sleeping sweetly:

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 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


• Treatable

Type 2 Diabetes Mellitus (DM) is

• Common

• Dangerous


• 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

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


• Medications: metformin

• No tobacco or alcohol use

• Physical exam: BMI = 48.71 (311 pounds, 5’7” tall); very crowded posterior pharyngeal airway; obese neck


• Epworth sleepiness scale = 15 (>10 is abnormal)

• Fasting glucose (lab draw) 155

• Hg A1C 7.6

• TSH 2.77


• 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


• 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)


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


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.


• 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.


• 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.


• 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.


• 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:

sleeping sweetly:

Documents

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