1. SLEEPING SWEETLY:
How Sleep Deprivation & Obstructive Sleep Apnea Effect Type 2 Diabetes Mellitus

2. 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 ;

3. Pre-test QUESTION 1
Sleep deprivation in healthy, non-diabetics leads to impaired glucose metabolism
True
False

4. Pre-test QUESTION 1
Sleep deprivation in healthy, non-diabetics leads to impaired glucose metabolism
True
False

5. Pre-test QUESTION 2
Proposed factors linking obstructive sleep apnea with impairments in glucose metabolism include:
Interleukin 6
Catecholamines
Cortisol
2 & 3
All of the above

6. Pre-test QUESTION 2
Proposed factors linking obstructive sleep apnea with impairments in glucose metabolism include:
Interleukin 6
Catecholamines
Cortisol
2 & 3
All of the above

7. Chronic sleep deprivation is
Common
Dangerous
Easily recognized
Treatable

8. Obstructive Sleep Apnea Syndrome (OSAS) is
Common
Dangerous
Easily recognized
Treatable
The important message to take home from this talk is that sleep apnea is a common disorder; it is dangerous for the patient and others; and it is easily recognizable and is treatable.
We will first define what sleep apnea is, then describe the physiological consequences of the disorder and how these lead to the presenting features. This will be followed by a discussion of clinical features and risk factors suggestive of the presence of sleep apnea and methods for making the diagnosis. Finally, we will discuss the treatment options available for patients with sleep apnea.

9. Type 2 Diabetes Mellitus (DM) is
Common
Dangerous
Easily recognized
Treatable

10. I hope to convince you today that OSAS is independently associated with impairments in glucose metabolism & type 2 DM (independent of obesity)

11. 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
The important message to take home from this talk is that sleep apnea is a common disorder; it is dangerous for the patient and others; and it is easily recognizable and is treatable.
We will first define what sleep apnea is, then describe the physiological consequences of the disorder and how these lead to the presenting features. This will be followed by a discussion of clinical features and risk factors suggestive of the presence of sleep apnea and methods for making the diagnosis. Finally, we will discuss the treatment options available for patients with sleep apnea.

12. Overview of The obstructive sleep apnea syndrome

13. What is the “apnea” in sleep apnea?
Cessation of airflow > 10 seconds
Hypopnea
Decreased airflow > 10 seconds associated with:
Arousal from sleep
Oxyhemoglobin desaturation
When abnormal breathing patterns disrupt sleep, this is called sleep-disordered breathing. There are different types which can occur in one of several patterns. An apnea is defined as the cessation of airflow for 10 or more seconds.1 Controversy exists about the definition of hypopnea. Because of the relationship of sleep fragmentation and daytime sleepiness, many investigators consider a decrease in airflow for > 10 seconds accompanied by an arousal as a significant disordered breathing (hypopnea) event without requiring a specific level of desaturation.2
Recently, the presence of apneas and hypopneas has been associated with an increased prevalence of cardiovascular disease.3 In this study, hypopnea was defined as an event lasting at least 10 seconds with a greater than 30% reduction in thorocoabdominal movement or airflow, and with at least a 4% oxygen desaturation. When a 4% desaturation criteria is applied to the definition of hypopnea significant cardiovascular co-morbidity has been detected at an AHI => 5 per hour.
For this talk, hypopnea will be broadly defined as those obstructive events, lasting > 10 seconds, accompanied by either oxyhemoglobin desaturation or an arousal.
1. American Thoracic Society. Indications and standards for the use of nasal continuous positive airway pressure (CPAP) in sleep apnea syndromes. Am J Respir Crit Care Med 1994;150(6 Pt 1):
2. American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. SLEEP 1999;22(5):
3. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, O’Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163(1):19-25.

14. 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
These are the terms most commonly used to describe the frequency of sleep apnea. The Apnea Index is defined as the number of apneas per hour of sleep. The Apnea/Hypopnea Index, or AHI, represents the total number of apneas and hypopneas per hour of sleep. This has also been called the Respiratory Disturbance Index or RDI.
An AHI < 5 is considered normal.5 What frequency above this level requires therapy or leads to adverse clinical consequences is controversial. The sleep apnea syndrome, or clinical sleep apnea, is defined as recurrent apneas or hypopneas that are associated with clinical impairment, such as daytime sleepiness, motor vehicle accidents or cardiovascular disease.1
5. National Center on Sleep Disorders Research. Sleep apnea: is your patient at risk? Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Publication No , September 1995.
1. American Thoracic Society. Indications and standards for the use of nasal continuous positive airway pressure (CPAP) in sleep apnea syndromes. Am J Respir Crit Care Med 1994;150:

15. Pathophysiology of an obstructive apnea
This slide shows the effect of sleep on the upper airway in a sleep apnea patient. In the figure on the left, the patient is awake and the airway is narrowed but patent. The upper airway dilator muscles are responsible for maintaining the patency of the airway despite the reduced size of the airway, which may be due to fat deposition from obesity or structural abnormalities such as retrognathia. Note that collapse, shown on the right, may occur anywhere along the upper airway, from the retropalatal space to the hypopharynx, and often occurs in multiple places.

16. Pathophysiology of Obstructive Sleep Apnea
Awake: Small airway + neuromuscular compensation
Loss of neuromuscular compensation
Sleep Onset
Hyperventilate: connect hypoxia & hypercapnia
Decreased pharyngeal muscle activity
Airway opens
Airway collapses
Pharyngeal muscle activity restored
Apnea
Arousal from sleep
Hypoxia & Hypercapnia
Increased ventilatory effort +
This figure depicts the repetitive pathophysiologic events which occur during sleep apnea. The primary problem in the sleep apnea patient is the presence of an anatomically small pharyngeal airway. To prevent airway collapse during wakefulness, the action of the airway dilator muscles is augmented – a neuromuscular compensation for the small airway. With sleep onset, there is a loss of the upper airway reflex which drives this neuromuscular compensation. As a result, dilator muscle activity falls, the pharynx closes and the apnea begins. During the apnea, hypoxia and hypercapnia develop, leading to increasing ventilatory effort. Once this effort reaches a threshold level, the patient arouses. Pharyngeal muscle activity is restored, and the airway opens. The patient then hyperventilates to correct the blood gas derangements, returns to sleep, and the cycle begins again.
As a result, sleep can be severely disrupted by the repetitive arousals needed to end the apneas, and episodes of cyclic hypoxia and hypercapnia occur. These events lead to the observed clinical consequences.

17. Clinical Consequences
Obstructive Sleep Apnea
Sleep fragmentation, Hypoxia / Hypercapnia
excessive daytime sleepiness
cardiovascular & metabolic complications
As we proceed to detail the many clinical consequences of sleep apnea, it will be helpful to recall that all these adverse effects are the result of the two fundamental abnormalities which characterize sleep apnea.
First, the patient cycles from apnea to arousal many times each night which leads to severe sleep fragmentation.
Second, most apneic episodes are accompanied by hypoxemia and hypercapnia, which repeatedly stress the patient’s cardiovascular system.
The many ill-effects which result from these two abnormalities can be broadly grouped into two categories: excessive daytime sleepiness and cardiovascular dysfunction.
The end result of all these adverse effects is a substantial increase in both morbidity and mortality among sleep apnea patients.
Morbidity
Mortality

18. 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
A number of factors which put people at higher risk for developing sleep apnea are listed on this slide. The most common risk factor is the presence of obesity, specifically measures of central obesity. Upper body fat distribution is one of the major contributing factors to the development of sleep apnea. In both sexes the syndrome is more prevalent with increasing age,6 reaching very high rates in patients over 65 years.24 Males appear to have a higher rate of sleep apnea than women, with a ratio of 2:1 to 10:1, depending on the study.11 Any condition resulting in an anatomic abnormality which narrows the posterior airspace can predispose to the development of sleep apnea. This includes nasal obstruction, retro- or micrognathia, tonsillar hypertrophy and macroglossia. Several studies have demonstrated a higher risk for development of sleep apnea if there is a family history of the disorder, with increasing risk with increasing number of affected relatives.25 Use of alcohol or sedative medication can contribute to the development of sleep apnea through their relaxant effect on the upper airway muscles.26 A longitudinal epidemiological study showed that smokers are at an increased risk for developing sleep apnea, with current smokers at greater risk than nonsmokers, and heavy smokers having the greatest risk.27 Cessation of smoking resulted in the elimination of the increased risk. Associated conditions: Hypothyroidism can contribute to the development of sleep apnea through the development of macroglossia or obesity, and through its effect on upper airway muscle function. Other conditions in which sleep apnea has been reported – due to their effects on upper airway anatomy or muscle function – include acromegaly, amyloidosis, vocal cord paralysis, post-polio syndrome, neuromuscular disorders, Marfan syndrome and Down syndrome.11
6. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328(17):
24. Ancoli-Israel S, Klauber MR, Kripke DF, Parker L, Cobarrubias M. Sleep apnea in female patients in a nursing home. Increased risk of mortality. Chest 1989;96(5):
11. Strohl KP, Redline S. Recognition of obstructive sleep apnea. Am J Respir Crit Care Med 1996;154(2 Pt 1):
25. Redline S, Tishler PV, Tosteson TD, et al. The familial aggregation of obstructive sleep apnea. Am J Respir Crit Care Med 1995:151(3 Pt 1):
26. Issa FG, Sullivan CD. Alcohol, snoring and sleep apnea. J Neurol Neruosurg Psychiatry 1982;45(4):
27. Wetter DW, Young BT, Bidwell TR, Badr MS, Palta M. Smoking as a risk factor for sleep-disordered breathing. Arch Intern Med 1994;154(19):

19. 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
The first step in making a diagnosis of sleep apnea is taking a thorough history of the patient’s sleep schedule and sleep apnea symptoms. The responses shown on this slide indicate an increased probability of obstructive sleep apnea.5 Patients with loud, long-standing snoring are at an increased risk of having sleep apnea,41 especially if paired with gasping or choking episodes during sleep. These episodes may represent apneic events. It is very important that an attempt be made to elicit information from the patient’s bed partner. The patient is often unaware of what occurs during sleep and may not be aware of symptoms such as snoring. A bed partner’s description of witnessed apneas is highly suggestive of the presence of sleep apnea.42 A history of multiple automobile or work-related accidents, especially when associated with tiredness or fatigue, should prompt an investigation for sleep apnea.43 Information concerning risk factors – such as family history, alcohol or sedative use, predisposing medical conditions or cigarette smoking – should be elicited from anyone suspected of having sleep apnea. Most patients with sleep apnea are objectively sleepy, although daytime sleepiness is frequently underreported. As a result, it is important to know how to assess daytime sleepiness.
Sleep Apnea: Is Your Patient at Risk? NIH Publication, No
5. National Center on Sleep Disorders Research. Sleep apnea: Is your patient at risk? Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Publication No , September 1995.
41. Stradling JR, Crosby JH. Predictors and prevalence of obstructive sleep apnoea and snoring in 1001 middle aged men. Thorax 1991;46(2):85-90.
42. Kump K, Whalen C, Tishler PV, Browner I, Ferrette V, Strohl KP, Rosenberg C, Redline S. Assessment of the validity and utility of a sleep-symptom questionnaire. Am J Respir Crit Care Med 1994;150(3):
43. American Thoracic Society. Sleep apnea, sleepiness, and driving risk. Am J Respir Crit Care Med 1994;150(5 Pt 1):

20. Diagnosis: Physical Examination
Upper body obesity / thick neck
> 17” males
> 16” females
Hypertension
Obvious airway abnormality
The presence of these physical characteristics on physical examination should raise the physicians’ suspicion about the presence of sleep apnea.
Obesity, particularly upper body obesity, is associated with the presence and severity of sleep apnea.29 In general, men with a neck circumference of 17 inches or greater and women with a neck circumference of 16 inches or greater are at a higher risk for sleep apnea.28
Systemic hypertension is common in sleep apnea patients.44
The presence of any obvious airway abnormality – such as a crowded oropharynx, tonsillar hypertrophy, retrognathia or nasal obstruction – puts the patient at risk for the development of sleep apnea.45
29. Millman RP, Carlisle CC, McGarvey ST, Eveloff SE, Levinson PD. Body fat distribution and sleep apnea severity in women. Chest 1995;107(2):
28. Davies RJ, Stradling JE. The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. Eur Respir J (Denmark) 1990;3(5):
44. Hla KM, Young TB, Bidwell T, Palta M, Skatrud JB, Dempsey J. Sleep apnea and hypertension. A population-based study. Ann Intern Med 1994;120(5):
45. Shepard JW Jr., Gefter WB, Guilleminault C, et al. Evaluation of the upper airway in patients with obstructive sleep apnea. SLEEP 1991;14(4):

21. Exam: Oropharynx Slide 21 Level 2
This picture demonstrates a common finding in sleep apnea patients, the crowded oropharynx. The soft palate hangs low, the uvula is slightly enlarged and there is crowding by the lateral tonsillar pillars. The palatine tonsils are not visualized.
Slide 21
Level 2
46. Shepard JW Jr, Olsen KD. Uvulopalatopharygoplasty for treatment of obstructive sleep apnea. Mayo Clin Proc 1990;65(9):

22. Physical Examination
This patient demonstrates structural abnormalities which can lead to airway narrowing and sleep apnea. Note the presence of a thick neck and retrognathia.47
Guilleminault C et al. Sleep Apnea Syndromes. New York: Alan R. Liss, 1978.
47. Coccagna G, et al. The bird-like face syndrome (acquired micrognathia, hypersomnia, and sleep apnea). In: Guilleminault C, Dement WC, eds. Sleep apnea syndromes. New York: Alan R Liss, 1978:

23. 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
A sleep study is performed to confirm the presence of sleep apnea and to assess the level of severity of the disorder. Although identification of patients at risk for sleep apnea can be made through the history and physical, the signs and symptoms in any particular patient are poor indicators of the level of disease severity.51 The severity of illness determines the type and urgency of treatment.
Delay in confirming the diagnosis and determining the severity of sleep apnea can lead to delay in initiating treatment. This can lead to increased morbidity from the cardiovascular consequences, increased risk of motor vehicle accidents and, as a result, increased mortality.
Before initiating treatment, it is also important to confirm the diagnosis and rule out other possible causes of excessive daytime sleepiness such as periodic limb movements of sleep, narcolepsy or insufficient amounts of sleep. Because sleepiness is a nonspecific symptom that can be caused by other disorders, and snoring is common even in people without sleep apnea, it is necessary to confirm the presence of sleep apnea. A sleep study will provide this information.
51. Viner S, Szalai JP, Hoffstein V. Are history and physical examination a good screening test for sleep apnea? Ann Intern Med 1991;115(5):

24. Polysomnography
This slide shows the setup of equipment on a patient undergoing overnight polysomnography. Note the multiple EEG, EOG, EMG and respiratory electrodes required for full physiologic monitoring.

25. Treatment of Obstructive Sleep Apnea Syndrome

26. Treatment Objectives Reduce mortality and morbidity
Decrease cardiovascular complications
Reduce sleepiness
Improve metabolic derangements, including type 2 diabetes mellitus
Improve quality of life
The goal of treatment for patients with sleep apnea should be the reduction of morbidity and mortality and improvement of their quality of life. This can be accomplished by preventing the cardiovascular consequences of sleep apnea and reducing the complications of daytime sleepiness.

27. Therapeutic Approach Risk counseling Apnea treatment
Motor vehicle crashes
Job-related hazards
Judgment impairment
Apnea treatment
Weight loss; avoidance of alcohol & sedatives
CPAP
Oral appliance
Surgery (UPPP)
As part of the therapeutic approach to sleep apnea, all patients should be counseled regarding their increased risk of motor vehicle crashes, job related injuries and impairment of judgement.43
The treatment of sleep apnea and existing or consequent comorbidities can include behavioral, medical or surgical interventions.57
43. American Thoracic Society. Sleep apnea, sleepiness, and driving risk. Am J Respir Crit Care Med 1994;150(5 Pt 1):
57. Strollo PJ Jr., Rogers RM. Obstructive sleep apnea. N Engl J Med 1996;334(2):

28. Positive Airway Pressure
This slide depicts the therapeutic effect of continuous positive airway pressure (CPAP). In the panel on the left, you can see upper airway closure in an untreated sleep apnea patient. Note that the airway closure is diffuse, involving both the palate and the base of the tongue. In the second panel, CPAP is applied and the airway is splinted open by the positive pressure.
69. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981;1(8225):

29. Positive Airway Pressure
This slide depicts a patient sleeping while using a positive airway pressure system. These devices are highly portable, fit on a nightstand, and can easily be transported outside of the home.

30. Oral Appliance: Mechanics
There are several types of oral appliances available for the treatment of sleep apnea. This slide depicts a mandibular repositioning device. The oral appliance causes the mandible to move forward and the bite to open slightly. The effect of this mandibular repositioning is to enlarge the airway, reduce airway collapsibility and decrease airway resistance.82
The device also anchors the mandible so that contraction of the genioglossus muscle moves the hyoid bone forward rather than just opening the mouth.
Another proposed mechanism is the activation of upper airway muscles, although this has not been proven conclusively. In some patients, oral appliances are an effective treatment for sleep apnea.
82. Schmidt-Nowara W, Lowe A, Wiegand L, Cartwright R, Perez-Guerra F, Menn S. Oral appliances for the treatment of snoring and obstructive sleep apnea: a review. SLEEP 1995;18(6):

31. Uvulopalatopharyngoplasty (UPPP)
This slide depicts the uvulopalatopharyngoplasty (UPPP) surgical technique.
The panel on the left depicts the preoperative upper airway, demonstrating a long soft palate and the presence of palatine tonsils. The incision site is marked with the dotted line.
The panel on the right depicts the postoperative oropharynx, with amputation of the uvula, bilateral palatine tonsillectomy, and trimming and suturing together of the anterior and posterior tonsillar pillars.
89. Fujita S, Conway W, Zorick F, Roth T. Surgical correction of anatomic abnormalities in obstructive sleep apnea syndrome: uvulopalatopharyngoplasty. Otolaryngol Head Neck Surg 1981;89(6):

32. 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
A variety of issues should be addressed by the primary care clinician5:
1. Risk counseling should be provided for all patients with sleep apnea.
2. Initiation of appropriate behavioral modification treatments such as weight loss and smoking cessation.
3. Patients undergoing treatment require monitoring for efficacy of and compliance with treatment and resolution of symptoms. Weight loss and changes in blood pressure should be monitored. Patients should be periodically re-evaluated for recurrence of symptoms after successful treatment. CPAP equipment should be checked periodically for proper functioning. Finally, objective compliance with CPAP should be documented, using hour meters currently available on most machines, and side effects or troubles with use detected and resolved.
Sleep Apnea: Is Your Patient at Risk? NIH Publication No
5. National Center on Sleep Disorders Research. Sleep Apnea: Is Your Patient at Risk? U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute, NIH Publication No , September 1995.

33. CASE
PRESENTATION

34. 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

35. 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

36. Case Presentation, cont’d
Medications: metformin
No tobacco or alcohol use
Physical exam: BMI = (311 pounds, 5’7” tall); very crowded posterior pharyngeal airway; obese neck

37. Case Presentation, cont’d
Epworth sleepiness scale = 15 (>10 is abnormal)
Fasting glucose (lab draw) 155
Hg A1C 7.6
TSH 2.77

38. 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

39. 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%

40. Case Presentation: diagnostic sleep study

41. Case Presentation, cont’d
Treatment: CPAP
CPAP titration done with resolution of respiratory events and stabilization of oxygen desaturations
Optimal pressure: 15 cm H20

42. Case Presentation: CPAP titration

43. 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 points (from mid-150s to low 130s, as low as 127) with no change in medication

44. Effects of sleep restriction & sleep deprivation on glucose metabolism

45. 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

46. Sleep restriction & sleep deprivation adversely effect glucose metabolism

47. 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 levels
Nedeltcheva, J Clin Endocrinol Metab 2009 Sep; 94(9):

48. 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

49. Short sleep duration is associated with development of type 2 Diabetes Mellitus

50. 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, Mar; 29(3):
Gangwisch, Sleep, Dec 1; 30(12):

51. Effects of sleep restriction & sleep deprivation on appetite (the leptin/ghrelin & obesity link)

52. 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:
Everson, Sleep, 1989; 12:13-21.

53. 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:

54. 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:

55. 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:

56. 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: ). Principles & Practice of Sleep Medicine (Kryger, Roth and Dement), 2005, chapter 86, p
Danguir, Physiol Behav 1979; 22:

57. Relationship between OSAS and glucose metabolism & development of type 2 DM

58. Obstructive sleep apnea
Relationship between obstructive sleep apnea and type 2 diabetes mellitus
Glucose intolerance
Insulin resistance
Diabetes Mellitus
Obesity
Obstructive sleep apnea
Principles & Practice of Sleep Medicine (Kryger, Roth and Dement), 2005, chapter 86, figure 86-1, page 1036.

59. Association between OSAS and impaired glucose metabolism

60. 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.

61. 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 Feb 1; 179(3):

62. 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):

63. Association between OSAS and type 2 DM (unrelated to obesity)

64. 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.

65. 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, Dec 15; 172(12):

66. 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

67. 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.

68. 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

69. 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;
J Appl Physiol 2001;
J Physiol 2003; 552:

70. 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;

71. 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,
Diabetologia 2000; 43:
Proc Assoc Am Physicians 1999; 111:

72. 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:
Lancet 1999;
J Physiol 1976; 261:
J Physiol 1977; 269:

73. Inflammatory mediators
IL-6 (interleukin 6)
TNF-alpha (tumor necrosis factor)

74. 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: Pradham, JAMA 2001; 286: Klausen, Eur J Appl Physiol Occup Physiol 1997; 76: Hartmann, Cytokine 2000; 12: Yokoe, Circulation 2003; 107: Vgontzas, J Clin Endocrinol Metab 2000; 85:

75. 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: Liu, J Tongji Med Univ 2000;20:

76. OSAS treatment with CPAP improves glucose metabolism & diabetic control

77. 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.

78. 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.

79. 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, Dec; 9(4):

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 points (from mid-150s to low 130s, as low as 127) with no change in medication

81. IN CONCLUSION

82. Chronic sleep deprivation, OSAS and type 2 diabetes mellitus are
Dangerous
Common
Easily recognized
Treatable
Inter-related

83. Think about and ask about symptoms of OSAS in your patients with
Obesity
Impaired glucose tolerance
Type 2 DM

84. The ultimate goal: