The Effects of Obstructive Sleep Apnea and Visceral Fat on Insulin Resistance
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Transcript of The Effects of Obstructive Sleep Apnea and Visceral Fat on Insulin Resistance
The Effects of Obstructive Sleep Apnea and Visceral Faton Insulin Resistance:
The Icelandic Sleep Apnea Cohort
Greg Maislin Director, Biostatistics Core
Adjunct Associate Professorof Biostatistics in MedicineDivision of Sleep Medicine
University of Pennsylvania School of Medicine
Dept. of Respiratory Medicine and Sleep
Landspitali University Hospital
Reykjavik Iceland
Bryndis Benediktsdottir
Erna Sif Arnardóttir
Isleifur Olafsson
Thorarinn Gislason
Center for Sleep and Respiratory NeurobiologyDivision of Sleep MedicineUniversity of Pennsylvania
School of MedicinePhiladelphia PA
Richard J. Schwab
Allan I. Pack
Co-Authors
Quick Background I
Mary Ip et al AJRCCM 2002, 165:670“OSA is Independently Associated with Insulin
Resistance”
Hong Kong sleep center population, N=270, excluded
known diabetes, homeostasis model assessment method
(HOMA).
“Stepwise multiple linear regression analyses showed that
obesity was the major determinant of insulin resistance but
sleep disordered breathing parameters were also
independent predictors of insulin resistance.”
Quick Background II
Naresh Punjabi et al AJRCCM 2002 165:677 “Sleep-disorded Breathing and Insulin Resistance in
Middle-aged and Overweight Men”
Community population, N=150 without diabetes or
cardiopulmonary disease, PSG, MSLT, OGGT and
fasting insulin and lipids
“Multivariable linear regression analyses revealed that
increasing AHI was associated with worsening insulin
resistance independent of obesity”
Quick Background III
Naresh Punjabi et al Am J Epid 2004, 160:521.”Sleep-Disordered Breathing, Glucose Intolerence,
and Insulin Resistance: The Sleep Heart Health Study”
Community dwelling, N=2656, RDI and O2 sat., fasting
and glucose 2-hour glocuse (OGTT) within 1 year of PSG.
“The results from this study suggest that SDB in
independently associated with glucose intolerance and
insulin resistance and may lead to type 2 diabetes
mellitus.”
Quick Background IV
Igor Harsch et al AJRCCM 2004, 169:156.“CPAP Treatment Rapidly Improves Insulin
Sensitivity in Patients with OSA”
N=40, euglycemic clamp (invasive)
“The effect of CPAP on insulin sensitivity is smaller in non
obese individuals suggesting that in obese patients
insulin sensivity is mainly determined by obesity, and to a
smaller extent, by sleep apnea.”
Potential Mechanisms
Elevated sympathetic nervous system activity
Alterations in glucocorticoid regulation induced
by sleep loss
Recurrent intermittant hypoxemia associated with
sleep-disorded breather
Aim of Study To compare the relative importance of OSA
and obesity on insulin resistance (IR)
To assess if the effect of OSA on IR varies
among non-obese, mildly obese, and severely
obese
To use MR imaging volumetric determinations
of abdominal fat
Icelandic Sleep Cohort
Patients diagnosed with OSA at one of five health
clinics within Iceland and referred for CPAP to the
Landspitali University Hospital in Reykjavik from Sept
2005 - Dec 2009. >90% agreed to participate in the
study.
Subjects were initially diagnosed as having OSA by
sleep studies. Anthropometric measurements,
medical history, health related quality of life and other
questionnaires, MR imaging, and fasting insulin and
glucose (to determine HOMA) were obtained at
baseline.
Iceland Sleep Apnea Cohort (ISAC)Overall and by Obesity Category
Demographics
Icelandic Sleep Apnea Cohort
BMI < 30 kg/m2
BMI 30 -< 35 kg/m2
BMI ≥ 35 kg/m2
p-value
for comparison
between groups
(Ranks or χ2) n = 826 n = 180 n = 192 n = 126
Age (years) 54.4 ± 10.7 55.8 ± 9.7 55.2 ± 10.6 52.5 ± 11.2 0.001
% of males 81.0 82.9 82.39 78.1 0.28
Body mass index (kg/m2) 33.5 ± 5.7 27.4 ± 2.0 32.4 ± 1.5 39.7 ± 4.0 N/A
Abdominal fat vol. (MRI times 103) (N=665)
4.34 (1.83) 3.21 (1.37) 4.61 (1.54) 5.29 (1.93) <0.0001
Current smokers (%) 21.1 24.2 19.5 20.0 0.37
Epworth Sleepiness Score 11.6 ±5.1 11.5 ± 4.9 11.3 ± 5.2 12.1 ± 5.1 0.20
Why restrict analysis cohort byAHI 14-80 and ODI 10-65?
AHI
1501209060300
BM
I
60
50
40
30
20
BMI tertiles
BMI above 35
BMI 30-35
BMI below 30
To simultaneously estimate the effects of BMI category and OSA severity, the range of the OSA severity must be restricted to be the same across the BMI tertiles for both AHI and ODI (called ‘double overlap cohort’) in order to avoid extrapolation.
All subjects Overlap cohort
Description of Overlap CohortOverall and by Obesity Category
Demographics
All
BMI < 30 kg/m2
BMI 30 -< 35 kg/m2
BMI ≥ 35 kg/m2
p-value
for comparison
between groups
(Ranks or χ2) N = 498 n = 180 n = 192 n = 126
Age (years) 54.5 ± 10.4 55.4 ± 9.5 54.8 ± 10.9 52.8 ± 10.8 0.09
% of males 82.1 86.7 83.9 73.0 0.007
Body mass index (kg/m2) 32.1 ± 4.7 27.5 ± 2.0 32.3 ± 1.4 38.32 ± 2.9 N/A
Abdominal fat vol. (MRI times 103)
4.25 (1.75) 3.26 (1.37) 4.61 (1.54) 5.11 (1.87) <0.0001
Current smokers %) 20.5 23.3 19.8 17.4 0.45
Epworth Sleepiness Score 11.6 ±4.9 11.9 ± 5.0 11.1 ± 4.7 12.1 ± 5.1 0.17
Description of Overlap CohortOverall and by Obesity Category
Sleep disordered breathing
All BMI < 30
kg/m2 BMI 30 -< 35
kg/m2 BMI ≥ 35
kg/m2
p-value
for comparison
between groups
(Wilcoxon or χ2)
Apnea-hypopnea index (events/hour)
40.7 ± 15.4 (14.8-79.6)
39.2 ± 14.2 (15.3-79.4)
42.6 ± 16.0 (14.8-79.6)
40.0 ± 15.7 (14.8-75.7)
0.14
Oxygen desaturation index (events/hour)
31.2 ± 13.7 (10.3-65)
28.5 ± 12.4 (10.3-63.7)
33.2 ± 14.8 (10.3-65.0)
31.9 ± 13.3 (10.8-61.2)
0.008
Minimum SaO2 (%) 77.4 ± 6.8 78.7 ± 5.9 77.4 ± 7.2 75.5 ± 7.0 <0.0001
Hypoxia time (minutes) 42.5 ± 60.0 30.4 ± 42.8 45.7 ± 63.7 55.0 ± 71.5
<0.0001
Summary of Insulin Resistance Measures
Measure
All
(N=498)
BMI<30
(N=180)
BMI 30-35
(N=192)
BMI>35
(N=126) P-value
Glucose 5.60 (0.63) 5.43 (0.50) 5.61 (0.61) 5.83 (0.75) <0.0001
Insulin 17.60 (14.24) 11.29 (8.77) 17.17 (11.75) 27.26 (18.25) <0.0001
HOMA 4.52 (4.06) 2.75 (2.09) 4.38 (3.23) 7.27 (5.58) <0.0001
Log(HOMA) 1.26 (0.68) 0.86 (0.54) 1.29 (0.59) 1.78 (0.62) <0.0001
HOMA>3.99 40.4% 12.2% 42.2% 77.8% <0.0001
SAT: 3568 cm3
VAT: 2556 cm3
SAT: 5926 cm3
VAT: 4318 cm3SAT: 9153 cm3
VAT: 5902 cm3
BMI: 27.7 kg/m2 BMI: 32.3 kg/m2
= Subcutaneous Adipose Tissue (SAT) = Visceral Adipose Tissue (VAT) = Liver = Kidneys = Spine
BMI: 39.0 kg/m2
MRI Imaging of the Abdominal Region
Correlations between log(HOMA) andObesity Measures
Obesity Measures Log(HOMA)
r p
Total abdominal fat volume (cm3) 0.56 <0.0001
Body mass index (kg/m2) 0.55 <0.0001
Waist circumference (cm) 0.54 <0.0001
Subcutaneous fat volume (cm3) 0.47 <0.0001
Visceral fat volume (cm3) 0.44 <0.0001
Waist-to-hip ratio (cm/cm) 0.29 <0.0001
Note: Similar correlations were obtained when assessed using Spearman correlation
Bootstrap Tests for Differences between Correlations with log(HOMA)
Measure 1 Measure 2 Mean difference
95% non-parametric CI
P-value
Total abdominal fat Visceral fat 0.123 (.073 – 0.173) <0.001
BMI Visceral fat 0.110 (.043 - .186) <0.001
Waist circumference Visceral fat 0.102 (.046 - .162) <0.001
Subcutaneous fat Visceral fat 0.036 (-.043 – .128) 0.16
Waist to hip ratio Visceral fat -0.144 (-.212 - -.081) <0.001
Correlations between log(HOMA)and Apnea Severity Measures
Overall and by Obesity Category
Measure All
(N=498)
BMI < 30 kg/m2
(N=180)
BMI ≥30 and <35 kg/m2
(N=192)
BMI ≥35 kg/m2
(N=126)
r p r p r p r p
Apnea-hypopnea index 0.05 0.26 0.08 0.27 -0.04 0.55 0.13 0.16
Oxygen desaturation index 0.14 0.002 0.21 0.005 -0.01 0.84 0.16 0.07
Minimum SaO2 (%) -0.18 <0.001 -0.07 0.37 -0.10 0.16 -0.16 0.07
Hypoxia time (minutes) 0.18 <0.001 0.24 0.0009 0.11 0.13 0.03 0.78
Correlations between log(IL-6) andApnea Severity Measures
Measure All
(N=347)
BMI < 30 kg/m2
(N=142)
BMI ≥30 and <35 kg/m2
(N=131)
BMI ≥35 kg/m2 (N=74)
r p r p r p r p
Apnea-hypopnea index -0.02 0.70 -0.23 0.005 0.12 0.16 0.02 0.87
Oxygen desaturation index 0.08 0.12 -0.09 0.30 0.16 0.07 0.07 0.57
Minimum SaO2 (%) -0.13 0.01 0.12 0.17 -0.24 0.005 -0.16 0.18
Hypoxia time (minutes) 0.18 0.001 -0.06 0.45 0.36 <0.0001 0.09 0.43
Response Surface Methodology
Y=f(X1, X2, X3,) + , ~N(0, 2)
E[log(HOMA)] was modeled as a third order
linear model with terms defined by apnea (A)
and obesity severity (O)
Normal and constant variance assumptions
verified for log transformed outcomes
Response Surface Methodology
The specific model used was:
E[log(HOMA] =
0 +
1*A + 2*(A)2 +
3*O + 4*(O)2 +
5*(A*O) +
6*A*(O)2 +7*O*(A)2
A = apnea severity measure; O = obesity severity
measure
RSM: log(HOMA)=f(ODI, BMI)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
25
30
35
40
45
101520
253035
4045505560
log
(HO
MA
)
BMI
ODI
R2=33.3%(p<0.0001)
Partial R2’sObesity = 32.6%
(p<0.0001)
Apnea = 3.1%(p=0.01)
O x A = 2.2%(p=0.01)
Non-linear = 5%(p=0.0005)
Response Surface Methodology
0
1
2
3
4
25
30
35
40
45
1520
2530
3540
4550
5560
6570
7580
log
(HO
MA
)
BMI
AHI
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
25
30
35
40
45
1015202530354045
505560
log
(HO
MA
)
BMI
ODI
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
25
30
35
40
45
7274
7678
8082
8486
88
log
(HO
MA
)
BMIMinimum SAO
2
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
25
30
35
40
45
025
5075
100125
log
(HO
MA
)
BMI
Minutes O2 <90%
RSM: log(HOMA)=f(ODI, Total Abd. Fat)
R2=34.1%(p<0.0001)
Partial R2’sObesity = 32.8%
(p<0.0001)
Apnea = 1.4%(p=0.20)
O x A = 0.9%(p=0.21)
Non-linear = 3.4%(p=0.002)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
6
8
10
12
14
1020
3040
5060
log
(HO
MA
)
Abdominal Fat V
olume (MRI)
(x 1000)ODI
Response Surface Methodology
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.01.5
3.04.5
6.07.5
9.0
15202530
3540
455055
606570
75
log
(HO
MA
)
Visceral Fat V
olume (MRI)
(x 1000)AHI
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.01.5
3.04.5
6.07.5
9.0
1020
3040
5060
log
(HO
MA
)
Visceral Fat V
olume (MRI)
(x 1000)ODI
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.01.5
3.04.5
6.07.5
9.0
7274
7678
8082
8486
88
log
(HO
MA
)
Visceral Fat V
olume (MRI)
(x 1000)
Minimum SAO2
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.01.5
3.04.5
6.07.5
9.0
025
5075
100125
log
(HO
MA
)
Visceral Fat V
olume (MRI)
(x 1000)
Minutes O2 <90%
Conclusions
Obesity is a much more important determinant of insulin
resistance than obstructive sleep apnea.
There is a complex interaction between obesity and OSA and
insulin resistance.
Different metrics produce different results which may be
related to differences in what these metrics actually measure.
Depending upon which metrics are examined, our study
provides additional confirmation that among non-obese, OSA
increases insulin resistance.
There may also be differentially important amplification of
OSA effects among the most obese.
BMI, Total Fat, and Visceral Fat by BMI Category
N Std
BMI3GRP Obs Variable Label N Mean Dev Min Max
---------------------------------------------------------------------------------------------
<30 180 BMI Body Mass Index (k/m-sq) 180 27.5 2.0 20.0 29.9
MR54 ab total fat vol. 180 7.2 2.1 1.2 12.4
MR56 ab visc fat vol. 180 3.3 1.4 0.2 8.0
30-<35 192 BMI Body Mass Index (k/m-sq) 192 32.3 1.4 30.0 35.0
MR54 ab total fat vol. 192 10.6 2.2 4.7 16.9
MR56 ab visc fat vol. 192 4.6 1.5 0.7 10.1
>=35 126 BMI Body Mass Index (k/m-sq) 126 38.3 2.9 35.1 51.2
MR54 ab total fat vol. 126 14.2 2.7 7.4 22.7
MR56 ab visc fat vol. 126 5.1 1.9 1.4 11.2
---------------------------------------------------------------------------------------------
Response Surface Methodologyusing BMI as Measure of Obesity
Null hypothesis tested
No BMI or OSA
effects (df=7)
No BMI Effect (df=5)
No OSA Effect (df=5)
No BMI*OSA
interaction (df=3)
No Non-
linearity (df=4)
AHI p-value for rejecting Ho: <0.0001 <0.0001 0.01 0.02 <0.0001
R2 or Partial R2 33.9% 32.8% 3.0% 1.9% 4.7%
ODI p-value for rejecting Ho: <0.0001 <0.0001 0.01 0.01 0.0003
R2 or Partial R2 33.9% 32.6% 3.1% 2.2% 5.0%
Min SAO2 p-value for rejecting Ho: <0.0001 <0.0001 0.10 0.11 0.001
R2 or Partial R2 33.1% 30.7% 1.9% 1.2% 3.7%
Minutes O2 p-value for rejecting Ho: <0.0001 <0.0001 <0.0001 0.001 0.0003
< 90% R2 or Partial R2 33.8% 31.3% 2.9% 2.1% 3.6%
Response Surface MethodologyUsing Abdominal Visceral Fat Volume
Null hypothesis tested
No VisFAT or OSA effects (df=7)
No VISFAT Effect (df=5)
No OSA Effect (df=5)
No VISFAT*OSA interaction
(df=3)
No Non-
linearity (df=4)
AHI p-value for rejecting Ho: <0.0001 <0.0001 0.25 0.77 0.003
R2 or Partial R2 21.9% 26.0% 1.2% 0.1% 3.2%
ODI p-value for rejecting Ho: <0.0001 <0.0001 0.36 0.73 0.02
R2 or Partial R2 21.7% 25.3% 1.1% 0.3% 2.4%
Min SAO2 p-value for rejecting Ho: <0.0001 <0.0001 0.01 0.62 0.02
R2 or Partial R2 23.2% 20.5% 1.9% 1.2% 3.7%
Minutes p-value for rejecting Ho: <0.0001 <0.0001 0.06 0.12 0.07
O2< 90% R2 or Partial R2 22.5% 20.6% 2.1% 1.1% 1.8%
Description of Overlap CohortOverall and by Obesity Category
Medical history
All
(N=498) BMI < 30
kg/m2 BMI 30 -< 35
kg/m2 BMI ≥ 35
kg/m2
p-value
for comparison
between groups
(Wilcoxon or χ2)
Hypertension (%) 41.0 31.3 42.6 52.4 <0.001
Cardiovascular disease (%) 16.0 17.4 16.3 13.5 0.65
Obstructive lung disease (%) 18.2 16.2 16.8 23.2 0.25 Diabetes (%) (current users of diabetes medication excluded from cohort)
1.4 0.6 1.1 3.2 0.14
Statin use (%) 19.5 18.3 19.8 20.6 0.87
Participate in exercise (%) 65.5 76.3 63.0 54.4 <0.001
Construction of the ‘Double Overlap Cohort’ AHI 14-80 and ODI 10-65