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

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Presentation on theme: "SLEEPING SWEETLY: How Sleep Deprivation & Obstructive Sleep Apnea Effect Type 2 Diabetes Mellitus."— Presentation transcript:

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 1.True 2.False

4 Pre-test QUESTION 1 Sleep deprivation in healthy, non- diabetics leads to impaired glucose metabolism 1.True 2.False

5 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

6 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

7 Chronic sleep deprivation is Common Dangerous Easily recognized Treatable

8 Obstructive Sleep Apnea Syndrome (OSAS) is Common Dangerous Easily recognized Treatable

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

12 Overview of The obstructive sleep apnea syndrome

13 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

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

15 Pathophysiology of an obstructive apnea

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 +

17 Clinical Consequences Obstructive Sleep Apnea excessive daytime sleepiness Sleep fragmentation, Hypoxia / Hypercapnia cardiovascular & metabolic complications MorbidityMortality

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

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 Sleep Apnea: Is Your Patient at Risk? NIH Publication, No

20 Diagnosis: Physical Examination Upper body obesity / thick neck > 17” males > 16” females Hypertension Obvious airway abnormality

21 Exam: Oropharynx

22 Physical Examination Guilleminault C et al. 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

24 Polysomnography

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

27 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)

28 Positive Airway Pressure

29

30 Oral Appliance: Mechanics

31 Uvulopalatopharyngoplasty (UPPP)

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 Sleep Apnea: Is Your Patient at Risk? NIH Publication No

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 1 st 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 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, B Brooks, J Clin Endocrinol Metab 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 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:


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