SLEEPING SWEETLY:How Sleep Deprivation &
Obstructive Sleep Apnea Effect Type 2 Diabetes Mellitus
Ronald J. Green, MD, FCCP, FAASM
Diplomate, American Board of Sleep MedicineSleep Medicine, Pulmonary Disease & Smoking
Cessation, The Everett Clinic
Associate Medical DirectorNorth Puget Sound Center for Sleep Disorders
Everett, WA425-339-5410; www.ilikesleep.com
Pre-test QUESTION 1
• Sleep deprivation in healthy, non-diabetics leads to impaired glucose metabolism
1. True
2. False
Pre-test QUESTION 1
• Sleep deprivation in healthy, non-diabetics leads to impaired glucose metabolism
1. True
2. False
Pre-test QUESTION 2
• Proposed factors linking obstructive sleep apnea with impairments in glucose metabolism include:
1. Interleukin 6
2. Catecholamines
3. Cortisol
4. 2 & 3
5. All of the above
Pre-test QUESTION 2
• Proposed factors linking obstructive sleep apnea with impairments in glucose metabolism include:
1. Interleukin 6
2. Catecholamines
3. Cortisol
4. 2 & 3
5. All of the above
Chronic sleep deprivation is
• Common
• Dangerous
• Easily recognized
• Treatable
Obstructive Sleep Apnea Syndrome (OSAS) is
• Common
• Dangerous
• Easily recognized
• Treatable
Type 2 Diabetes Mellitus (DM) is
• Common
• Dangerous
• Easily recognized
• Treatable
I hope to convince you today that OSAS is independently associated with
impairments in glucose metabolism & type 2 DM
(independent of obesity)
OUTLINE• Overview of obstructive sleep apnea syndrome
(OSAS)• Case presentation• Effects of sleep restriction & sleep deprivation on
glucose metabolism• OSAS’s effects on glucose metabolism and type 2
diabetes mellitus (DM)• Proposed mechanisms linking OSAS with
impairments in glucose metabolism• Effects of treatment of OSAS on type 2 DM
Overview of The obstructive sleep
apnea syndrome
What is the “apnea” in sleep apnea?
• Apnea– Cessation of airflow > 10 seconds
• Hypopnea– Decreased airflow > 10 seconds
associated with:• Arousal from sleep• Oxyhemoglobin desaturation
Measures of Sleep Apnea Frequency
• Apnea Index
– # apneas per hour of sleep
• Apnea / Hypopnea Index (AHI)
– # apneas + hypopneas per hour of sleep
– > 5 considered abnormal in adults
Pathophysiology of an obstructive apnea
Pathophysiology of Obstructive Sleep Apnea
Awake: Small airway + neuromuscular compensationAwake: Small airway + neuromuscular compensationLoss of Loss of
neuromuscular neuromuscular compensationcompensation
SleepSleep OnsetOnset Hyperventilate: Hyperventilate: connect hypoxia connect hypoxia & hypercapnia& hypercapniaDecreased Decreased
pharyngeal muscle pharyngeal muscle activityactivity Airway opensAirway opens
Airway collapsesAirway collapsesPharyngeal Pharyngeal
muscle activity muscle activity restoredrestoredApneaApnea
Arousal from Arousal from sleepsleep
Hypoxia & Hypoxia & HypercapniaHypercapnia
Increased Increased ventilatory ventilatory
efforteffort
++
Clinical Consequences
Obstructive Sleep ApneaObstructive Sleep Apnea
excessive excessive daytime daytime
sleepinesssleepiness
Sleep fragmentation, Sleep fragmentation, Hypoxia / HypercapniaHypoxia / Hypercapnia
cardiovascular cardiovascular & metabolic & metabolic complicationscomplications
MorbidityMorbidityMortalityMortality
Obstructive Sleep Apnea: Most common risk factors
• Obesity• Increasing age• Male gender• Anatomic abnormalities of upper airway• Family history of OSAS• Alcohol or sedative use
Diagnosis: History
• Loud snoring (not all snore)• Nocturnal gasping and choking
– Ask bed partner (witnessed apneas)• Automobile or work related accidents• Personality changes or cognitive problems• Risk factors• Excessive daytime sleepiness (often not recognized by
patient)• Frequent nocturia
Sleep Apnea: Is Your Patient at Risk? NIH Publication, No 95-3803.Sleep Apnea: Is Your Patient at Risk? NIH Publication, No 95-3803.
Diagnosis: Physical Examination
• Upper body obesity / thick neck
> 17” males
> 16” females
• Hypertension
• Obvious airway abnormality
Exam: Oropharynx
Physical Examination
Guilleminault C et al. Sleep Apnea Syndromes. New York: Alan R. Liss, 1978.Guilleminault C et al. Sleep Apnea Syndromes. New York: Alan R. Liss, 1978.
Why Get a Sleep Study?
• Signs and symptoms poorly predict disease severity
• Appropriate therapy dependent on severity
• Failure to treat leads to:
– Increased morbidity– Motor vehicle crashes– Mortality
• Help diagnose other causes of daytime sleepiness
Polysomnography
Treatment of Obstructive Sleep Apnea
Syndrome
Treatment Objectives
• Reduce mortality and morbidity
– Decrease cardiovascular complications
– Reduce sleepiness
– Improve metabolic derangements, including type 2 diabetes mellitus
• Improve quality of life
Therapeutic Approach
• Risk counseling– Motor vehicle crashes
– Job-related hazards
– Judgment impairment
• Apnea treatment– Weight loss; avoidance of alcohol & sedatives
– CPAP
– Oral appliance
– Surgery (UPPP)
Positive Airway Pressure
Positive Airway Pressure
Oral Appliance: Mechanics
Uvulopalatopharyngoplasty (UPPP)
Primary Care Management
• Risk counseling
• Behavior modification (weight loss, etc)
• Monitor symptoms and compliance
– Monitor weight and blood pressure
– Ask about recurrence of symptoms
– Evaluate CPAP use and side effectsSleep Apnea: Is Your Patient at Risk? NIH Publication No.95-3803.Sleep Apnea: Is Your Patient at Risk? NIH Publication No.95-3803.
CASE
PRESENTATION
Case Presentation• 34 year old woman with history of
morbid obesity, type 2 DM & polycystic ovarian syndrome
• Per husband, loud snoring & witnessed apneas at night for yrs
• Awakens herself choking/gasping at night and during naps
Case Presentation, cont’d
• Hypersomnolence for years
• Near misses driving due to falling asleep briefly at the wheel
• Steady weight gain for years
• Drinks one pot coffee daily plus caffeinated soda all day long
Case Presentation, cont’d
• Medications: metformin
• No tobacco or alcohol use
• Physical exam: BMI = 48.71 (311 pounds, 5’7” tall); very crowded posterior pharyngeal airway; obese neck
Case Presentation, cont’d
• Epworth sleepiness scale = 15 (>10 is abnormal)
• Fasting glucose (lab draw) 155
• Hg A1C 7.6
• TSH 2.77
Case Presentation, cont’d
• IMPRESSION: severe, long standing obstructive sleep apnea syndrome
• RECOMMENDATIONS:
– Overnight sleep study and titration of CPAP, and initiate CPAP therapy
– Risk counseling: driving safety, weight loss
Case Presentation:diagnostic sleep study
• Apnea/hypopnea index = 136 per hr
• 33% of the events caused arousals (45 arousals per hour)
• Low oxygen saturation = 63%
• 40% of the night spent with oxygen saturations below 90%
Case Presentation:diagnostic sleep study
Case Presentation, cont’d
• Treatment: CPAP
• CPAP titration done with resolution of respiratory events and stabilization of oxygen desaturations
• Optimal pressure: 15 cm H20
Case Presentation:CPAP titration
Case Presentation:Treatment with CPAP
• On CPAP at pressure of 15 cm H2O
– “It’s just like a whole new world.”
– Able to exercise again and has great energy
– Excessive Daytime Sleepiness gone (ESS = 5 vs 15 pre-Tx)
– 13 pound weight loss in 6 weeks (unable to lose any weight prior to CPAP)
– Fasting, morning glucose dropped 15-20 points (from mid-150s to low 130s, as low as 127) with no change in medication
Effects of sleep restriction & sleep deprivation
on glucose metabolism
Definition of terms
• Insulin resistance: normal amounts of insulin are inadequate to produce a normal drop in blood glucose
• Insulin sensitivity: systemic responsiveness to glucose
• Glucose intolerance: blood glucose levels are higher than normal, but not high enough to classify as diabetes mellitus
• Glucose effectiveness: ability of glucose to mobilize itself independent of an insulin response
Sleep restriction & sleep deprivation adversely effect
glucose metabolism
Effects of sleep restriction on glucose metabolism (no OSAS)
• Results of sleep restriction (5.5h vs 8.5h for 14 nights) on healthy, non-diabetic, non-obese subjects (Nedelcheva, et al)
• Sleep restriction resulted in:– Reduced oral glucose tolerance – Reduced insulin sensitivity– Modest increase in epinephrine & norepinephrine
levelsNedeltcheva, J Clin Endocrinol Metab 2009 Sep; 94(9): 3242-50
Effects of sleep fragmentation on glucose metabolism (no OSAS)
• Normal, healthy non-diabetics were subjected to sleep fragmentation with auditory & mechanical stimuli for just two nights (Stamatakis & Punjabi)
• Results:– Insulin sensitivity decreased– Glucose effectiveness decreased– Morning cortisol levels increased
Stamatakis, Chest 2010 Jan; 137(1):95-101
Short sleep duration is associated with development of
type 2 Diabetes Mellitus
Short sleep duration is associated with development of type 2 DM
• Yaggi, et al (Cohort of Mass. Male Aging Study)– Short sleepers (< 6h per night) twice as likely to
develop DM vs those sleeping 7-8h per night– Adjusted for age, HTN, waist circum, health
status• Gangwisch, et al (Cohort of 1st National Health &
Nutrition Examination Survey)– Short sleepers (< 5h per night) were 1.5 times
more likely to develop DM vs 7-8h per night
Yaggi, Diabetes Care, 2006. Mar; 29(3): 657-61.Gangwisch, Sleep, 2007. Dec 1; 30(12): 1667-73.
Effects of sleep restriction & sleep deprivation on appetite
(the leptin/ghrelin & obesity link)
Leptin and Ghrelin
• Peripheral signals (hormones) which regulate food intake
• Influenced by sleep restriction• Have a Yin/Yang effect on appetite
Danguir, Physiol Behav 1979; 22:735-40.Everson, Sleep, 1989; 12:13-21.
Leptin: The Yin effect on appetite
• Released from adipocytes (fat cells)• Results in decreased appetite• Levels rapidly rise/fall in response to acute
caloric shortage/surplus respectively• Rising/falling levels result in reciprocal
changes in hunger (up---less hungry; down---more hungry)
Spiegel, Ann Intern Med 2004; 141:846-850.
Ghrelin: The Yang effect on appetite
• Released from the stomach • Results in increased appetite• Rising/falling levels result in changes in
hunger (up---more hungry; down---less hungry)
Spiegel, Ann Intern Med 2004; 141:846-850.
Leptin and Ghrelin
• In healthy, young, non-diabetic men sleep restriction (4 hrs per night for two nights):– 18% decrease in leptin levels– 28% increase in ghrelin levels– Increase in hunger by 24%– Increase in appetite by 23%– Most pronounced was increase in craving for calorie-
dense, high carbohydrate foods
Spiegel, Ann Intern Med 2004; 141:846-850.
Leptin and Ghrelin
• Obese pts have elevated leptin levels and leptin resistance. Leptin resistance can promote hyperinsulinemia.
• OSAS pts have elevated leptin levels which decrease with CPAP treatment
Ceddia, FASEB Journal. 2002;16:1163-1176.). Principles & Practice of Sleep Medicine (Kryger, Roth and Dement), 2005, chapter 86, p. 1039.Danguir, Physiol Behav 1979; 22:735-40.
Relationship between OSAS and
glucose metabolism & development of type 2 DM
Relationship between obstructive sleep apnea and type 2 diabetes mellitus
Principles & Practice of Sleep Medicine (Kryger, Roth and Dement), 2005, chapter 86, figure 86-1, page 1036.
Association between OSAS and impaired glucose metabolism
Association between obstructive sleep apnea and glucose metabolism
• Severity of sleep-related hypoxemia correlated with glucose intolerance & insulin resistance
• Frequency of nocturnal arousals was independently correlated with degree of insulin resistance (Sleep Heart Health Study)
NM Punjabi, Am J Respir Crit Care Med, 2002. B Brooks, J Clin Endocrinol Metab 1994. IA Harsch, Am J Respir Crit Care Med 2003.
Reduction in insulin sensitivity in OSAS
• Punjabi and Beamer– Pts with OSAS had reduction in insulin
sensitivity vs normal controls, independent of age, sex, percent body fat
– As OSAS severity increased, insulin resistance increased as well
– Insulin sensitivity correlated with degree of nocturnal oxygen desaturation
Punjabi & Beamer, Am J Respir Crit Care Med. 2009 Feb 1; 179(3): 235-40
Impact of OSAS on insulin resistance & glucose tolerance in polycystic ovarian syndrome (PCOS)
• Tasali, et al– Women with PCOS & OSAS were
• more insulin resistant than PCOS women without OSAS • more likely to have glucose intolerance than PCOS
women without OSAS– Severity of OSAS
• highly significant predictor of fasting glucose & insulin levels
• Highly correlated with insulin resistance & glucose tolerance
Findings were all controlled for BMI, age & ethnicityTasali E, et al. J Clin Endocrinol Metab 2008 Oct; 93 (10): 3878-84
Association between OSAS and type 2 DM
(unrelated to obesity)
Studies linking OSAS to type 2 DM
• In Nurses’ Health Study, women who snored regularly had double the relative risk of developing type 2 DM (adjusted for age & BMI)
• Habitual snoring in Swedish men associated with higher incidence of DM over 10 yr period
WK Al Delaimy, Am J Epidemiol 2002. A Elmasry, J Intern Ded, 2000.
Studies linking OSAS to type 2 DM
• Wisconsin Sleep Cohort (cross-sectional, longitudinal study)– Adjusted for age, sex & body habitus– 15% of subjects with AHI >15 had type 2 DM vs
3% of subjects with AHI < 5
Reichmuth, Am J Resp Crit Care Med, 2005. Dec 15; 172(12):1590-5.
Studies linking OSAS to type 2 DM
• Ronksely, et al– Prevalence of DM increased with increasing
OSAS severity, even adjusted for weight & neck circumference
– In stratified analysis: relationship was only observed in sleepy patients
Ronksley, Thorax 2009; 64(10): 834-9
The proposed causes of impaired glucose metabolism &
type 2 DM in OSAS
Principles & Practice of Sleep Medicine (Kryger, Roth and Dement), 2005, chapter 86, page 1037.
The proposed causes of impaired glucose metabolism & type 2 DM in OSAS
Principles & Practice of Sleep Medicine (Kryger, Roth and Dement), 2005, figure 86-2, p. 1038.
Hypoxia as a cause of impaired glucose metabolism
• 50% decrease in insulin sensitivity within 2 days of rapid ascent from sea level to 4600 m, associated with increases in cortisol & norepinephrine (NE)
• 61% decrease in insulin sensitivity in hyperbaric chamber (4300 m altitude), associated with increases in NE & epinephrine levels
• Obese mice show increase in insulin levels & worsening glucose tolerance with chronic exposure to intermittent hypoxia
J Physiol (Lond) 1997;504.241-249.J Appl Physiol 2001;91.623-631.J Physiol 2003; 552: 253-264.
Sleep disruption as a cause of impaired glucose metabolism
• Sleep restriction (4 hrs/night x 6 nights) in healthy men: 30% drop in glu effectiveness (pre vs post sleep restriction was same as difference between non-diabetic vs diabetic patients under normal conditions)
• Sleep Heart Health Study: arousal frequency correlated with insulin resistance
Lancet 1999;354.1435-1439.
The Sympathetic Nervous System
• OSAS patients have elevated sympathetic tone during both wake & sleep which decreases with CPAP therapy
• Sympathetic stimulation increases muscle glycogenolysis & hepatic glucose output
• Sympathetic stimulation promotes lipolysis & free fatty acid release, which can induce insulin resistanceActa Physiol Scand 2003;177,385-90.Diabetologia 2000; 43:533-549.Proc Assoc Am Physicians 1999; 111: 241-248.
Hypothalamic-pituitary-adrenal axis
• Partial & total sleep deprivation increase plasma cortisol levels by 37% & 45% respectively on the following evening
• In animals, hypoxia & hypercapnia stimulate glucagon & glucocortocoid production, leading to insulin resistance & glucose intolerance
Sleep 1997; 20:865-870. Lancet 1999;354.1435-1439.J Physiol 1976; 261: 271-283.J Physiol 1977; 269: 131-154.
Inflammatory mediators
• IL-6 (interleukin 6)• TNF-alpha (tumor necrosis factor)
IL-6 (interleukin 6)
• Is an inflammatory mediator released (in part) by subcutaneous adipose tissue
• Serum levels correlate with insulin resistance• Higher levels increase risk of type 2 DM• Levels increase with altitude hypoxia• OSAS pts have higher levels than controls• 1 month of CPAP decreased IL-6 levels
Kern, Am J Physiol Endocrinol Metab 2001; 280:E745-E751. Fernandez-Real, J Clin Endocrinol Metab 2001;86:1154-1159. Pradham, JAMA 2001; 286: 327-334. Klausen, Eur J Appl Physiol Occup Physiol 1997; 76: 480-482. Hartmann, Cytokine 2000; 12:246-252. Yokoe, Circulation 2003; 107: 1129-1134. Vgontzas, J Clin Endocrinol Metab 2000; 85:1151-1158.
TNF-alpha
• Important role in development of insulin resistance by antagonizing insulin action
• OSAS pts have higher levels than controls• Further work is needed in this area
Vgontzas, J Clin Endocrinol Metab 2000; 85:1151-1158. Liu, J Tongji Med Univ 2000;20: 200-202.
OSAS treatment with CPAP improves glucose metabolism &
diabetic control
OSAS treatment with CPAP improves diabetic control
• CPAP improves glucose metabolism– OSAS with AHI > 20– Looked at insulin sensitivity before then after 2
days & 3 months on CPAP– Significant improvement in insulin sensitivity at 2
days and remained at 3 months– Biggest change in less obese pts (BMI < 30)
IA Harsch, Am J Respir Crit Care Med 2003.
OSAS treatment with CPAP improves diabetic control
• In type 2 diabetics with OSAS, glucose levels during sleep are lower & more stable with CPAP treatment – Glucose measured every 5 min during sleep– Baseline vs after 41d on average on CPAP– No change in meds or diet– Mean sleeping glucose dropped from 122 to 103
A Dawson, Journal Clinical Sleep Medicine 2008.
OSAS treatment with CPAP improves diabetic control
• CPAP improves glycemic control– Retrospective analysis, no change in DM meds– Average AHI = 53 per hour– HgA1C dropped from 7.8 to 7.3 (p<0.001)
Hassaballa, Sleep Breath, 2005. Dec; 9(4): 176-80.
In summary:Review of the case presentation
• 34 year old woman with type 2 DM & morbid obesity, diagnosed with OSAS
• AHI = 136 & low oxygen saturation = 63%• Treated with CPAP at 15 cm H2O• Daytime symptoms resolved• Fasting, morning glucose dropped 15-20
points (from mid-150s to low 130s, as low as 127) with no change in medication
IN CONCLUSION
Chronic sleep deprivation, OSAS and type 2 diabetes mellitus are
• Dangerous• Common• Easily recognized• Treatable
• Inter-related
Think about and ask about symptoms of OSAS in your patients with
• Obesity• Impaired glucose
tolerance• Type 2 DM
The ultimate goal: