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. TiengoUniversity of Padova (Italy)

Lazar M. Nat Med 2006

Sleep Disorders-Metabolic SyndromeSleep Disorders-Metabolic Syndrome

Sleep FragmentationSleep Fragmentation

Sleep DeprivationSleep Deprivation

Intermittent Intermittent HypoxemiaHypoxemia

Increased Increased Sympathetic DriveSympathetic Drive

Sleep Disorders

/SDBMetabolic Metabolic SyndromeSyndrome

Co-Aggregation of Features of Metabolic Co-Aggregation of Features of Metabolic Syndrome and SDBSyndrome 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, 1994-1999.

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, 1994-1999.

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 Biochemical Perturbations with Sleep Disorders/SDBDisorders/SDB

SDBSDB

• Increased IGF-1 Increased 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

Interval p Value

Adjusted for sex and age

AHI 5-15 vs. AHI <5

AHI > 15 vs. AHI <5

1.83

4.75

1.07-3.11

2.62-8.63

0.026

<0.0001

Adjusted for sex, age

and body habitus

AHI 5-15 vs. AHI <5

AHI > 15 vs. AHI <5

1.25

2.30

0.75-2.07

1.28-4.11

0.4

0.005

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

Interval p Value

Adjusted for sex and age

AHI 5-15 vs. AHI <5

AHI > 15 vs. AHI <5

2.81

4.06

1.51-5.23

1.86-8.85

0.001

0.0004

Adjusted for sex, age

and body habitus

AHI 5-15 vs. AHI <5

AHI > 15 vs. AHI <5

1.56

1.62

0.80-3.02

0.67-3.65

0.19

0.24

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 O2 Odds Ratio* 95% CI

I (>95.7%) 1.00 Reference

IIII (94.6% – 95.7%)(94.6% – 95.7%) 1.481.48 1.03 – 2.141.03 – 2.14

IIIIII (93.3% – 94.5%)(93.3% – 94.5%) 1.701.70 1.18 – 2.441.18 – 2.44

IVIV (< 93.3%)(< 93.3%) 1.861.86 1.28 – 2.691.28 – 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

Quartiles of Percent Sleep Time with Oxygen Saturation below 90%

I II III IV

HO

MA

Index (units)

2.0

2.2

2.4

2.6

2.8

3.0

3.2

3.4

Quartiles of Average Saturation during Sleep

I II III IV

Quartiles Quartiles

III : < 0.01III : 0.01 - 0.25III : 0.26 - 2.16IV : > 2.17

III : < 93.32%III : 93.32% - 94.56%III : 94.57% - 95.71%IV : > 95.72%*

* *

*p < 0.05 for comparisons to the first quartile; † Adjusted for age, gender, sex, smoking status, BMI, and waist circumference

Insulin Resistance and HypoxemiaH

OM

A I

ndex

Spiegel, K. et al. J Appl Physiol 99: 2008-2019 2005;

Babu, A. R. et al. Arch Intern Med 2005;165:447-452.

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;165:447-452.

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 (110-125.99 mg/dl) (n=262)

Diabetic (>126 mg/dl) (n=118)

0

-75.2

-126.2

-109.4, -41.1

-160.1, -92.3

0

-60.8

-93.8

-95.7, -25.8

-127.4, -60.2

Glucose level 2 hours post-glucose-load

Normal (<140 mg/dl) (n=1,258)

Impaired (140-199.99 mg/dl) (n=250)

Diabetic (>200 mg/dl) (n=104)

0

-60.5

-154.5

-134.8, 13.9

-265.6, -43.4

0

-34.3

-108.8

-114.5, -45.9

-217.3, -0.3

Haemoglobin A1c concentration

<7% (n= 4.196)

>7% (n=61)

0

-110.3 -269.7, 49.0

0

-75.0 -231.0, 80.9

Model 1Model 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, 1988-1994

McKeever et al, Am J Epidemiol 2005

Comparison

(ml) 95% CI (ml) 95% CI

Diabetes status

No diabetes (n=4,257)

Diabetes (n=512)

0

-119.1 -161.5, -76.6

0

-70.8 -118.7, -38.8

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)

0

-91.6

-144.9

-157.4

-200.5, -89.2

0

-54.2

-100.1

-116.2, 7.3

-155.3, -44.9

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, 1988-1994

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 FEV1/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.

Control Diabetic0

7070

80

90

100P

erce

nta

ge

pre

dic

ted

FV

C

*p<0.001 compared to control group and predicted value

*

Reduced vital capacity in insulin-dependent Diabetes

Primhak, Diabetes 36: 324-26, 1987

Dieta

MORBID OBESITY

SLEEPAPNEA

RAISED CHOLESTEROL

DIABETES

CARDIOVASCULARDISEASE

HYPERTENSION

Syndrome Z

Sleep Apnea

InsulinResistance

Obesity

Susceptibility genes forming a common soilSusceptibility 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.