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SLEEPING SWEETLY:
How Sleep Deprivation &
Obstructive Sleep Apnea Effect
Type 2 Diabetes Mellitus
Ronald J. Green, MD, FCCP, FAASM
Diplomate, American Board of Sleep Medicine
Sleep Medicine, Pulmonary Disease & Smoking
Cessation, The Everett Clinic
Associate Medical Director
North Puget Sound Center for Sleep Disorders
Everett, WA
425-339-5410; www.ilikesleep.com
Pre-test QUESTION 1
• Sleep deprivation in healthy, nondiabetics leads to impaired glucose
metabolism
1. True
2. False
Pre-test QUESTION 1
• Sleep deprivation in healthy, nondiabetics 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 compensation
Loss of
neuromuscular
compensation
Sleep Onset
+
Decreased
pharyngeal muscle
activity
Airway opens
Airway collapses
Pharyngeal
muscle activity
restored
Apnea
Hypoxia &
Hypercapnia
Hyperventilate:
connect hypoxia
& hypercapnia
Increased
ventilatory
effort
Arousal from
sleep
Clinical Consequences
Obstructive Sleep Apnea
Sleep fragmentation,
Hypoxia / Hypercapnia
excessive
daytime
sleepiness
cardiovascular
& metabolic
complications
Morbidity
Mortality
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.
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.
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 effects
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 mid150s 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, nonobese subjects (Nedelcheva, et al)
• Sleep restriction resulted in:
– Reduced oral glucose tolerance
– Reduced insulin sensitivity
– Modest increase in epinephrine & norepinephrine
levels
Nedeltcheva, 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 caloriedense, 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
Glucose
intolerance
Insulin resistance
Obstructive sleep
apnea
Obesity
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 & ethnicity
Tasali 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 resistance
Acta 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: