10th Meeting of the Mediterranean Group for the Study of Diabetes Istanbul – April 26-29, 2007 Lung dysfunctions in Metabolic Syndrome and Diabetes Prof. A. Tiengo University of Padova (Italy)

Lazar M. Nat Med 2006

Sleep Disorders-Metabolic Syndrome Sleep Fragmentation Sleep Deprivation Intermittent Hypoxemia Increased Sympathetic Drive Sleep Disorders /SDB Metabolic Syndrome

Co-Aggregation of Features of Metabolic Syndrome and SDB  2/3's OSA patients are obese  2/3's obese patients have OSA O.R. = 4-10  Central / "android" obesity neck size / waist circumference  2/3’s OSA patients HTN  High prevalence of hyperlipidemia

Vgonzas et al., Sleep Med Rew, 2005 Correlation between visceral fat and indices of apnea., sleep apneics,, obese control

ISI composite, hepatic ISI and Δl30-0/ΔG30-0 in normal subjects (NS) obese patients (OB) and obese patients with obstructive sleep apnoea syndrome (OSAS) Tassone et al. Clin Endocrinol, 59, 374, 2003 Obstructive sleep apnoea syndrome and insulin sensitivity

Punjabi et al, Am J Epidemiol 2004 Adjusted mean value of HOMA index as a function of the respiratory disturbance index (RDI) for 12-month (n=1,067) and 3- month (n=405) time windows. Sleep Heart Health Study,

Punjabi et al, Am J Epidemiol 2004 Adjusted mean value of HOMA index according to two different indices of sleep-related hypoxemia (12-month time windows; n=1,067) Sleep Heart Health Study,

Vgonzas et al., Sleep Med Rew, 2005 Prevalence of obstructive sleep apnea and excessive daytime sleepiness (EDS) in women with the polycystic ovary syndrome

Cleveland Family Data  OSA (+) associated with increasing: IL6/sIL6 CRP D-dimer Fibrinogen PAI-1 Leptin Urinary Microalbumin Fasting Insulin/Glucose  Not or (-) associated with: TNFa MPO

Biochemical Perturbations with Sleep Disorders/SDB  SDB Increased IGF-1Increased IGF-1 Increased insulinIncreased insulin Increased am cortisolIncreased am cortisol Inflammatory cytokinesInflammatory cytokines  Sleep deprivation Increased cortisol Decreased growth hormone and thyrotropin Decreased glucose intolerance

Vgonzas et al., Sleep Med Rew, 2005 A heuristic model of the complex feed forward associations between visceral fat/insulin resistance, inflammatory cytokines, stress hormones, excessive daytime sleepiness and fatigue, and sleep apnea

Odds Ratio 95% Confidence Intervalp Value Adjusted for sex and age AHI 5-15 vs. AHI <5 AHI > 15 vs. AHI < < Adjusted for sex, age and body habitus AHI 5-15 vs. AHI <5 AHI > 15 vs. AHI < Odds Ratios for prevalent, physician-diagnosed diabetes for two levels of sleep-disordered breathing AHI = apnea-hypopnea index Reichmuth et al., Am J Respir Crit Care Med 2005

Odds Ratio 95% Confidence Intervalp Value Adjusted for sex and age AHI 5-15 vs. AHI <5 AHI > 15 vs. AHI < Adjusted for sex, age and body habitus AHI 5-15 vs. AHI <5 AHI > 15 vs. AHI < AHI = apnea-hypopnea index Reichmuth et al., Am J Respir Crit Care Med 2005 Odds Ratios for 4 years incidence of physician-diagnosed diabetes for two levels of sleep-disordered breathing

Fasting Glucose and Hypoxemia Average Sleep O 2 Odds Ratio*95% CI I(>95.7%)1.00Reference II(94.6% – 95.7%) – 2.14 III(93.3% – 94.5%) – 2.44 IV(< 93.3%) – 2.69 Adjusted* Odds Ratio for Impaired or Diabetic Fasting Glucose *Adjusted for age, gender, race, BMI, waist circumference, cohort, smoking

Nine-year adjusted hazard ratios (HR) for incidence for forced vital capacity (FVC) (% predicted) quartile, sex and smoking status Yeh et al., Diabetes Care 2005

Insulin Resistance and Hypoxemia HOMA Index

Spiegel, K. et al. J Appl Physiol 99: ;

Babu, A. R. et al. Arch Intern Med 2005;165: Mean hemoglobin A1c (HbA1c) levels before and after continuous positive airway pressure (CPAP) treatment in the entire study population and patients with a baseline HbA1c level greater than 7%

Babu, A. R. et al. Arch Intern Med 2005;165: Number of glucose values greater than 200 mg/dL (11.1 mmol/L) before and after continuous positive airway pressure (CPAP) treatment for the entire study population and patients with an initial hemoglobin A1c (HbA1c) level greater than 7%

Definition of diabetes and glucose tolerance  (ml) 95% CI  (ml) 95% CI Fasting plasma glucose level Normal (<110 mg/dl) (n=3,877) Impaired ( mg/dl) (n=262) Diabetic (>126 mg/dl) (n=118) , , , , Glucose level 2 hours post-glucose-load Normal (<140 mg/dl) (n=1,258) Impaired ( mg/dl) (n=250) Diabetic (>200 mg/dl) (n=104) , , , , -0.3 Haemoglobin A1c concentration <7% (n= 4.196) >7% (n=61) , , 80.9 Model 1 Model 1 with additional adjustment for BMI and W/H ratio Association between various clinical definition of diabetes and forced expiratory volume in 1 second, Third National Health and Nutrition Examination Survey, McKeever et al, Am J Epidemiol 2005

Comparison  (ml) 95% CI  (ml) 95% CI Diabetes status No diabetes (n=4,257) Diabetes (n=512) , , Level of control of diabetes No diabetes (n=4,196) Well-controlled diabetes (haemoglobin A1c<7%) (n=253) Poorly-controlled diabetes (haemoglobin A1c>7%) (n=395) , , , Model 1 Model 1 with additional adjustment for BMI and W/H ratio Association between known diagnosis of diabetes and forced exiratory volume in 1 second, Third National Health and Nutrition Examination Survey, McKeever et al, Am J Epidemiol 2005

Relationship of residual FEV1 to level of fasting glucose. Quartiles of blood glucose: first quartile, 48–88 mg/dl; second quartile, 89–94 mg/dl; third quartile, 95–101 mg/dl; and fourth quartile, 102–305 mg/dl; p values are for linear trend across quartiles. Error bars are SDs. Association between glycemic state and lung function Walter Am.J.Respir. Crit. Care Med. 2003:916

Relationship of residual FVC to level of fasting glucose. Quartiles of blood glucose: first quartile, 48–88 mg/dl; second quartile, 89–94 mg/dl; third quartile, 95–101 mg/dl; and fourth quartile, 102–305 mg/dl; p values are for linear trend across quartiles. Error bars are SDs Association between glycemic state and lung function Walter Am.J.Respir. Crit. Care Med. 2003:916

Association between glycemic state and lung function Walter Am.J.Respir. Crit. Care Med. 2003:916 Relationship of residual FEV 1 /FVC to level of fasting glucose. Quartiles of blood glucose: first quartile, 48–88 mg/dl; second quartile, 89–94 mg/dl; third quartile, 95–101 mg/dl; and fourth quartile, 102–305 mg/dl; p values are for linear trend across quartiles.

* p<0.001 compared to control group and predicted value * Reduced vital capacity in insulin-dependent Diabetes Primhak, Diabetes 36: , 1987

Dieta MORBID OBESITY SLEEP APNEA RAISED CHOLESTEROL DIABETES CARDIOVASCULAR DISEASE HYPERTENSION

Syndrome Z Sleep Apnea Insulin Resistance Obesity Susceptibility genes forming a common soil Hypertension Dyslipidemia

Conclusions Sleep disordered breathing is a prevalent condition associated with significant comorbidities including obesity, diabetes, hypertension, insulin-resistance and cardiovascular diseases. The severity of insulin-resistance is related to the severity of sleep disordered breathing. The hypoxemia and the sleep disorderes breathing may favour the incidence of diabetes. Diabetic condition and the degree of poorly glycemic control induce an impairment of lung functions.