31.05.

2013 Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome
www.ncbi.nlm.nih.gov/pmc/articles/PMC3524733/ 1/9
Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome
Sabine Zirlik, Tabea Hauck, [...], and Igor Alexander Harsch
Summary
Background
Recent st udies suggest t hat adipose t issue hor mones ar e inv olv ed in t he pat hogenesis of obst r uct iv e
sleep apnoea sy ndr ome (OSAS). The r ole of lept in, obest at in and apelin st ill needs t o be est ablished.
Material/Methods
Ten pat ient s wit h newly diagnosed OSAS (AHI >1 0/h and ESS >1 0 point s) wer e enr olled in t he st udy
as well as t en healt hy v olunt eer s as cont r ols. All under went measur ement s for Lept in, Obest at in
and Apelin in four hour int er v als dur ing diagnost ic poly somnogr aphy for 2 4 h and t he pat ient s also
t hr ee mont hs aft er onset of CPAP t r eat ment . Fur t her mor e t he HOMA-index and body composit ion
wer e quant ified.
Results
Plasma apelin lev els in t he pat ient s decr eased under CPAP t her apy , but showed no significant
differ ence in pat ient s and v olunt eer s. We found a posit iv e cor r elat ion t o AHI, BMI in t he t her apy
gr oup at all obser v at ion point s.
Lept in plasma lev els wer e higher in t he pat ient gr oup and decr eased aft er onset of CPAP t her apy .
Lept in plasma lev els wer e posit iv ely cor r elat ed t o t he BMI, min. 02 and AHI in t he pat ient gr oup
befor e t her apy .
Plasma obest at in lev els did not differ significant ly in t hese t hr ee obser v at ion gr oups, but wer e
par t ly cor r elat ed t o AHI and weight in t he newly diagnosed OSAS gr oup.
Conclusions
In agr eement wit h pr ev ious inv est igat ions, we could demonst r at e a differ ence in lept in plasma
lev els bet ween healt hy v olunt eer s and pat ient s wit h newly diagnosed OSAS. Apelin decr eases under
CPAP t her apy , but not significant ly .
Obest at in r emains unchanged aft er onset of CPAP. We fur t her found a linkage bet ween lept in
plasma lev els and BMI, AHI and weight in t he unt r eat ed pat ient gr oup.
Keywords: OSAS, adipose t issue hor mones, CPAP t her apy , apelin, obest at in, lept in
Background
The obst r uct iv e sleep apnoea sy ndr ome (OSAS) is a disor der wit h a high pr ev alence char act er ized
by an incr eased car diov ascular r isk. Obesit y and insulin r esist ance ar e t y pical met abolical feat ur es
of OSAS. Since obesit y has r eached epidemic pr opor t ions globally [1 ] numer ous effor t s hav e been
made t o under st and t he complex mechanisms inv olv ed in t he r egulat ion of food int ake, hunger ,
sat iet y , ener gy st or age and consumpt ion.
In t he last t wo decades, sev er al nov el r egulat or y pept ides such as lept in, ghr elin or adiponect in
hav e been discov er ed and st udied emphasizing t heir r ole in ener gy homeost asis. The demonst r at ion
of a possible r ole of some of t hese pept ides in sleep r egulat ion as independent effect s apar t fr om t hose
in ener gy r egulat ion was a fascinat ing addit ional finding [2 , 3 ].
31.05.2013 Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome
www.ncbi.nlm.nih.gov/pmc/articles/PMC3524733/ 2/9
Apelin is a pept ide t hat was ident ified in 1 998 [4]. The effect best char act er ized of t his hor mone is
wit hin t he car diov ascular sy st em. A hy pot ensiv e effect of apelin r esult s fr om t he act iv at ion of
r ecept or s expr essed at t he sur face of endot helial cells [5 ], but t he hor mone has also been int r igued
in angiogenesis [6]. Apelin r ecept or s hav e been found wit hin t he lung [7 ] and Ey r ies et al. r ecent ly
demonst r at ed t hat apelin expr ession was induced by hy poxia in cell cult ur es as well as in mice
exposed t o hy poxia [8].
Wit h t his in mind, we inv est igat ed, whet her t her e might be differ ences in Apelin secr et ion in
pat ient s wit h OSAS compar ed t o healt hy people due t o chr onic noct ur nal hy poxia in t he fir st gr oup
and pot ent ial effect s of CPAP t her apy aft er r ev er sal of t hese ev ent s. Since pat ient s wit h OSAS ar e
insulin-r esist ant [9], and insulin-induced apelin expr ession was r ecent ly demonst r at ed in
adipocy t es [1 0] t he gr oups might hav e differ ent apelin secr et ion in gener al and not only dur ing
some per iods.
Anot her nov el aminopept ide is obest at in. To dat e, effect s on food int ake, weight gain and int est inal
mot ilit y hav e been inv est igat ed due t o it s encodement on t he same gene as ghr elin [1 1 ]. We wer e
par t icular ly int er est ed in it s r ole in sleep r egulat ion t hat has been inv est igat ed in r at s [1 2 , 1 3 ], but
not humans y et . To our knowledge, ser ial measur ement s of obest at in wit h r egar d t o it s put at iv e
r ole in sleep r egulat ion wer e not per for med. Pat ient s wit h OSAS t hus, ser v ed as a biomodel of
dist ur bed sleep behav iour wer e compar ed t o healt hy cont r ols and fur t her mor e, we inv est igat ed
possible alt er at ions of obest at in secr et ion aft er r est or at ion of nor mal sleep in OSAS pat ient s.
An int er act ion of apelin and obest at in wit h insulin r esist ance as a well char act er ized feat ur e of
OSAS pat ient s has alr eady been descr ibed; and we also det er mined t heir st at e of insulin
(in)sensit iv it y by use of t he HOMA model.
The r ole of lept in in OSAS has alr eady been mor e pr ecisely char act er ized. Fast ing lept in lev els in
pat ient s wit h OSAS decr ease aft er init iat ion of CPAP (cont inuous posit iv e air way pr essur e)
t r eat ment wit hout changes in weight and ar e discussed as a r espir at or y st imulus [1 4]. Wit h
int er act ions bet ween insulin r esist ance and lept in [1 5 , 1 6] as well as bet ween lept in and apelin [7 ]
and obest at in [1 2 ], we chose t o det er mine ser ial lept in measur ement s as well t o char act er ize
possible int er act ions bet ween t hese t hr ee hor mones.
Material and Methods
Subjects
Ten pat ient s (n=1 0, male) wit h newly diagnosed sy mpt omat ic obst r uct iv e sleep apnoea sy ndr ome
(apnoea-hy popnea-index, AHI >1 0 per hour and Epwor t h-sleepiness-scale, ESS >1 0 point s) wer e
enr olled in t he st udy . Obst r uct iv e apnoeas wer e defined as t he absence of or onasal flow for at least
1 0s. Hy popnoeas wer e defined as r educt ion in air flow t o 5 0% of t he pr eceding st able baseline for
1 0s or longer t oget her wit h a dip in oxy gen sat ur at ion 4%. The mean number of apnoeas and
hy popnoeas per hour of sleep was calculat ed as t he apnoea/hy popnoea index (AHI). The Epwor t h-
sleepiness-scale is a quest ionnair e t o ev aluat e especially day t ime sleepiness.
As a fir st st ep diagnost ic poly somnogr aphy was per for med. In t his set t ing t he degr ee of t he OSAS
and t he sleep dist ur bance was quant ified. The AHI as well as t he sleep qualit y wer e assessed. Befor e
poly somnogr aphic measur ement s subject s under went a complet e medical hist or y , clinical
chemist r y and phy sical examinat ion. This was done t o r ule out ser ious ot her diseases (such as
diabet es, hepat it is, cancer ) and medicat ion wit h an impact on insulin sensit iv it y , which might
influence t he analy ses of adipocy t e-der iv ed hor mones.
Thr ee mont hs lat er and hav ing used t he nCPAP t her apy r eliably all examinat ions wer e r epeat ed
(poly somnogr aphy under nCPAP t her apy , quest ionnair e, clinical chemist r y and DXA) und
compar ed wit h t he init ial r esult s.
31.05.2013 Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome
www.ncbi.nlm.nih.gov/pmc/articles/PMC3524733/ 3/9
The hor mones lept in, obest at in and apelin wer e measur ed in four hour int er v als (2 , 6, 1 0 a. m. and
2 , 6, 1 0 p. m. ) including t he night of diagnost ic and t her apeut ic poly somnogr aphy . Nor mal sleep
wake r hy t hms wer e r et ained, t he av er age sleep t ime dur at ion lay bet ween six and nine hour s. The
light was t ur ned off at 1 0 t o 1 1 p. m. , t he pat ient s wer e waked up at about 6 t o 7 a. m.
Blood dr awings wer e per for med t hr oughout an indwelling super ficial for ear m cat het er t o
minimalize t he pat ient s dist ur bance. In t he second night a t it r at ion t o find out t he minimal
sufficient t her apeut ic pr essur e was made. The goal was t o r educe t he pat hologic AHI t o a nor mal
r age (<5 /h). Addit ionally as a pot ent ial mar ker of influence t he exact body composit ion was
measur ed by using DXA (Lunar Pr odigy ). Befor e demission each pat ient was inst r uct ed t o use t he
nCPAP t her apy r egular ly each night for at least six hour s t o r each a t her apeut ic effect . To clar ify
CPAP adher ence, t he built -in dat a st or es of t he CPAP dev ices wer e r ead out . This allows t o est ablish
t he number of day s of use wit hin t he last t hr ee mont hs and t o calculat e t he mean dur at ion of use
per night of t r eat ment .
Ten healt hy v olunt eer s (n=9 male and n=1 female) wit h no sleep disor der wer e r ecr uit ed t o ser v e as
a cont r ol gr oup. As t he t en pat ient s wit h OSAS t hey under went t he same examinat ions (DXA,
clinical chemist r y , quest ionnair e et c. ). To r ule out subject s wit h OSAS t he v olunt eer s wer e
measur ed under st udy condit ions wit h Apnoe Scr een (ApnoeScr een Pr o, VIASYS Healt hcar e GmbH,
Leibnizst r asse 7 , 97 2 04 Hchber g, Ger many ). Finally a compar ison of t he dat a of t he v olunt eer s
and t he pat ient s r egar ding cir cadian r hy t hm of t he adipocy t e-der iv ed hor mones wer e made.
All per sons st udied gav e wr it t en infor med consent t o par t icipat e in t he st udy , t he st udy pr ot ocol
was appr ov ed by t he local et hics commit t ee.
The samples wer e collect ed in et hy lendiamine t et r aacet at e-coat ed poly pr opy lene t ubes, cent r ifuged
immediat ely at 3 . 000 r pm for 2 0 min at 0C, and t he clear plasma super nat ant was t hen st or ed
unt il plasma lept in, obest at in and apelin lev els wer e measur ed as follows:
Measurement of serum apelin Ser um apelin was measur ed dir ect ly by a specific r adioimmunoassay kit
wit h a measur ement r ange fr om 1 01 2 80 pg/ml (Human Apelin-3 6 RIA kit , Phoenix
Phar maceut icals, Inc. , 3 3 0 Beach Road, Bur lingame, CA 9401 0, U. S. A. ). All samples and st andar ds
wer e assay ed in duplicat e wit hin t he same assay .
Measurement of serum obestatin Per ipher al obest at in lev els wer e measur ed using a commer cial
r adioimmunoassay kit wit h a measur ement r ange fr om 5 06400 pg/ml (Human Obest at in RIA
kit , Phoenix Phar maceut icals, Inc. , 3 3 0 Beach Road, Bur lingame, CA 9401 0, U. S. A. ). All samples
and st andar ds wer e assay ed in duplicat e wit hin t he same assay .
Measurement of serum leptin Ser um lept in lev els wer e measur ed by a commer cially av ailable
r adioimmunoassay kit (Human Lept in RIA kit , Millipor e Cor por at ion, 2 90 Concor d Road, Biller ica,
MA 01 82 1 ). The sensit iv it y limit was 0, 5 ng/mL. All samples and st andar ds wer e assay ed in
duplicat e wit hin t he same assay .
Sleep studies
The poly somnogr aphies wer e per for med accor ding t o t he r ecommendat ions of t he Amer ican
Thor acic Societ y [1 7 ] and t he Ger man Sleep Societ y [1 8, 1 9]. Sleep par amet er s wer e det er mined
using t he cr it er ia of Recht schaffen and Kahles [2 0] and micr oar ousals wer e defined in accor dance
wit h t he definit ions of t he Amer ican Sleep Disor der s Associat ion (ASDA) [2 1 ]. All pat ient s wer e
monit or ed for at least 6h in our sleep labor at or y . The measur ed par amet er s included subment al
elect r omy ogr aphy , snor ing det ect ed by a micr ophone, elect r ocar diogr aphy , t hor acic and
abdominal mov ement s, bilat er al elect r ooculogr aphy , elect r oencephalogr aphy , nasal air flow
measur ed by or onasal t her mist or s dur ing diagnost ic poly somnogr aphics and by an
pneumot achogr aph dur ing CPAP st udies and oxy haemoglobin sat ur at ion using a finger oxy met er
31.05.2013 Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome
www.ncbi.nlm.nih.gov/pmc/articles/PMC3524733/ 4/9
(Micr ospan 3 040G, Jaeger amd Toennies, Wr zbur g, Ger many ). The measur ed dat a wer e
ev aluat ed by t he same qualified doct or .
Results
Pat ient s and t he healt hy cont r ols wer e appr oximat ly t he same age (5 8. 91 0. 2 vs. 5 3 . 67 . 7 ,
p>0. 05 ). As t o be expect ed for caucasian subject s t he t wo gr oups differ significant ly r egar ding
weight (BMI 3 1 . 7 3 . 2 vs. 2 6. 7 2 . 3 kg/m , p<0. 05 ). Cor r esponding t o t his fact t he pat ient s had a
significant higher per cent al body fat (2 6. 67 . 5 vs. 3 3 . 7 3 . 7 , p<0. 05 ). The pat ient s befor e t her apy
had a significant higher AHI (40. 41 8. 9 vs. 2 . 7 3 . 1 /h, p<0. 05 ) and a lower sleep qualit y (ESS
1 1 . 7 1 . 7 vs. 5 . 1 2 . 1 point s, p<0. 05 ) compar ed t o t he healt hy v olunt eer s. In t ot al 1 0 pat ient s and
1 0 healt hy cont r ols wer e st udied. Fr om t he 1 0 pat ient s at t he beginning 3 r efused fur t her CPAP
t her apy in t he fir st 46 weeks due t o discomfor t . The r emaining 7 pat ient s applied t he t her apy
accor ding t o t he init ial inst r uct ions for use (at least 6 hour s per night ). The pat ient gr oup was
measur ed t wice: Befor e t her apy and aft er t hr ee mont hs of applicat ion of CPAP. The CPAP t r eat ment
significant ly eliminat ed t he pr ev iously obser v ed obst r uct ions. In consequence t he init ial AHI was
r educed t o a nor mal r ange (42 . 1 1 6. 2 vs. 4. 7 6. 0 /h, p<0. 05 ) and t he mean SaO was ensur ed
(91 . 2 4. 1 vs. 94. 61 . 7 %, p<0. 05 ). The subject iv e sleepiness and sleep qualit y wer e impr ov ed (ESS
1 1 . 81 . 8 vs. 5 . 02 . 0, p<0. 05 ) (Table 1 ).
Tabl e 1
Char acter i sti cs of pati ents and contr ol s.
HOMA-index bet ween pat ient s befor e and aft er t her apy showed no significant differ ences
(2 2 . 3 5 42 . 64 vs. 1 1 . 62 1 6, 3 6, p>0. 05 ). In cont r ast t he HOMA-index compar ing pat ient s befor e
t her apy and healt hy cont r ols differ in a significant manner (1 9. 1 5 2 9, 83 vs. 2 . 7 3 3 . 3 7 , p<0. 05 ).
Ot her par amet er s such as pCO2 , pO2 , pH and lung funct ion par amet er s (FEV1 and VC) wer e also
analy sed. None of t hem could line out significancies bet ween pat ient s befor e or under t her apy and
v olunt eer s, except pO2 . The healt hy v olunt eer s showed a significant higher mean pO2 in
compar ison t o t he pat ient s wit h newly diagnosed OSAS (82 . 1 8. 01 vs. 7 2 . 5 1 1 . 3 , p<0. 05 ).
Fur t her mor e we examined any possible cor r elat ion of t he par amet er s (pO2 , pCO2 , VC, FEV1 , pH,
age, height , weight , HOMA-Index, body fat , t her apeut ical pr essur e of CPAP, min. O2 , basal O2 ,
glucose, insulin, BMI, AHI and ESS point s) t o t he pept ide hor mones (apelin, lept in, obest at in):
Leptin plasma lev els of t he pat ient gr oup befor e t her apy had at each t ime of t he obser v at ion a
significant cor r elat ion t o t he body mass index (pmin. 0. 5 5 ; pmax. 0. 69), min. O2 (pmin. 0. 7 6;
pmax. 0. 5 8) and AHI (pmin. 0. 5 5 ; pmax. 0. 62 ). A significant cor r elat ion was found bet ween
Lept in measur ement s of newly diagnosed OSAS pat ient s and weight at 2 a. m. , 2 , 6, 1 0 p. m. as well
as t he body fat per cent age at 6, 1 0 a. m. , 2 p. m. . In t he t her apy gr oup posit iv e significant
cor r elat ions could be obser v ed bet ween lept in plasma lev els and pH (at 2 , 6, 1 0 a. m. , 2 , 6, 1 0 p. m. ),
BMC in g (at 2 , 6, 1 0 a. m. , 2 , 6, 1 0 p. m. ), body fat in% (at 6 a. m. , 2 p. m. ), FEV1 and VC (at 2 , 6, 1 0
a. m. , 2 , 1 0 p. m. ) and age (6, 1 0 a. m. , 2 , 1 0 p. m. ).
Bet ween Apelin plasma lev els and t he ment ioned par amet er s we could not find any significancies in
t he newly diagnosed OSAS gr oup. In cont r ast t he plasma apelin lev els showed a significant
cor r elat ion t o t he AHI (pmin. 0. 82 ; pmax. 0. 91 ), min. O2 (pmin. 0. 7 5 ; pmax. 0. 86) and BMI
(pmin. 0. 7 8; pmax. 0. 85 ) in t he t her apy gr oup at all obser v at ion point s. Fur t her mor e t her e was a
significant cor r elat ion t o t he basal O2 (at 2 , 6 p. m. ), pr essur e and pO2 (at 2 , 6, 1 0 a. m. , 6, 1 0
p. m. ).
2
2
31.05.2013 Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome
www.ncbi.nlm.nih.gov/pmc/articles/PMC3524733/ 5/9
Obestatin plasma lev els wer e significant ly cor r elat ed at t ime of OSAS diagnosis t o AHI and weight (at
6, 1 0 p. m. ), t o body fat in% (at 2 , 6 a. m. , 2 p. m. ), BMC in g (at 1 0 a. m. , 2 p. m. ) and pCO2 (at 6
a. m. , 2 p. m. ). Aft er t hr ee mont hs of t her apy t her e was only a significant cor r elat ion t o weight and
height (at 1 0 a. m. ).
Fur t her we analy sed t he plasma lev els of t he t hr ee adipose t issue hor mones in t he t hr ee differ ent
obser v at ion gr oups:
Leptin
Cont r ols had significant lower plasma lept in lev els as t he pat ient s at t ime of diagnosis of OSAS at all
obser v at ion point s. Lept in lev els decr ease aft er 3 t her apeut ic mont hs, in a significant manner at
6. 00 and 1 0. 00 a. m. (Figur e 1 ).
Fi gur e 1
Lev el s of pl asma l epti n i n contr ol s and pati ents bef or e and under ther apy (gr een: contr ol s, bl ack:
pati ents at ti me of di agnosi s of OSAS, r ed: pati ents thr ee months af ter nCPAP ther apy ).
Apelin
The mean plasma apelin lev els of pat ient s wit h newly diagnosed OSAS ar e higher t han t hose of t he
pat ient s under t her apy , but failed t o r each significance (Figur e 2 ).
Fi gur e 2
Lev el s of pl asma apel i n i n contr ol s and pati ents bef or e and under ther apy (gr een: contr ol s, bl ack:
pati ents at ti me of di agnosi s of OSAS, r ed: pati ents thr ee months af ter nCPAP ther apy ).
Obestatin
Plasma obest at in lev els of t he v olunt eer s wer e higher in compar ison t o t he pat ient s befor e or aft er
t hr ee mont hs of t her apy except at 6 and 1 0 p. m. (Figur e 3 ).
Fi gur e 3
Lev el s of pl asma obestati n i n contr ol s and pati ents bef or e and under ther apy (gr een: contr ol s,
bl ack: pati ents at ti me of di agnosi s of OSAS, r ed: pati ents thr ee months af ter nCPAP ther apy ).
We also analy sed cor r elat ions bet ween t he t hr ee adipose t issue hor mones. We found a significant
cor r elat ion bet ween lept in and obest at in in t he pat ient gr oup befor e and aft er onset of CPAP t her apy
(except at 2 a. m. in t he CPAP gr oup).
Discussion
The obst r uct iv e sleep apnoea sy ndr ome is a common disor der in t he adult populat ion, especially in
men. It is char act er ised by r epet it iv e episodes of hy poxaemia caused by an obst r uct ion of t he upper
air way s. In consequence t he pat ient s suffer fr om sleep dist ur bance at night due t o ar ousals [2 2 ].
Fur t her mor e ot her diseases such as diabet es and hy per t ension ar e associat ed wit h OSAS [1 4, 2 3 ].
Tr eat ment wit h posit iv e cont inous air way pr essur e (CPAP t her apy ) can eliminat e t he obst r uct ions
and t her efor e t he st at es of hy poxaemia [2 4]. Sleep qualit y and day t ime v igilance r est or es and t he
r isk of suffer ing fr om associat ed ot her diseases like hy per t ension, insulin r esist ance or
31.05.2013 Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome
www.ncbi.nlm.nih.gov/pmc/articles/PMC3524733/ 6/9
car diov ascular complicat ions, et c. is r educed. Unfor t unat ely , besides t hese posit iv e effect s CPAP
does not alway s impact on t he weight of t he pat ient s, as demonst r at ed in our st udy gr oup.
Wit h t he r ecent discov er y of nov el pept ides like apelin and obest at in [2 5 ], dat a fr om animal models
suggest ed, t hat some of t hese hor mones play a r ole in OSAS independent ly of obesit y . This has also
been hy pot hesized in t he case of lept in. Lept in r egulat es body fat mass by decr easing food int ake and
incr easing r est ing ener gy expendit ur e [2 6]. It s pr oduct ion declines dur ing st ar v at ion [2 7 ]. It is
est ablished, t hat lept in lev els ar e elev at ed in an obese populat ion as well as in pat ient s wit h OSAS.
Lept in lev els decr ease under CPAP t her apy independent ly fr om t he obesit y of t he pat ient s, which
can be confir med in our st udy . In pr ev ious st udies, lept in was alr eady discussed as a r espir at or y
st imulus, which has t o dat e only been confir med in animal models [1 4].
Apelin is a hor mone wit h car diov ascular pr oper t ies and impact on glucose homoeost asis [2 8, 2 9].
Apelin is secr et ed and expr essed by human adipocy t es and up-r egulat ed by insulin and obesit y
[3 0]. The expr ession is st r ongly inhibit ed by fast ing [3 1 ] and r ecov er ed aft er r efeeding, in a similar
way t o insulin [3 0]. Sev er al st udies hav e demonst r at ed t hat Apelin is a pot ent angiogenic fact or .
And like ot her angiogenic fact or s t he apelin gene is upr egulat ed under hy poxia condit ions [3 2 ]. In
addit ion, inhibit ion of apelin signaling dur ing fr og embr y onic dev elopment r esult ed in sev er e
r educt ion in t he for mat ion of v ascular st r uct ur es [3 3 ]. A most r ecent st udy on t he pat hophy siologic
r ole play ed by apelin showed t hat int r aper it oneal administ r at ion in nor mal and obese mice for 1 4
day s r educed body fat wit hout affect ing food int ake, r educed insulin, lept in and t r igly cer ides lev el
and r espir at or y quot ient [2 9]. It is ment ioned t hat Apelin might hav e differ ent effect s, depending
on whet her it is act ing in br ain or per ipher ally [3 2 ]. As OSAS is st r ongly cor r elat ed wit h obesit y ,
hy per insulinaemia and hy poxic st at es we analy sed t his hor mone befor e and aft er onset of CPAP
t her apy . Our measur ement s dur ing a 2 4h per iod in pat ient s wit h newly diagnosed OSAS could
show higher apelin plasma lev els t han in t he same obser v at ion gr oup t hr ee mont hs aft er sufficient
nCPAP t her apy . Apelin lev els had a t r end t o decr ease in CPAP t r eat ed subject s as pr ev iously
demonst r at ed in lept in, t oo. This could be r elat ed t o changes in t he body fat dist r ibut ion, t hat we
could not ev aluat e in our st udy . Howev er , t he weight of our pat ient s r emained unchanged. Thus,
r espir at or y effect s of apelin (e. g. maint aining r espir at or y dr iv e in t he chr onically hy poxic st at e of
OSAS) can be discussed and war r ant fur t her st udies. Elev at ed apelin lev els in pat ient s wit h OSAS
hav e also r ecent ly been r epor t ed by Henley et al. aft er glucose challenge. They did also not find a
salient v ar iabilit y of apelin lev els dur ing a 2 4h per iod. They r epor t ed lower apelin lev els aft er CPAP
t her apy ov er night , a t r end t hat we can confir m in our pat ient gr oup. As in pr ev ious obser v at ions
[3 1 ] apelin plasma lev els in our st udy gr oup (t her apied OSAS pat ient s) wer e posit iv ely cor r elat ed t o
t he body mass index. Like Henley et al. we found no cor r elat ion bet ween plasma apelin and BMI in
unt r eat ed OSAS pat ient s [2 5 ].
Obest at in, as well as Ghr elin, is der iv ed fr om a 1 1 7 -r esidue pr epr o-pept ide by post t r anslat ional
cleav age (Pr epr o Ghr elin) [1 1 ]. Fr om animal models, Obest at in was fir st discussed as an ant agonist
of ghr elin due t o suppr ession of food int ake, inhibit ion of insulin secr et ion and suppr ession of gast r ic
empt y ing [3 4]. Dat a about effect s on sleep behav iour ar e r ar e. A significant incr ease in non REM
sleep was r epor t ed aft er int r aper it oneal or int r acer ebr ov ent r icular inject ion in r at s [1 3 ]. To our
knowledge, dat a about humans wit h OSAS ar e not av ailable. Wit h our appr oach, we could not
demonst r at e differ ences in t he obest at in lev els of our obese pat ient gr oup wit h OSAS befor e and 3
mont hs aft er onset of CPAP t her apy . Apar t fr om t he conclusion, t hat t her e seem t o be no significant
dir ect effect s of obest at in on r espir at or y funct ion, t hese dat a fit well wit h t he st udy of Ander wald-
St adler et al. [3 5 ], who obser v ed almost no effect s of insulin on obest at in dur ing a clamp st udy in
insulin-r esist ant humans. Pat ient s wit h OSAS ar e t y pically insulin-r esist ant [3 63 8]. The small
amount of an impr ov ement of insulin sensit iv it y by CPAP in OSAS subject s demonst r at ed by our
st udy gr oup [3 6] does obv iously not impact on obest at in lev els.
Conclusions
31.05.2013 Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome
www.ncbi.nlm.nih.gov/pmc/articles/PMC3524733/ 7/9
Pr ev ious st udies r aised suspicion t hat r egulat or y pept ides such as lept in, apelin and obest at in might
play a r ole in t he pat hogenesis of OSAS. In our st udy we could demonst r at e differ ent plasma lev els of
lept in and apelin r egar ding OSAS pat ient s befor e and aft er onset of CPAP t her apy in compar ison t o
healt hy v olunt eer s, but not in obest at in. Fur t her inv est igat ions and differ ent appr oaches will hav e
t o inv est igat e, if t hese hor mones might hav e dir ect effect s on OSAS and t hr ough which signaling
pat hway s t hey might exhibit t heir effect s, or if t hese hor monal changes ar e r at her associat ed t o
concomit ant met abolical changes in t r eat ed OSAS pat ient s such as a modulat ion of insulin
sensit iv it y or changes in body fat dist r ibut ion.
Footnotes
Source of support: Self financing
Article information
Med Sci Monit. 2011; 17(3): CR159CR164.
Published online 2011 March 1. doi: 10.12659/MSM.881450
PMCID: PMC3524733
Sabine Zirlik, Tabea Hauck, Florian Siegfried Fuchs, Markus Friedrich Neurath, Peter Christopher Konturek, and Igor
Alexander Harsch
Medical Department 1, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
Department of Internal Medicine, Thuringia Clinic, Saalfeld, Germany
Sabine Zirlik, Medical Department 1, Friedrich-Alexander University of Erlangen-Nuremberg, Ulmenweg 18, D-91054 Erlangen, Germany, e-mail:
sabine.zirlik/at/uk-erlangen.de
Study Design
Data Collection
Statistical Analysis
Data Interpretation
Manuscript Preparation
Literature Search
Funds Collection
Received January 2, 2011; Accepted January 28, 2010.
Copyright Med Sci Monit, 2011
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.
This article has been cited by other articles in PMC.
Articles from Medical Science Monitor : International Medical Journal of Experimental and Clinical Research are provided here courtesy of International
Scientific Literature, Inc.
References
1. http://www.who.i nt/di etphysi cal acti vi ty/publ i cati ons/facts/obesi ty/en/
2. Chi n K, Shi mi zu K, Nakamura T, et al . Changes i n i ntra-abdomi nal vi sceral fat and serum l epti n l evel s i n pati ents
wi th obstructi ve sl eep apnea syndrome fol l owi ng nasal conti nuous posi ti ve ai rway pressure therapy. Ci rcul ati on.
1999;100(7):70612. [PubMed]
3. Harsch IA, Konturek PC, Koebni ck C, et al . Lepti n and ghrel i n l evel s i n pati ents wi th obstructi ve sl eep apnoea: effect
of CPAP treatment. Eur Respi r J. 2003;22(2):25157. [PubMed]
4. Tatemoto K, Hosoya M, Habata Y , et al . Isol ati on and characteri zati on of a novel endogenous pepti de l i gand for the
human APJ receptor. Bi ochem Bi ophys Res Commun. 1998;251(2):47176. [PubMed]
5. Lee DK, Cheng R, Nguyen T, et al . Characteri zati on of apel i n, the l i gand for the APJ receptor. J Neurochem.
1,A,B,C,D,E,F,G 1,B,F 1,A,G 1,A,G 2,A,G
2,A,C,D,E,F
1
2
A
B
C
D
E
F
G
31.05.2013 Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome
www.ncbi.nlm.nih.gov/pmc/articles/PMC3524733/ 8/9
2000;74(1):3441. [PubMed]
6. Cox CM, Dgosti no S, Mi l l er MK, et al . Apel i n, the l i gand for the endothel i al G-protei n-coupl ed receptor, APJ, i s a
potent angi ogeni c factor requi red for normal vascul ar devel opment of the frog embryo. Dev Bi ol . 2006;296(1):17789.
[PubMed]
7. OCarrol l AM, Sel by T, Pal kovi ts M, Lol ai t SJ. Di stri buti on of mRNA encodi ng B78/apj, the rat homol ogue of the
human APJ receptor, and i ts endogenous l i gand apel i n i n brai n and peri pheral ti ssues. Bi ochi m Bi ophys Acta.
2000;1492(1):7280. [PubMed]
8. Eyri es M, Si egfri ed G, Ci umas M, et al . Hypoxi a-i nduced apel i n expressi on regul ates endothel i al cel l prol i ferati on
and regenerati ve angi ogenesi s. Ci rc Res. 2008;103(4):43240. [PubMed]
9. Harsch IA, Hahn EG, Konturek PC. Insul i n resi stance and other metabol i c aspects of the obstructi ve sl eep apnea
syndrome. Med Sci Moni t. 2005;11(3):RA7075. [PubMed]
10. Gl assford AJ, Y ue P, Shei kh AY , et al . HIF-1 regul ates hypoxi a- and i nsul i n-i nduced expressi on of apel i n i n
adi pocytes. Am J Physi ol Endocri nol Metab. 2007;293(6):E159096. [PMC free arti cl e] [PubMed]
11. Tang SQ, Ji ang Q, Zhang Y L, et al . Obestati n: i ts physi cochemi cal characteri sti cs and physi ol ogi cal functi ons.
Pepti des. 2008;29(4):63945. [PubMed]
12. Bodosi B, Gardi J, Hajdu I, et al . Rhythms of ghrel i n, l epti n, and sl eep i n rats: effects of the normal di urnal cycl e,
restri cted feedi ng, and sl eep depri vati on. Am J Physi ol Regul Integr Comp Physi ol . 2004;287(5):R107179. [PubMed]
13. Szenti rmai E, Krueger J. Obestati n al ters sl eep i n rats. Neurosci Lett. 2006;404(12):22226. [PubMed]
14. Ip MS, Lam K, Ho C, et al . Serum l epti n and vascul ar ri sk factors i n obstructi ve sl eep apnea. Chest.
2000;118(3):58086. [PubMed]
15. Boden G, Chen X, Kol aczynski JW, Pol ansky M. Effects of prol onged hyperi nsul i nemi a on serum l epti n i n normal
human subjects. J Cl i n Invest. 1997;100(5):110713. [PMC free arti cl e] [PubMed]
16. Vgontzas AN, Papani col aou D, Bi xl er EO, et al . Sl eep apnea and dayti me sl eepi ness and fati gue: rel ati on to
vi sceral obesi ty, i nsul i n resi stance, and hypercytoki nemi a. J Cl i n Endocri nol Metab. 2000;85(3):115158. [PubMed]
17. Ameri can Thoraci c Soci ety. Indi cati ons and standards for use of nasal conti nuous posi ti ve ai rway pressure
(CPAP) i n sl eep apnea syndromes. Ameri can Thoraci c Soci ety. Offi ci al statement adopted March 1944. Am J Respi r
Cri t Care Med. 1994;150(6 Pt 1):173845. [PubMed]
18. Penzel T, Hajak G, Hoffmann RM. Empfehl ungen zur Drchfhrung und Auswertung pol ygraphi scher
Abl ei tungen i m di agnosti schen Schl afl abor. EEG-EMG. 1993;24:6570. [i n German]
19. Fi cker JH, Wi est G, Lehnert G, et al . Eval uati on of an auto-CPAP devi ce for treatment of obstructi ve sl eep apnoea.
Thorax. 1998;53(8):64348. [PMC free arti cl e] [PubMed]
20. Rechtschaffen A, Kahl es A. A manual of standardi zed termi nol ogy, techni ques and scori ng system for sl eep stages
of human subjects. Publ i c Heal th Servi ce, US Government Pri nti ng Offi ce; 1968. [PubMed]
21. Bonnet M, Charl ey D, Carskadon MA. EEG arousal s: Scori ng rul es and exampl es. Sl eep. 1992;15:17484.
22. Hernandez C, Abreu J, Abreu P, et al . Nocturnal mel atoni n pl asma l evel s i n pati ents wi th OSAS: the effect of
CPAP. Eur Respi r J. 2007;30:496500. [PubMed]
23. Tokuda F, Sando Y , Matsui H, et al . Serum Level s of Adi pocytoki nes, Adi ponecti n and Lepti n, i n Pati ents wi th
Obstructi ve Sl eep Apnea Syndrome. Inter Med. 2008;47:184349. [PubMed]
24. Shapi ro GK, Shapi ro GM. Factors that i nfl uence CPAP adherence: an overvi ew. Sl eep Breath. 2010;14(4):32335.
[PubMed]
25. Henl ey DE, Buchanan F, Gi bson R, et al . Pl asma apel i n l evel s i n obstructi ve sl eep apnea and the effect of
conti nuous posi ti ve ai rway pressure therapy. J Endocri nol . 2009;203:18188. [PubMed]
31.05.2013 Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome
www.ncbi.nlm.nih.gov/pmc/articles/PMC3524733/ 9/9
26. Ci ftci TU, Kokturk O, Bukan N, Bi l gi han A. Lepti n and Ghrel i n Level s i n Pati ents wi th Obstructi ve Sl eep Apnea
Syndrome. Respi rati on. 2005;72:395401. [PubMed]
27. Al eman MR, Santol ari a F, Bati sta N, et al . Lepti n rol e i n advanced l ung cancer. A medi ator of the acute phase
response or marker of the status of nutri ti on? Cytoki ne. 2002;19:2126. [PubMed]
28. Bel towski J. Apel i n and vi sfati n: Uni que benefi ci al adi poki nes upregul ated i n obesi ty? Med Sci Moni t.
2006;12(6):RA11219. [PubMed]
29. Ladei ras-Lopes R, Ferrei ra-Marti ns J, Lei te-Morei ra A. The Apel i nergi c System: The Rol e Pl ayed i n Human
Physi ol ogy and Pathol ogy and Potenti al Therapeuti c Appl i cati ons. Arq Bras Cardi ol . 2008;90(5):34349. [PubMed]
30. Boucher J, Masri B, Davi aud D, et al . Apel i n, a Newl y Identi fi ed Adi poki ne Up-Regul ated by Insul i n and Obesi ty.
Endocri nol ogy. 2005;146:176471. [PubMed]
31. Castan-Laurel l I, Vi tkova M, Davi aud D, et al . Effect of hypocal ori c di et-i nduced wei ght l oss i n obese women on
pl asma apel i n and adi pose ti ssue expressi on of apel i n and APJ. European Journal of Endocri nol ogy. 2008;158:90510.
[PMC free arti cl e] [PubMed]
32. Rayal am S, Del l a-Fera MA, Kri eg PA, et al . A putati ve rol e for apel i n i n the eti ol ogy of obesi ty. Bi ochem Bi ophys
Res Commun. 2008;368:81519. [PubMed]
33. Cox CM, DAgosti no SL, Mi l l er MK, et al . Apel i n, the l i gand for the endothel i al G-protei n-coupl ed receptor, APJ, i s a
potent angi ogeni c factor requi red for normal vascul ar devel opement of the frog embryo. Dev Bi ol . 2006;296:17789.
[PubMed]
34. Rei mer MK, Paci ni G, Ahrn B. Dose-dependent i nhi bi ti on by ghrel i n of i nsul i n secreti on i n the mouse.
Endocri nol ogy. 2003;144(3):91621. [PubMed]
35. Anderwal d-Stadl er M, Krebs M, Promi ntzer M, et al . Pl asma obestati n i s l ower at fasti ng and not suppressed by
i nsul i n i n i nsul i n-resi stant humans. Am J Physi ol Endocri nol Metab. 2007;293(5):E139398. [PubMed]
36. Harsch IA, Pour Schahi n S, Radespi el -Trger M, et al . Conti nuous posi ti ve ai rway pressure treatment rapi dl y
i mproves i nsul i n sensi ti vi ty i n pati ents wi th obstructi ve sl eep apnea syndrome. Am J Respi r Cri t Care Med.
2004;169:15662. [PubMed]
37. Ip MS, Lam B, Ng MMT, et al . Obstructi ve sl eep apnea i s i ndependentl y associ ated wi th i nsul i n resi stance. Am J
Respi r Cri t Care Med. 2002;165:67076. [PubMed]
38. Harsch IA, Koebni ck C, Wal l aschofski H, et al . Resi sti n l evel s i n pati ents wi th obstructi ve sl eep apnoea syndrome
the l i nk to subcl i ni cal i nfl ammati on? Med Sci Moni t. 2004;10(9):CR51015. [PubMed]