will be awakened at habitual wake time in dim-lighting for a baseline "day". During baseline, participants will be given three energy-balanced meals. After baseline, participants' sleep/wake schedule will be advanced by 4h daily for the next 12 calendar days with the participants having access to ad libitum food. Prior to arriving to the laboratory, participants will be randomized to either sleep restriction first (equivalent to obtaining 5.5h of sleep per 24h; n=10) or control conditions first (equivalent to 8h sleep per 24h; n=10); crossover to the other condition will occur on day 8 of the protocol. Because the protocol requires participants to live on a 20h-day, during the control condition participants will experience 13.33-hour wake episodes followed by 6.67-hour sleep opportunities, while during the sleep restriction condition they will experience 15.33-hour wake episodes followed by sleep episodes of 4.67 hours long, in the range typically experienced by individuals who habitually restrict their sleep. Providing ad libitum food during this time will be accomplished, as done previously, by providing participants a breakfast, lunch and dinner at \~130-150% more calories than their baseline day and switching out sets of snacks between meals - "morning" (between breakfast and lunch), "afternoon" (between lunch and dinner), and after-dinner (between dinner and sleep). Snacks will be of a variety of healthy (i.e., grapes, low-fat yogurts, whole-grain crackers, nuts, etc.) and unhealthy (i.e., ice cream, cookies, chips, sodas, etc.) options and participants will not need to ask or record what they eat.

Eligibility Criteria:
Inclusion Criteria:

* Between 18 and 40 years of age
* Drug free
* Established disease-free status

Exclusion Criteria:

1. Dietary restrictions

   Participants must not have dietary restrictions that could systematically bias their macronutrient intake. The following will exclude participants from enrolling in the study based on their diet:
   * Participants who choose not to or cannot consume dairy products (milk, yogurt, cheese, ice cream)
2. Body Composition

   A body mass index (BMI) of 18.5\< \[BMI\] \< 25 kg/m2 and a waist circumference \<94/80cm.
3. Psychiatric/psychological suitability

   Each participant will undergo a structured interview (Mini International Neuropsychiatric Interview) with a qualified OHSU physician. This physician will supervise the administration and scoring of a Beck Depression Inventory II (BDI-II) questionnaire for each potential participant. The following will exclude individuals from participating based on their psychiatric or psychological evaluation:
   * Individuals with evidence of psychopathology on the BDI-II, or in a structured clinical interview with the physician
   * A history of severe psychiatric illnesses
   * Alcoholism
   * Drug dependency
   * Major depression
   * Manic depressive illness
   * Schizophrenic disorders
   * Panic disorder
   * Generalized anxiety disorder
   * Post-traumatic stress disorder
   * Agoraphobia
   * Claustrophobia
   * Paranoid personality disorder
   * Schizoid personality disorder
   * Schizotypal personality disorder
   * Borderline personality disorder
   * Antisocial personality disorder.
   * History of using antidepressant medication
   * History of using neuroleptic medication
   * History of using tranquilizers
4. Drug/alcohol use

   Volunteers must be drug-free (including caffeine, nicotine, alcohol and herbal medications) for the entire duration of the outpatient and in-laboratory study period, with no history of drug or alcohol dependency. All participants must be:
   * Current non-smokers, and are required to have a history of less than 5 'pack years' of smoking
5. Medication/drug use

   Volunteers must not be taking any prescribed medications or over the counter medications, with an exception for birth control.
6. Prior shift work

   For stability of endogenous circadian rhythmicity, volunteers must have no history of the following 1 year prior to the study:
   * Working irregular day and night hours
   * Regular night work
   * Rotating shift work f
   * Not have traveled more than 1 time zone during 3 months prior to the study
7. Chronobiologic and sleep disorders

   * Hypernychthemeral sleep/wake cycle
   * Delayed sleep phase syndrome (wake time \> 2 hours later than desired or habitually after 10:00 AM)
   * Advanced sleep phase syndrome (wake time \> 2 h earlier than desired or habitually before 5:00 AM)
   * Narcolepsy
   * Sleep apnea (apnea index \>15)
   * Insomnia (sleep complaint by history or polygraphically recorded sleep efficiency \< 80%)
   * Hypersomnia
   * Periodic Limb Movement (PLMS) (PLMS index \>15)
   * Nocturnal Paroxysmal Dystonia
   * REM-sleep behavior disorder
   * Nocturnal Enuresis; (self-report and first night in the laboratory)
   * Obstructive sleep apnea (apnea/hypopnea index \>5/h as determined by at-home monitoring)
   * The investigators will also exclude individuals with extreme chronotype using the Horne-Ostberg Morningness/Eveningness questionnaire (i.e., the Owl/Lark Questionnaire)
8. Diseases of the Cardiovascular System

   * Hypertension (systolic blood pressure \> 140 or diastolic blood pressure \> 90)
   * Heart failure
   * Cardiomyopathy
   * Cor pulmonale
   * Ischemic heart disease
   * Valvular heart disease
   * History of heart transplantation
   * Cardiac tumors
   * Pericardial disease
9. Metabolic Syndrome

   Following American Heart Association cutoffs, participants who have, in addition to abdominal fat (obese exclusion criteria), two or more of these factors will be excluded from the study:
   * HDL cholesterol of less than 40 mg/dL in men or less than 50 mg/dL in women
   * Systolic blood pressure \>135 mmHg or diastolic blood pressure \>85 mmHg
   * Fasting blood glucose ≥ 100 mg/dL
   * Triglycerides ≥ 150 mg/dL
10. Pre-Diabetes/Diabetes

    For participants who have a fasting blood glucose level of ≥ 100 mg/dL the investigators will measure hemoglobin A1c to exclude for diabetes (HbA1c\>5.7%).
11. Hypertension

    An upper cut off of 140/90 mmHg during an office blood pressure measure will be used as an exclusion criterion. After 5 minutes of rest in a seated position, blood pressure will be measured 3 times, taken 1 minute apart. The average will be used to confirm eligibility criteria. Current or history of beta blocker use will also be exclusionary.
12. Disorders of the Respiratory System

    * Asthma
    * Cystic fibroses
    * Chronic bronchitis
    * Emphysema
    * Airway obstruction
    * Interstitial lung diseases
    * Pulmonary hypertension
    * Lung neoplasms
    * ARDS
13. Disorders of the Kidney and Urinary Tract

    * Acute or chronic renal failure
    * History of renal transplantation
    * Tubulointerstitial diseases of the kidney
    * Urinary tract obstruction
    * Tumors of the urinary tract
14. Infectious Diseases

    * Infective endocarditis
    * HIV infection
    * Sexually transmitted diseases \[e.g., syphilis (including congenital syphilis and its sequelae), gonorrhea\],
    * Urinary tract infection
    * Osteomyelitis
    * Brucellosis
    * Toxoplasmosis,
    * Tuberculosis
    * Leptospirosis
    * Lyme disease
    * Mononucleosis
    * Hepatitis
    * Parasitic infections such as malaria, toxoplasmosis, giardiasis, schistosomiasis, leishmaniasis
15. Disorders of the Gastrointestinal System

    * Esophagitis
    * Peptic ulcer and gastritis
    * Neoplasms of the esophagus, stomach or bowel
    * Disorders of absorption
    * Inflammatory bowel disease
    * Diseases of the small and large intestine
    * Acute appendicitis
    * Cirrhosis or neoplasms of the liver
    * History of liver transplantation
    * Diseases of the gallbladder and bile ducts
    * Pancreatic disease
16. Disorders of the Immune System, Connective Tissue and Joints

    * AIDS
    * Systemic lupus erythematosus
    * Rheumatoid arthritis
    * Scleroderma
    * Ankylosing spondylitis
    * Vasculitis
    * Sarcoidosis
17. Disorders of the Hematopoietic System

    * Anemia
    * Leukemia
    * Myeloproliferative diseases
    * History of bone marrow transplantation
18. Neoplastic Diseases

    * Lymphoma
    * Carcinoma
    * Melanoma
    * Any other neoplastic diseases
19. Endocrine and Metabolic Diseases

    * Thyroid disease
    * Addison's Disease
    * Cushing's Syndrome
    * Aldosteronism
    * Hypoaldosteronism
    * Pheochromocytoma
    * Disorders of sexual differentiation that require hormone supplementation that may alter body weight
    * Disorders of neuroendocrine regulation
    * Diseases of the anterior pituitary and hypothalamus
    * Hemochromatosis porphyria
    * Wilson's Disease
    * Glycogen storage diseases
    * Diseases of the parathyroid gland
    * Metabolic bone disease
    * Disorders of phosphorus or magnesium metabolism
    * Paget's Disease
20. Neurologic Disorders

    * Epilepsy and disorders of consciousness
    * Dementia
    * Amnesic disorders
    * Neoplastic diseases of the central nervous system
    * Demyelinating diseases
    * Parkinson's Disease
    * Muscular dystrophy
    * Myasthenia gravis
    * Periodic paralysis
    * Dermatomyositis
    * Polymyositis
    * Infections of the nervous system
    * Stroke
    * History of transient ischemic attacks
    * Hydrocephalus
    * Tumors of the pituitary gland
    * Pinealoma
    * Intervertebral disc disease
    * Ataxia
    * Gilles de la Tourette Syndrome
    * Huntington's Disease
    * Tardive dyskinesia
    * History of recurrent migraine headaches
    * Neuromuscular disease.
21. Subjects must not be currently participating in another research study that would influence their safe participation in our study. Subjects must not be participating in a research study in which they do the following:

    * Ingest experimental medication
    * Give blood samples