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Orfeu M. Buxton, Ph.D.

Sleep, sleep loss, sleep disorders, and metabolism. Orfeu M. Buxton, Ph.D. Instructor in Medicine Division of Sleep Medicine Brigham and Women’s Hospital, Harvard Medical School Boston, Massachusetts. Seminar for Harvard undergraduate course MCB186, 11/16/2005.

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Orfeu M. Buxton, Ph.D.

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  1. Sleep, sleep loss, sleep disorders, and metabolism Orfeu M. Buxton, Ph.D. Instructor in Medicine Division of Sleep Medicine Brigham and Women’s Hospital, Harvard Medical School Boston, Massachusetts Seminar for Harvard undergraduate course MCB186, 11/16/2005

  2. Objectives:What you might want to know about sleep Sleep/wake homeostasis and circadian rhythms affect sleep and wake patterns and endocrine function How much sleep does an individual need? • Insufficient sleep can • impair vigilance and performance • alter energy balance and metabolism • increase risk of obesity, diabetes, CVD, mortality

  3. No sleep Sleep Cortisol (µg/dl) Thyrotropin (µU/ml) acutesleepdeprivation Prolactin (ng/ml) Buxton, Spiegel, and Van Cauter. Modulation of endocrine function and metabolism by sleep and sleep loss. In: Sleep Medicine, 2001. Growth Hormone (µg/L) Clock Time

  4. Melatonin: Circadian phase marker Melatonin (pg/ml) Clock time VanCauter et al. Amer J Physiol 1994.

  5. TSH: circadian control, sleep inhibition TSH (mUI/ml) Clock time (hour) Nocturnal sleep Nocturnal sleep deprivation Daytime recovery sleep Van Cauter & Aschoff, Endocrinology, DeGroot, ed, 1989.

  6. Cortisol: circadian control, sleep modulation Cortisol (ng/ml) Clock time (hour) Nocturnal sleep Nocturnal sleep deprivation Daytime recovery sleep Van Cauter et al., JCI, 1991.

  7. Cortisol: Sleep component Leproult et al, SLEEP, 1996.

  8. 54-hr profiles of glucose and insulin Glucose (% mean) Insulin Secretion Rate (ISR, % mean) Nocturnal sleep Nocturnal sleep deprivation Daytime recovery sleep Clock time (hour)

  9. How much sleep does an individual need? May depend on the activity/function or organ system being investigated Sleep duration an individual trait 7-9 hours the range for most people

  10. How much sleep do we “need”? Time in Bed: 14 hrs/night 8 hrs/night Conservation of photoperiod-responsive mechanisms in humans. Wehr TA, et al., Am J Physiol 1993: R846-R857

  11. Sleep Dose Response: Mean Sleep Mean Sleep Experimental Days 9 hr group – 7.9 hrs 7 hr group – 6.3 hrs 5 hr group – 4.7 hrs 3 hr group – 2.9 hrs Belenky et al, 2003

  12. Restricted sleep impairs vigilance Baseline Recovery Sleep Restriction Performance (% baseline) Belenky et al, JSR 2003

  13. Chronic Sleep Loss: Overwork • Longer workday: • Since 1969, Americans have added 158 hours/year to workday. • longer commute (census data). • 24-hour society: • Shift work and night work. New York Times, 10 / 99

  14. “Sleep debt” studies: impact on human health • “Sleep Debt”: • chronic, partial sleep restriction • Association of obesity and short sleep? • Effects on neurobehavioral performance • Broad endocrine impact • Inducing a pre-diabetic state

  15. Overweight (but not obese) 34% Obese 30.5% Not overweight 34.5% Ogden et al, JAMA 2002 Prevalence of Overweight & Obesity US, 1999-2000

  16. Perils of obesity • 50% of morbidly obese have sleep disorder • increased risk of diabetes • Most diabetics have disturbed sleep • Health care costs • Personal & Family: • Diabetes • Cancer • Early mortality • Lower quality of life

  17. Significance of sleep for US obesity? SOURCES Obesity: CDC (NHES, NHANES) Sleep: Roffwarg Science 1966, NHIS (unpublished data), National Sleep Foundation polls, Hale J Public Health 2005

  18. American Cancer Society: Association between BMI & Sleep Duration Women BMI (kg/m2) Men BMI (kg/m2) Hours of sleep Kripke et al, Arch Gen Psych, 2002

  19. The Obstructed Upper Airway From: Quietsleep.com, Laurence I. Barsh, DMD

  20. Glucose intolerance, insulin resistance associated with SDB severity Glucose (mg/dL) Insulin (µU/ml) Punjabi et al, 2002

  21. Insulin Sensitivity in OSAS improved with CPAP & BMI<30 • OSAS patients • (compliant n=31) • Euglycemic hyperinsulinemic clamp to estimate insulin sensitivity (Si) Post Si - Pre Si BMI (kg/m2) Harsch et al, AJRCCM (169) 2004

  22. Cross-sectional evidence linking short sleep and metabolism Sleep Heart Health Study (SHHS), n>1100 • Metabolism characterized by oral glucose tolerance test • normal, impaired glucose tolerance, or type 2 diabetes • Sleep and/or insomnia by self report • Short sleep duration (<6 hrs night) • with or without an insomnia-like symptom of difficulty sleeping relative to a 7-8 hour sleep duration, short sleep is associated with a significant increase in the Odds Ratio for a worsening of glucose tolerance

  23. Longitudinal evidence linking short sleep or insomnia and metabolism • Nurses Health Study • 10-year follow-up • Self-reported short sleep duration (≤5 hours/night) • RR (adjusted) 1.45 [1.08-1.92] of developing symptomatic diabetes • Controlling for confounders such as BMI reduced the relative risk: sleep restriction may be an independent predictor for symptomatic diabetes, or may mediate its effect on diabetes via weight gain. • Malmö Preventative Project (Malmö, Sweden) • 15 year follow-up of non-diabetic healthy men • Diabetes by questionnaire and/or fasting blood glucose levels • Self report of “difficulties falling asleep” or regular hypnotic use • OR of 1.52 [1.05-2.20] for development of diabetes Ayas NT et al. Arch Int Med 163 (2003) Nillson, PM et al. Diabetes Care 27:10 (2004)

  24. It’s the naps you don’t take that you regret the most

  25. Sleep Debt Study: Protocol DAY B 1 BASELINE 8-h bedtime M M M B 2 M M M B 3 D 1 D 2 SLEEP DEBT 4-h bedtime D 3 D 4 Influenza vaccination D 5 M M IVGTT D 6 M M M R 1 R 2 R 3 SLEEP RECOVERY 12-h bedtime R 4 R 5 IVGTT M M R 6 M M M R 7 13 09 17 21 01 05 09 CLOCK TIME

  26. Background: Intravenous Glucose Tolerance Test (IVGTT) • Parameters : • Glucose Tolerance (Kg) • 1st and 2nd Phase Insulin Secretion • Insulin Sensitivity (Si)* • Glucose Effectiveness (Sg)* • * Calculated by Bergman’s Minimal Model GLUCOSE (mg.dl-1) 250 150 50 600 INSULIN (pM) 400 200 0 -25 0 25 50 75 100 TIME (min) Glucose Injection at t = 0. Tolbutamide Injection at t = 20. Bergman, RN, Diabetes, 38 (1989), 1512-1527.

  27. Sleep Debt Study Results: IVGTT SLEEP DEBT SLEEP EXTENSION 250 GLUCOSE (mg.dl-1) 150 50 600 INSULIN (pM) 400 200 0 -25 0 25 50 75 100 -25 0 25 50 75 100 TIME (min) TIME (min) p<0.04 p<0.03 p<0.01 NS 3 3 10 400 2 2 10-5.min-1.pM-1 %.min-1 %.min-1 pM.min 5 200 1 1 0 0 0 0 GLUCOSE TOLERANCE GLUCOSE EFFECTIVENESS ACUTE INSULIN RESPONSE INSULIN SENSITIVITY Spiegel et al., Lancet, (1999)

  28. SYMPATHO-VAGAL BALANCE SLEEPINESS EVENING LEVELS OF FREE CORTISOL p<0.007 p=0.0001 p<0.02 5.5 0.8 5 4 5.0 (nmol.L-1) (16:00-21:00) 0.7 S S S (10:00-14:00) r R R (9:00-14:00) 4.5 3 0.6 4.0 2 0.5 3.5 1 4 8 12 4 8 12 4 8 12 HOURS IN BED HOURS IN BED HOURS IN BED Sleep Debt Study results: Sleepiness, Sympatho-vagal Balance, Cortisol Spiegel et al., Lancet, (1999)

  29. Sleep Debt Study results: Thyrotropic Axis SLEEP DEBT SLEEP EXTENSION • Reduced TSH levels and abolished circadian rhythm Spiegel et al., Lancet, (1999)

  30. A Sleep Debt impairs immune response to Influenza Vaccination 6 p<0.03 Sleep Deprived, n=11 1.50 Control, n=14 1.25 NS 1.00 Mean Antibody Titers (10 ) 0.75 0.50 NS 0.25 0 21 to 31 0 10 Time relative to influenza vaccination (days) Spiegel et al., JAMA, 2002

  31. A Sleep Debt signals a need to overeat, risks obesity Spiegel et al., submitted • Lower leptin levels signal negative energy balance • Increased risk for overeating >>> obesity • -Difference corresponds to underfeeding by 1000 Kcal for 3 days Chin-Chance et al., JCEM 2000

  32. Sleep Duration is related to Leptin Taheri S et al., PLoS Medicine, 2004

  33. Sleep Duration is related to ghrelin Taheri S et al., PLoS Medicine, 2004

  34. Sleep Duration is related to BMI Taheri S et al., PLoS Medicine, 2004

  35. Sleep loss >> negative energy balance Spiegel et al JCEM 2004

  36. Laboratory-based study Epidemiology study Mean age: 22 Mean BMI: 24 Mean age: 79 Mean BMI: 30 short sleep:  leptin  ghrelin Spiegel et al Annals Internal Medicine 2004 Taheri et al., PLoS Medicine, 2004 Short sleep may lead to overweight  hunger  BMI

  37. Risks of short sleep and impact on human health • Degraded neurobehavioral performance • Broad endocrine impact • Short-term: induces a pre-diabetic state • Long-term risk: Obesity, Diabetes, CVD, mortality

  38. “Sleep Debt” Studies How much do you sleep? Do you get enough good sleep? Sleep for balance New York Times, 01/1997

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