General Outline. General Outline. Pathogenesis of Metabolic Dysfunction in Sleep Apnea: The Role of Sleep Fragmentation and Intermittent Hypoxemia

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1 Pathogenesis of Metabolic in Sleep Apnea: The Role of Sleep Fragmentation and Intermittent Hypoxemia Naresh M. Punjabi, MD, PhD Associate Professor of Medicine and Epidemiology Johns Hopkins University, School of Medicine Baltimore, Maryland (USA) General Outline Metabolic and Sleep Apnea Background: Sleep Apnea and Metabolic Effects of Intermittent Hypoxia on Glucose Effects of Sleep Fragmentation on Glucose General Outline Disease Definition: Metabolic Diabetes and Glucose Tolerance Metabolic and Sleep Apnea Diabetes Mellitus Diabetes Mellitus Background: Sleep Apnea and Metabolic 126 mg/dl 1 mg/dl Impaired Fasting Glucose 7. mmol/l 2 mg/dl 6.1 mmol/l 14 mg/dl Impaired Glucose Tolerance 11.1 mmol/l 7.8 mmol/l Effects of Intermittent Hypoxia on Glucose Effects of Sleep Fragmentation on Glucose Normal Fasting Plasma Glucose Normal 2-hour post-glucose on OGTT Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 24. Prevalence of Diabetes in the US Diagnosed and Undiagnosed Diabetes (US) Estimated Cases Among Adults, 1997 Percent of Population Percent Number U.S Year Number with diabetes (millions) Millions of Cases Diagnosed 5.4 Undiagnosed Center for Disease Control (Division of Diabetes, 23) Harris, et al. Diabetes Care. 1998;21:

2 Diabetes in the World: 2 (in millions) Diabetes in the World: 21 (in millions) India 17.7 China India 3.3 China 8.4 USA USA 8.9 Indonesia Japan Indonesia Japan Wild S et al. Diabetes Care. 24; 27(5): Wild S et al. Diabetes Care. 24; 27(5): Diabetes and Obesity: Two Epidemics in Tandem General Outline Metabolic and Sleep Apnea Background: Sleep Apnea and Metabolic Effects of Intermittent Hypoxia on Glucose Effects of Sleep Fragmentation on Glucose Definition of the Disorder: Sleep Apnea Terminology: Obstructive sleep apnea (OSA) Sleep apnea (SA) Sleep apnea-hypopnea syndrome (SAS) Sleep-disordered breathing (SDB) Pathophysiology of Sleep Apnea snores Normal Partial Collapse Complete Collapse Hypopneas Apneas 2

3 Tracing of Obstructive Apneas Definition of the Disorder Disease Defining Metric: Apnea-Hypopnea Index (AHI) = Number of apneas and hypopneas per hour of sleep Respiratory Disturbance Index (RDI) Normal : AHI or RDI < 5 events / hour General Outline Metabolic and Sleep Apnea Background: Sleep Apnea and Metabolic Effects of Intermittent Hypoxia on Glucose Effects of Sleep Fragmentation on Glucose Sleep Apnea and Glucose Tolerance Study Design Community-based cohort study 15 healthy but overweight men No history of diabetes (normal glucose) No cardiovascular or pulmonary disease Normal stress test (Bruce Protocol) Sleep Apnea and Glucose Tolerance Sleep Apnea and Insulin Resistance Glucose Levels (mg/dl) Fasting 2-hour HOMA HOMA = Go x Io AHI < 5 AHI: 5-19 AHI: 2-39 AHI > 4 AHI < 5 AHI: 5-19 AHI: 2-39 AHI > 4 Sleep Apnea Severity Sleep Apnea Severity Punjabi et al. AJRCCM. 22 Punjabi et al. AJRCCM. 22 3

4 The Sleep Heart Health Study: Field Sites Minneapolis (185) South Dakota (21) Sacramento (51) Framingham (1) New York (76) Pittsburgh (398) Hagerstown (1184) Phoenix (21) Tucson (911) Oklahoma (2) Ip et al. AJRCCM. 22 Are there population data? National Heart Lung and Blood Institute (NHLBI). The Sleep Heart Health Study: Manuals of Operation. Accessed July 18, 27. Sleep Apnea and Glucose Sleep Apnea and Glucose Percentage Impaired Diabetic Percentage Impaired Diabetic < RDI (events/h) < RDI (events/h) Punjabi et al. Am J Epidemiol. 24;16:521. Punjabi et al. Am J Epidemiol. 24;16:521. Sleep Apnea and Glucose Predictor Respiratory disturbance index (no. of events/hour) < Average oxyhemoglobin saturation during sleep (%) < Punjabi et al. Am J Epidemiol. 24;16:521. Fasting Glucose Level (n = 2,656) Odds Ratio 95% CI Sleep Apnea and HOMA levels HOMA = Go x Io HOMA Index (Units) P =.8 P =.2 < RDI Is insulin resistance enough for diabetes? Adjusted for age, gender, smoking status, BMI, waist circumference, and sleep duration HOMA = homeostasis Punjabi et al. Am J Epidemiol. 24;16:521. model assessment 4

5 Sleep Apnea and Metabolic : HOMA and Oxygen Saturation HOMA = Go x Io HOMA Index (Units) ** Punjabi et al. Am J Epidemiol. 24;16:521. Worsening Hypoxemia * I II III IV Quartiles of Average Saturation During Sleep Quartiles I : < 93.32% II : 93.32% % III : 94.57% % IV : > 95.72% *P =.4 **P =.1 (for comparisons with the first quartile) Glucose Intolerance and Diabetes: Two Defects Insulin Secretion Genes Environment Glucose Intolerance Type 2 Diabetes Insulin Resistance Acute Insulin Response to IV Glucose: Normal Subjects 1 Glucose Acute Insulin Response to IV Glucose: Normal and Type 2 Diabetic Subjects 1 Glucose 1 Glucose Plasma Insulin (µu/ml) Plasma Insulin (µu/ml) Time (min) Time 3 (min) Normal 3 Time 3 (min) 3 Type 2 Diabetes Adapted from Robertson & Porte. J Clin Invest. 1973;52:87-876, with permission. Adapted from Robertson & Porte. J Clin Invest. 1973;52:87-876, with permission. Insulin Secretion: Modulation by Insulin Sensitivity Acute Insulin Response to Glucose (pm) Insulin Sensitivity Index ( 1 5 min 1 /pm) Adapted from Kahn, et al. Diabetes. 1993;42: , with permission Males Females 95th 5th 5th Insulin Sensitivity and Insulin Secretion: Relationship in Type 2 Diabetes and Groups at Risk Acute Insulin Response to Glucose (pm) IGT PCO women Former GDMs Older subjects Type 2 diabetes Insulin Sensitivity Index ( 1 Relatives, type 2 diabetes 5 min 1 /pm) 75th 5th 25th 5th 5

6 Changes in acute insulin response (AIR) relative to changes in Insulin Sensitivity Insulin Sensitivity and Insulin Secretion in Sleep Apnea subjects (no medical conditions) 4 AIR (µu/ml) NGT IGT DM NGT NGT NGT Men 71 and Women 47 Predominantly white (86.4%) Mean age was 45.7 years (range: 23 73) Insulin Sensitivity Weyer C et al. J Clin Invest 1999;14: Mean BMI was 29.4 kg/m 2 (range: ). Punjabi et al. ARJCCM. 28; In press Insulin and Glucose Profile: IVGTT Insulin and Glucose Profile: IVGTT 3 25 Normal Subject (AHI = 1.2/hr) Sleep Apnea Subject (AHI = 72/hr) 8 7 Glucose (mg /dl) Glucose Insulin Insulin (µu/ml) Glucose (mg /dl) Glucose Insulin Insulin (µu/ml) Time (minutes) Time (minutes) Insulin Sensitivity and Insulin Secretion Effects of Sleep Apnea Insulin Sensitivity and Oxygen Desaturation 1 8 S I ([mu/l] -1 [min] -1 ) Test for linear trend across groups: p <.7 < > 3. AIRG ([mu/l][min]) < > 3. S I ([mu/l] -1 [min] -1 ) Apnea-hypopnea index (events/hr) Apnea-hypopnea index (events/hr) Average SaO 2 (%) 6

7 General Outline Metabolic and Sleep Apnea Background: Sleep Apnea and Metabolic Effects of Intermittent Hypoxia on Glucose Effects of Sleep Fragmentation on Glucose General Outline Metabolic and Sleep Apnea Background: Sleep Apnea and Metabolic Effects of Intermittent Hypoxia on Glucose Effects of Sleep Fragmentation on Glucose Pathogenesis of Metabolic Animal Experiment Repetitive Intermittent Hypoxia Sleep Apnea 21 Day 1 Day 5 Hypoxia? Arousals Fi O 2 (%) Glucose Intolerance Insulin Resistance Type 2 Diabetes Light Cycle Fasting Blood Glucose/Insulin Dark Cycle 6 hrs Fasting Blood Glucose/Insulin IPGTT Human Experimental Approach Two distinct experimental paradigms Effects of acute intermittent hypoxia in normal subjects 5-hour exposure during wakefulness Intermittent hypoxia increases insulin levels Intermittent hypoxia worsens insulin sensitivity Effects of sleep fragmentation in normal subjects Two nights of sleep disruption with auditory and mechanical stimuli (~6/hr) 7

8 Human Experimental Approach Two distinct experimental paradigms Effects of acute intermittent hypoxia in normal subjects 5-hour exposure during wakefulness Acute Intermittent Hypoxia in Normal Subjects 21% Effects of sleep fragmentation in normal subjects Two nights of sleep disruption with auditory and mechanical stimuli (~6/hr) 5% Acute Intermittent Hypoxia in Normal Subjects Start Protocol (~8:3 am) 1 Start IVGTT (~1:3 pm) End Protocol (~4:3 pm) Study Protocol Hypoxia day 5% O 2 continued until O 2 saturation reaches 85% 21% O 2 continued until O 2 saturation reaches baseline level (95-97%) SaO 2 (%) FiO 2 (%) minutes Normoxia day 21% O 2 delivered throughout the 8-hour period Manual two-way valve used to alternate from one room air tank to another SaO 2 (%) EtCO 2 (%) EKG during one episode of desaturation S I ([mu/l] -1 [min] -1 ) Insulin Sensitivity and Insulin Secretion Effects of Hypoxia in Normal Subjects Normoxia p <.179 Intermittent Hypoxia AIRG ([mu/l][min]) Normoxia p =.85 Intermittent Hypoxia Intermittent Hypoxia is associated with decrease in insulin sensitivity but without an compensatory increase in insulin secretion 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 (~6/hr) 8

9 Sleep Fragmentation in Normal Subjects Sleep Fragmentation in Normal Subjects Baseline IVGTT Follow-up IVGTT Sleep Fragmentation Day 1 Habituation Night Day 2 Fragmentation Night Day 3 Fragmentation Night Day 4 N = 11 Baseline IVGTT Control Group Follow-up IVGTT Day 1 Habituation Night Day 2 Normal Night Day 3 Normal Night Day 4 N = 7 Sleep Fragmentation in Normal Subjects Insulin Sensitivity with Fragmented Sleep 7. Pre-Intervention Post-Intervention Insulin sensitivity (mu/l -1 min -1 ) p <.1. Fragmented Sleep Intervention Non-Fragmented Sleep Insulin Secretion with Fragmented Sleep Tasali E. et.al. PNAS 28;15: p = NS AIRG (mu/l -1 min -1 ) p = NS. Fragmented Sleep Intervention Non-Fragmented Sleep 9

10 Mechanistic Links: Sleep Apnea and Metabolic Sleep Fragmentation Is CPAP is Effective in Reversing the Metabolic Disturbance Sleep Apnea Sympathetic Activation HPA dysregulation Systemic Inflammation Insulin Resistance Type 2 Diabetes Intermittent Hypoxemia Susceptibility Genes β-cell 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 Baseline After 2 days CPAP therapy Improvement compared to baseline After 3 months CPAP therapy Improvement compared to baseline ISI (Whole group, n = 4) (After 3 months, n = 31) (µmol/kg min) P = P =.1 Harsch et al. Am J Respir Crit Care Med. 24;169:156. A man in love with his CPAP won t leave home without it Conclusions and Summary Independent of obesity, sleep apnea is associated with insulin resistance, glucose intolerance, and type 2 diabetes Intermittent hypoxemia and recurrent arousals may mediate the metabolic abnormalities in sleep apnea CPAP appears to mitigate the metabolic disturbance? (more research is still needed) 1