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Obstructive Sleep Apnea and Glucose Metabolism

Obstructive Sleep Apnea and Glucose Metabolism. Naresh M. Punjabi, MD, PhD Johns Hopkins University, School of Medicine Departments of Medicine and Epidemiology Baltimore, Maryland (USA). General Outline. Background Disease definition and epidemiology (e.g., glucose metabolism)

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Obstructive Sleep Apnea and Glucose Metabolism

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  1. Obstructive Sleep Apnea and Glucose Metabolism Naresh M. Punjabi, MD, PhD Johns Hopkins University, School of Medicine Departments of Medicine and Epidemiology Baltimore, Maryland (USA)

  2. General Outline • Background • Disease definition and epidemiology (e.g., glucose metabolism) • Association between sleep apnea and: • Insulin resistance and glucose intolerance • Insulin secretion • Effects of intermittent hypoxia and sleep fragmentation on glucose metabolism • Effects of CPAP treatment on glucose metabolism

  3. Disease Definition: Metabolic DysfunctionDiabetes and Glucose Tolerance DIABETES 126 IFG IFG + IGT Fasting glucose 100 IGT Normal 200 140 2-hour post-challenge glucose

  4. Diabetes Prevalence: 2010

  5. Diabetes Prevalence: 2030

  6. Diabetes and IGT

  7. 2008 1994 2000 2008 1994 2000 Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes Obesity (BMI ≥30 kg/m2) No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% Diabetes No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0% CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

  8. General Outline • Background • Disease definition and epidemiology (e.g., glucose metabolism) • Association between sleep apnea and: • Insulin resistance and glucose intolerance • Insulin secretion • Effects of intermittent hypoxia and sleep fragmentation on glucose metabolism • Effects of CPAP treatment on glucose metabolism

  9. The Sleep Heart Health Study: Field Sites Minneapolis (1085) Framingham (1000) ▲ ▲ New York (760) ▲ ▲ ▲ South Dakota (201) Pittsburgh (398) ▲ Sacramento (501) ▲ Hagerstown (1184) Oklahoma (200) ▲ Phoenix (201) ▲ Tucson (911) ▲ National Heart Lung and Blood Institute (NHLBI). The Sleep Heart Health Study: Manuals of Operation. http://www.jhucct.com/shhs/details/manual/demographics/01jul02received/shhs1demo1jul02.pdf. Accessed July 18, 2007.

  10. Sleep Apnea and Fasting Glucose Values Percentage RDI (events/h) Punjabi et al. Am J Epidemiol. 2004;160:521.

  11. Sleep Apnea and Glucose Tolerance Percentage RDI (events/h) Punjabi et al. Am J Epidemiol. 2004;160:521.

  12. Sleep Apnea and Fasting Glucose Punjabi et al. Am J Epidemiol. 2004;160:521.

  13. P = 0.008 P = 0.002 3.6 3.2 HOMA Index (Units) 2.8 2.4 2.0 < 5.0 5.0 – 14.9 ≥ 15.0 RDI Adjusted for age, gender, smoking status, BMI, waist circumference, and sleep duration Sleep Apnea and Insulin Resistance HOMA = Go x Io Is insulin resistance enough for diabetes? HOMA = homeostasis model assessment Punjabi et al. Am J Epidemiol. 2004;160:521.

  14. Sleep Apnea and Insulin Resistance: HOMA and Oxygen Saturation 3.4 Quartiles 3.2 I : < 93.32% II : 93.32% - 94.56% 3.0 III : 94.57% - 95.71% IV : > 95.72% 2.8 * HOMA Index (Units) ** 2.6 2.4 *P = 0.04 **P = 0.01 (for comparisons with the first quartile) 2.2 2.0 I II III IV Quartiles of Average Saturation During Sleep Punjabi et al. Am J Epidemiol. 2004;160:521.

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  17. Genes Insulin Secretion Insulin Resistance Environment Glucose Intolerance and Diabetes:Two Defects Glucose Intolerance Type 2 Diabetes

  18. 100 Glucose 80 60 Plasma Insulin (U/mL) 40 20 0 – 30 0 30 Time (min) Acute Insulin Response to IV Glucose:Normal Subjects Adapted from Robertson & Porte. J Clin Invest. 1973;52:870-876, with permission.

  19. G l u c o s e G l u c o s e 1 0 0 1 0 0 8 0 8 0 6 0 6 0 Plasma Insulin (U/mL) 4 0 4 0 2 0 2 0 0 0 T i m e T i m e – 3 0 0 3 0 – 3 0 0 3 0 ( m i n ) ( m i n ) N o r m a l T y p e 2 D i a b e t e s Acute Insulin Response to IV Glucose:Normal and Type 2 Diabetic Subjects Adapted from Robertson & Porte. J Clin Invest. 1973;52:870-876, with permission.

  20. NGT NGT NGT Changes in acute insulin response (AIR) relative to changes in Insulin Sensitivity 500 400 300 200 100 0 AIR (µU/ml) NGT IGT DM 0 1 2 3 4 5 Insulin Sensitivity Weyer C et al. J Clin Invest 1999;104:787–794

  21. Insulin Sensitivity and Insulin Secretion in Sleep Apnea • 118 subjects • Men 71; Women 47; 86.4% White • No medical conditions • Mean age was 45.7 years (range: 23 – 73) • Mean BMI was 29.4 kg/m2 (range: 17.2 – 52.2). • DEXA percent body fat 32.1% (range: 10.1 – 60.5). Punjabi et al. ARJCCM. 2008; In press

  22. 300 500 250 400 200 300 150 200 100 100 50 0 0 0 20 40 60 80 100 120 140 160 180 Insulin and Glucose Profile: IVGTT Normal Subject (AHI = 1.2/hr) Glucose Insulin Insulin (mU/ml) Glucose (mg /dl) Time (minutes)

  23. 800 350 700 300 600 250 500 200 400 150 300 100 200 50 100 0 0 0 20 40 60 80 100 120 140 160 180 Insulin and Glucose Profile: IVGTT Sleep Apnea Subject (AHI = 72/hr) Glucose Insulin Insulin (mU/ml) Glucose (mg /dl) Time (minutes)

  24. Insulin Sensitivity in Sleep Apnea Test for linear trend across groups: p < 0.0007 SI ([mU/L]-1[min]-1) Apnea-hypopnea index (events/hr)

  25. Insulin Sensitivity and Oxygen Desaturation 10 8 6 SI ([mU/L]-1[min]-1) 4 2 0 0 2 4 6 8 10 Average DSaO2 (%)

  26. Insulin Secretion in Sleep Apnea AIRG ([mU/L][min]) Apnea-hypopnea index (events/hr) Punjabi and Beamer. ARJCCM (2009)

  27. Integrated b-cell Function in Sleep Apnea Test for linear trend across groups: p < 0.034 Disposition Index Apnea-hypopnea index (events/hr) Punjabi and Beamer. ARJCCM (2009)

  28. Alterations in Glucose Metabolism in Sleep Apnea • Independent of total body fat, obstructive sleep apnea is associated with insulin resistance, glucose intolerance, type 2 diabetes • Obstructive sleep apnea may also impair the compensatory response in insulin secretion for a given degree of insulin resistance Punjabi and Beamer. ARJCCM (2009)

  29. Pathogenesis of Metabolic Abnormalities Sleep Apnea Arousals ? Hypoxia Glucose Intolerance Insulin Resistance Type 2 Diabetes

  30. Human Experimental Approach • Two distinct experimental paradigms • Effects of acute intermittent hypoxia in normal subjects • 5-hour exposure during wakefulness • Effects of sleep fragmentation in normal subjects • Two nights of sleep disruption with auditory and mechanical stimuli (~60/hr)

  31. Effects of Acute Intermittent Hypoxia on Glucose Metabolism in Awake Normal Subjects 21% 5% Louis and Punjabi. Journal of Applied Physiology (2009)

  32. Effects of Acute Intermittent Hypoxia on Glucose Metabolism in Awake Normal Subjects • Study Protocol • Hypoxia day • 5% O2 continued until O2 saturation reaches 85% • 21% O2 continued until O2 saturation reaches baseline level (95-97%) • Normoxia day • 21% O2 delivered throughout the 8-hour period • Manual two-way valve used to alternate from one room air tank to another Louis and Punjabi. Journal of Applied Physiology (2009)

  33. Start IVGTT (~1:30 pm) End Protocol (~4:30 pm) Start Protocol (~8:30 am) SaO2 (%) 5 minutes 21 FiO2 (%) 5 96 96 97 100 79 77 80 SaO2 (%) 60 5 EtCO2 (%) 0 EKG during one episode of desaturation Louis and Punjabi. Journal of Applied Physiology (2009)

  34. Effects of Acute Hypoxia: Insulin Sensitivity and Insulin Secretion p < 0.0179 p = 0.85 Louis and Punjabi. Journal of Applied Physiology (2009)

  35. Effects of Acute Intermittent Hypoxia on Glucose Metabolism in Awake Normal Subjects • Acute intermittent hypoxia for as little as 5-hours during wakefulness • Decreases insulin sensitivity • Not associated with a compensatory increase in insulin secretion • Decrease glucose effectiveness • Increases sympathetic nervous system activity • Not associated with any changes in serum cortisol Louis and Punjabi. Journal of Applied Physiology (2009)

  36. Am J Respir Crit Care Med. 2004 Increases in cortisol and catecholamines

  37. Sleep Fragmentation in Normal Subjects Follow-up IVGTT Baseline IVGTT Sleep Fragmentation Day 1 Habituation Night Day 2 Fragmentation Night Day 3 Fragmentation Night Day 4 N = 11 Stamatakis and Punjabi (Chest - 2010)

  38. Sleep Fragmentation in Normal Subjects

  39. Sleep Fragmentation in Normal Subjects Stamatakis and Punjabi (Chest - 2010)

  40. Sleep Fragmentation in Normal Subjects: Insulin Sensitivity and Insulin Secretion p < 0.001 p = 0.08 6.0 600.0 5.0 4.0 SI ([mU/L]-1[min]-1) 400.0 AIRg ([mU/L][min]) 3.0 2.0 200.0 1.0 0.0 0.0 Baseline Post-Fragmentation Baseline Post-Fragmentation Stamatakis and Punjabi (Chest - 2010)

  41. Effects of Sleep Fragmentation on Glucose Metabolism in Normal Subjects • Sleep fragmentation (non-specific) for two nights • Decreases insulin sensitivity (Si) • Increases insulin secretion to compensate for lower Si • Decrease glucose effectiveness • Increases sympathetic nervous system activity • Increase morning cortisol levels Stamatakis and Punjabi (Chest - 2010)

  42. Tasali E. et.al. PNAS 2008;105:1044-1049

  43. Tasali E. et.al. PNAS 2008;105:1044-1049

  44. Type 2 Diabetes b-cell Dysfunction Mechanistic Links: Sleep Apnea and Metabolic Dysfunction Sleep Fragmentation Sympathetic Activation Insulin Resistance Sleep Apnea HPA dysregulation Systemic Inflammation ? Intermittent Hypoxemia

  45. Effects of CPAP on Insulin Sensitivity Insulin Sensitivity Index (ISI) assessed with the hyperinsulinemic clamp at baseline, after 2 d, and after 3 m of CPAP therapy Harsch et al. Am J Respir Crit Care Med. 2004;169:156.

  46. Type 2 Diabetes, Glycemic Control, and Continuous Positive Airway Pressure in Obstructive Sleep Apnea.Babu et al. Arch Intern Med, 2005

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  48. Metabolic Dysfunction Sleep A bi-directional relation

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