1  

iv. javaxiSvilis saxelobis Tbilisis saxelmwifo universiteti

xelnaweris uflebiT

T a m a r z e r e k i Z e

cximovani qsovilis gadanawilebisa da kardiometaboluri

maxasiaTeblebis korelacia leptinTan

d i s e r t a c i a

doqtoris akademiuri xarisxis mosapoveblad

medicinaSi

2015 w.

avtoris stili daculia

2  

 

 

sadisertacio naSromi Sesrulebulia

 

Sps “endokrinologiis erovnuli instituti”-s bazaze

 

 

 

samecniero xelmZRvaneli - medicinis mecnierebaTa doqtori,

prof. elene giorgaZe

 

 

Tbilisi 2015 weli

3  

sarCevi

pirobiTi aRniSvnebi da Semoklebebi 4

Sesavali 5

Tavi 1 literaturis mimoxilva 16

1.1 leptinis aRmoCena 16

1.2 rezistentoba leptinis mimarT 20

1.3 leptinis genderuli dimorfizmi 24

1.4 leptinisa da naxSirwylovani cvlis

kavSiri

26

1.5 leptini da Saqriani diabeti tipi 2 29

1.6 leptini da kardiometaboluri

darRvevebis ganviTarebis riski

31

1.7

1.8

leptini da Zvlis mineraluri simkvrive

kvebis sxvadasxva stilis gavlena

leptinze

35

38

Tavi 2 gamokvlevis masala da meTodebi 41

Tavi 3 gamokvlevis Sedegebi 51

Tavi 4 gamokvlevis Sedegebis ganxilva 68

daskvnebi

praqtikuli rekomendaciebi

77

78

gamoyenebuli literatura 79

pirobiTi aRniSvnebi da Semoklebebi

4  

1. smi –sxeulis masis indeqsi

2. Tth - Tireotropuli hormoni

3. met. sindromi – metaboluri sindromi

4. dsl – dabali simkvrivis lipoproteinebi

5. msl – maRali simkvrivis lipoproteinebi

6. DXA – Dual  energy  X‐ray  absorbtiometry  (ormagenergetikuli rentgenuli

absorbciometria)

7. cns – centraluri nervuli sistema

8. hrb – hipoTalamusis rkalisebri birTvi

9. ob/ob – obese/obese

10. db/db – diabetes/diabetes

11. pomk – proopiomelanokortini

12. npγ - neiropeptidi γ

13. AgRP ‐ Agouti‐related protein 

14. gmp-1 ‐ glukagonismsgavsi-peptidi 1

15. IVF ‐ in vitro ganayofiereba

16. irs-1 – insulinis receptoris substrati 1

17. izh-1 – insulinismsgavsi zrdis hormoni 1 

 

 

 

 

 

 

 

 

Sesavali

5  

problemis aqtualoba

jandacvis msoflio organizaciis monacemebiT Warbi wona da simsuqne

msoflioSi sikvdilobis riskis mxriv mexuTe adgilzea. Warbi wonisa da

simsuqnis SedegadweliwadSi, sul mcire 2,5 milioni adamiani iRupeba

(1).Warbi wona da simsuqne zrdis iseTi sicocxlisTvis saSiSi daavadebebis

risks, rogoricaa Saqriani diabeti tipi 2(44%-mde), insulti da/an

infarqti(23%-mde) da sxvadasxva saxis simsivnuri daavadebebi(7-dan 41%-

mde)(1).aseve izrdeba sxva garTulebebis riskic, rogoricaa Zval-saxsrovani

dakunTovani daavadebebi [2]. simsuqne epidemiur maCvenebels aRwevs

msoflios TiTqmis yvela qveyanaSi, ganurCevlad ganviTarebis donisa.

jandacvis msoflio organizaciis monacemebiT 2008 wlisTvis Warbi wona

aReniSneboda 1.5 miliard zrdasruls (≥ 20 weli). aRniSnuli 1.5

miliardidan, daaxloebiT 200 milion mamakacs da 300 milion qals

aReniSneba simsuqne, rogorc ukve Camoyalibebuli daavadeba. dReisaTvis,

msoflios mosaxleobis yovel meaTe adamians aReniSneba daavadeba -

simsuqne. msgavsi sagangaSo mdgomareobaaa msoflios bavSvTa populaciaSi,

sadac 2010 wlis monacemebiT Warbwoniani bavSvebis ricxvi 5 wlamde asakSi

43 milionsSeadgens [1]. Isfaqti, rom 1980 wlidan Warbi wonisa da simsuqnis

SemTxvevebi gaormagda, sagangaSo da damafiqrebelia.

Warbi wona da simsuqne aseve dakavSirebulia metaboluri sindromis

ganviTarebasTan. Tavis mxriv, metaboluri sindromi orjer zrdis gul-

sisxlZarRvTa daavadebis ganviTarebis risks, 5-jer - Saqriani diabetisa da

2,5-jer- saerTo sikvdilianobis ganviTarebis SemTxvevebs [3].  

zemoTqmulidan gamomdinare, sakmaod mniSvnelovania Warbi wonisa da

simsuqnis prevencia. didi mniSvneloba eniWebasimsuqnis garTulebebis

adreul daignostikasa da mkurnalobas, rasac, Tavis mxriv, minimumamde

dayavs masTan dakavSirebuli daavadebebis ganviTarebis riski da

saxelmwifosa Tu kerZo piris mier gaweuli xarjebi.

6  

Warbi wonisa da simsuqnis prevenciisa da mkurnalobisTvis, aucilebelia

misi gamomwvevi mizezebis codna. Warbi wona da simsuqne cximovani qsovilis

anomaliuri an Warbi raodenobiT dagrovebis Sedegia. simsuqne kompleqsuri,

mravalfaqtoruli daavadebaa [4]. Warbi wonisa da simsuqnis ZiriTad

gamomwvev mizezad gvevlineba garemo faqtorebi (araswori kveba da umoZrao

cxovrebis wesi).darRveulia balansi energiis miRebasa da gacemas Soris.

bolo aTwleulebis manZilze mosaxleobis racionSi gaizarda iseTi

sakvebis moxmareba, romelic gamdidrebulia cximebiT, naxSirwylebiTa da

mariliT. sanacvlod, mniSvnelovnad Semcirda vitaminebiT, mineralebiTa da

mikroelementebiT mdidari sakvebis wili. Aseveizrdeba umoZrao cxovrebis

wesis mqone adamianTa ricxvi.Aamas garda, Warbi wonisa da simsuqnis

ganviTarebis erT-erT xelSemwyobfaqtorad transportis, teqnikisa da

urbanizaciis gazrdac gvevlineba.Warbi wonisa da simsuqnis ganviTarebis

aranakleb mniSvnelovan mizezs warmoadgens socio-ekonomikuri da

genetikuri faqtorebi.genetikuri winaswarganwyoba, erT-erTi yvelaze

mniSvnelovani faqtoria simsuqnis ganviTarebis meqanizmSi, rasac cxadyofs

ojaxis wevrebsa da tyupebze Catarebuli kvlevis Sedegebi [5-6]. dadgenilia,

rom simsuqnis ganviTarebis 40-70% dakavSirebulia genetikur

winaswarganwyobasTan.

cnobilia, rom madis regulaciaSicentraluri roli hipoTalamuss

ekuTvnis; hipoTalamusSi SimSilis centri ganlagebulia mis lateralur

birTvebSi, xolo maZRrobis centri ganlagebulia ventromedialur

birTvebSi. energiis homeostazis regulireba tvinis mier xdeba im

signalebis meSveobiT, romelic modis rogorc cximovani qsovilidan, ise

kuW-nawlavis traqtidan [7-9].

sul ufro meti axali kvleva cxadyofs, rom simsuqnis kidev erTi mizezi

SesaZloa iyos cximovan qsovilSi mimdinare anTebiTi procesi da/an

hormonuli cvlileba. cximovani qsovili gvevlineba sxvadasxva

metabolurad aqtiuri nivTierebebis – adipokinebis sinTezis adgilad. es

cilebi mniSvnelovan rols asruleben metaboluri procesebis

regulaciaSi, vinaidan aqvT auto- da parakrinuli moqmedeba. amas garda,

7  

isini aregulireben sxvadasxva organoTa sistemis muSaobas, anu avlenen

tipiur endokrinul aqtivobas. erT-erT aseT adipokins warmoadgens

leptini. Sesabamisad cximovani qsovili mniSvnelovani endokrinuli

organoa.cximovan qsovilSi gamomuSavebul Tavisufal cximovan mJavebsa da

adipokinebs mniSvnelovani gavlena aqvT glukozis homeostazze.

adipocitebi nawilobriv monawileoben insulinis mimarT mgrZnobelobis

regulaciaSi, ris gamoc gvevlinebian simsuqnesa da insulinrezistentobas

Soris damakavSirebel rgolad [10, 11]. simsuqniT gamowveuli hormonebisa da

anTebiTi citokinebis sekreciis darRvevam, SesaZloa gavlena iqonios

metaboluri garTulebebis ganviTarebaze [12].

cximovani qsoviliTavisi aRnagobiT, SemadgenlobiT sakmaod saintereso

endokrinuli organoa. mniSvnelovani gansxvavebaa kanqveSa da visceralur

cximovan qsovils Soris. visceralur cximovan qsovilSi gamomuSavebuli

hormonebi gadadian karis venis mimoqcevaSi da aqvT pirdapiri gavlena

RviZlSi mimdinare metabolur procesebze. kanqveSa cximovan qsovilSi

producirebuli nivTierebebi ki xvdebian sistemur cirkulaciaSi. kanqveSa

da visceralur cximovan qsovils Soris gansxvaveba receptorebis

ganlagebaSic SeimCneva. aRniSnulidan gamomdinare, cximovani qsovili

heterogenuli organoa; misi sekretoruli funqcia damokidebulia sakuTar

zedapirze arsebuli receptorebis lokalizaciaze [13-15].

sworedaRniSnulis gamo centralurad ganlagebuli cximovani qsovili,

romelic xSirad gvxvdeba simsuqnis dros, mWidrod korelirebs sxvadasxva

metabolur garTulebebTan.

leptins mniSvnelovani adgili uWiravs sxeulis masis regulaciaSi. misi

raodenoba sxeulis cximovani qsovilis pirdapirproporciulia, cximovani

qsovili ki,Tavis mxriv, gavlenas axdens leptinis doneze. amasTan, sxva

faqtorebi, rogoricaa maRalkaloriulida Warbi odenobiT sakvebis miReba,

Zili, sxeulis temperatura, sqesi, cirkaduli riTmi da sxva hormonebi, maT

Soris insulini, zrdis hormoni, glukokortikoidebi, testosteroni da

farisebri jirkvlis hormonebi, moqmedeben leptinis sekreciasa da

eqspresiaze.

8  

SratSi leptinis gazrdili done upiratesad gvxvdeba simsuqnisa da

cximovani qsovilis abdominur midamoSi Calagebis dros da is warmoadgens

damoukidebel risk-faqtors metaboluri darRvevebisganviTarebisa [16-18].

leptinis aRmoCenidan garkveuli periodis Semdeg, man yuradReba miipyro,

rogorc ara marto cximovani masis maregulirebeli erT-erTi komponenti,

aramed rogorc cximovani qsovilis mier Zvlovani qsovilis dacvis

savaraudo mediatori. Zvlovan qsovilze simsuqnis dacviTi gavlenis

mizezad didi odenobiT cximovani qsovili miiCneoda.cnobilia, rom

leptinis produqcia xdeba cximovani ujredebis mier da is pirdapir

asaxavs cximovani qsovilis odenobas organizmSi. didi xnis manZilze iyo

gavrclebuli mosazreba, rom simsuqniT daavadebul pirebs koronaruli

daavadebebis ganviTarebismaRali albaToba aqvT, Tumca dabali aqvT

osteoporozis ganviTarebis riski.dReisaTvis leptinsa da Zvlovan

sistemaze Catarebuli kvlevebis Sedegebi gansxvavebulia; kerZod, leptini

avlenda rogorc dadebiT, ise uaryofiT efeqts an araviTarigavlena ar

hqonda Zvlis mineralur simkvriveze.rigi kvlevebis Tanaxmad leptini wonis

matebasTan erTad xels uwyobs Zvlis simkvrivis gazrdasac. leptinis

absoluturi deficitis dros ob/ob virTagvebisTvis leptinis Seyvana wonis

klebasTan erTad amcirebda Zvlis simkvrivesac. rigi kvlevebis Tanaxmad

Warbi cximovani qsovili SesaZloa ar warmoadgendes damcav meqanizms,

Zvlis simkvrivis daqveiTebis winaaRmdeg [19].

rac ufro maRalia smi an welis garSemoweriloba, miT ufro metia Sratis

leptinis done [20]. Sratis leptinis momatebuli done dakavSirebulia

kardiometabolur risk- faqtorebTan, rogoricaa hipertenzia, insulinis

mimarT rezistentoba da Saqriani diabeti tipi 2 [21-28]; im kvlevebis

Sedegebi, romelSicikvleven leptinis kavSirs metabolur

markerebTangansxvavebulia[29-31]. upiratesad aseTi saxis kvlevebi

Catarebulia socio-ekonomikurad mZlavr qveynebSi. ganviTarebad qveynebSi

maTi ricxvi mcirea. saqarTveloSi ki msgavsi xasiaTis kvleva jer ar

Catarebula. saqarTveloSi leptinsa da Zvlis simkvrivis daqveiTebiT

mimdinare daavadebebs Soris kvleva ar Catarebula.

9  

aqedan gamomdinare, Cveni kvlevis mizania davadginoT:

leptinisgavlena metabolur maxasiaTeblebze, kardiometabolur risk-

faqtorebsada Zvlis mineralur simkvriveze20-dan 70 wlis asakis mqone

qarTvel qalebSi.

10  

kvlevis amocanebi:

kvlevis mizanis gansaxorcieleblad daisaxa Semdegi amocanebi:

1. Sratis leptinis saSualo ariTmetikuli maCveneblis gansazRvra

sakontrolo jgufSi, romelsac sxeulis normaluri masis mqone

pirebi Seadgenda;

2. Warbi wonis an/da simsuqnis mqone pacientebis gamokvleva, Sratis

leptinis saSualo ariTmetikuli maCveneblisdasadgenad;

3. aRniSnuli pacientebisTvis im parametrebis gamokvleva, romelic

zrdis kardiometaboluri darRvevebis risks.

4. sxeuliskompoziciis gansazRvra, romelic moicavs cximovani,

kunTovani da Zvlovani qsovilis raodenobis Sefasebas.

5. leptinsa da kardiometabolur risk-faqtorebs Soris korelaciis

gamovlena.

6. leptinsa da sxeulis kompozicias Soris korelaciis gamovlena.

7. Leptinsa daZvlis mineralur simkvrives Soris korelaciis dadgena.

8. kvebis sxvadasxva stilis gavlenis Seswavla leptinis donesa da

wonaze (kg), iseve rogorc maTi efeqturobis Sedareba.

11  

naSromissamecniero siaxle

kvlevis Sedegad SesaZlebeli gaxda leptinis saSualo

ariTmetikuli donis gansazRvra da misi kavSiris dadgena

metabolur darRvevebTan rogorc normaluri wonis, ise Warbi

wonisa da simsuqnis mqone 20-70 wlis qarTvel qalebSi.

aRniSnuli kvleva pirvelia saqarTveloSi, romelic gamoavlens

ara marto leptinis korelacias kardiometabolur risk-

faqtorebTan, aramed mis kavSirs cximovani qsovilis gadanawilebis

Taviseburebebsa da Zvlis mineralur simkvrivesTan.

aRniSnuli kvleva pirvelia saqarTveloSi, romelic ikvlevs

kvebissxvadasxva stilis gavlenas leptinis doneze.

12  

naSromis praqtikuli Rirebuleba

aRniSnuli kvlevasaSualebas mogvcems davadginoT hiperleptinemiiskavSiri

metaboluri darRvevebis ganviTarebis riskTan normaluri wonis, Warbi

wonisa da simsuqnis mqone pirebSi.asevegamovavlinoTleptinis korelacia

Zvlis mineralur simkvrivesTan, da ganvsazRvroT warmoadgens Tu ara

igimotexilobis ganviTarebis prediqtors da SevadaroT sxvadasxva kvebiTi

komponentisgan Semdgari dietis gavlenaleptinis doneze.

13  

disertaciis dasacavad gasatani ZiriTadi debulebebi

1.gamovlindakorelacia Sratis leptinsa da smi-s Soris. smi-is zrdasTan

erTad izrdeba Sratis leptinis done 20-70 wlis asakis mqone qarTvel

qalebSi.

2. Sratis leptini dadebiTad korelirebs iseT kardiometabolur risk-

faqtorebTan rogoricaa, welis garSemoweriloba, sistoluri da

diastoluri arteriuli wneva, abdominuri simsuqne, trigliceridebis,

dabali simkvrivis lipoproteinebisa da glukozis done uzmod.

3. Sratis leptinis donis zrdasTan erTad mcirdeba Zvlis mineraluri

simkvrive zrdasrul qalebSi.

4. naxSirwylovani sakvebis SezRudva sakveb racionSiufro metad aqveiTebs

leptinis dones, cximebiT Rarib dietasTan SedarebiT

14  

sadisertacio Temis garSemo gamoqveynebuli publikaciebis sia:

1. Bлияние лептина на минеральную плотность костив пременопаузе и постменопаузе

(Шанава Ш.Г., Зерекидзе Т.В., Амашукели М. Т., Асатиани К. А.,

GeorgianMedicalNews);

2. Serum Leptin Concentration with Body Fat Distribution in Georgian Population”; First 

International Diabetes and Obesity Forum, Athens, Greece, 21‐23 of October 2010,

poster presentation;

3. Androgen Deficiency and insulin resistance in obese male patients; First International 

Diabetes and Obesity Forum, Athens, Greece, 21‐23 of October 2010);

4. hiperleptinemia da kardiometaboluri maxasiaTeblebi; T. zerekiZe, S.

janjRava, l. uCava, q. asaTiani, e. giorgaZe; eqsperimentuli da

klinikuri medicina #4, 2014, gv. 57-63;

5. androgendeficiti da insulinrezistentoba simsuqniT daavadebul

mamakacebSi, S. janjRava, l. uCava, e. giorgaZe, q. asaTiani, T.

zerekiZe; #4, 2014, gv. 70-77;

6. Hyperletinemia May Protect From Cardio‐vascular Complications: A Small Georgian Study; 

T. Zerekidze, Sh. Janjgava, K. Asatiani, E. Giorgadze; Maced J Med Sci; doi. 

org/10.3889/MJMS.1857‐5773.2014.0433; 

7. Influence of testosterone replacement therapy on metabolic disorders in male patients 

with type 2 diabetes mellitus and androgen deficiency.Janjgava S, Zerekidze T, Uchava L, 

Giorgadze E, Asatiani K.Eur J Med Res. 2014 Oct 23;19(1):56. 

15  

sadisertacio naSromis struqtura da moculoba

sadisertacio naSromi gadmocemulia qarTul enaze,94nabeWdgverdze da

Sedgeba Semdegi Tavebisgan: Sesavali, literaturis mimoxilva, gamokvlevis

masala da meTodebi, sakuTari kvlevis Sedegebi, sakuTari kvlevis Sedegebis

ganxilva, daskvnebi, praqtikuli rekomendaciebi; citirebulia

245gamoyenebuli literaturis wyaro. sadisertacio naSromi moicavs10

cxrils, 2 suraTs da 12 grafiks.

16  

Tavi 1. literaturis mimoxilva

1.1 leptinis aRmoCena

leptini upiratesad TeTri cximovani ujredebis mier sinTezirebuli

hormonia [32-33]. Tumca,leptinis sinTezi aseve xdeba: rux cximovan qsovilSi,

placentaSi (sincitiotrofoblastebi), sakvercxeebSi, kunTovan qsovilSi,

kuWSi (fundusi da P/D1 ujredebi), sarZeve jirkvlis epiTelur ujredebSi,

Zvlis tvinSi, hipofizsa da RviZlSi [34‐37].

Hhormoni leptini aRmoaCines 1994 wlis dekemberSi.Friedman-is jgufma

moaxdina simsuqnis (ob) genis klonireba, romelic pasuxismgebelia

simsuqnis, diabetisa da insulinrezistentobis mqone ob/ob virTagvebis

fenotipze [38].maleve aRmoaCines am genis cilovani produqti da plazmaSi

misi koncentraciis gansazRvris meTodebic SemuSavda [39]. obgenis am

produqts leptini ewoda, rac warmosdgeba berZnuli sityva “leptos”-idanda

Txels niSnavs; saxelwodeba SeirCa im funqciis aRsaniSnavad, romelsac

maTi azriT es hormoni asrulebda. am aRmoCenis Semdeg daiwyo mravali

kvleva, raTa sxeulis masis regulaciaSi gansazRvruliyo leptinis

funqcia; am kvlevebis mizani adamianis simsuqnis paTofiziologiis axsna

iyo.

mravali kvleva da dagrovili masala adasturebs, rom leptini

mniSvnelovania ara marto sakvebis miRebisa da energiis balansis

regulaciaSi, aramed mas rigi sxva metaboluri da neiroendokrinuli

gavlena aqvs. misi monawileobiT mimdinareobs normaluri seqsualuri

ganviTareba da reproduqcia; is aseve urTierTqmedebs hipoTalamo-hipofiz-

Tirkmelzeda jirkvlis RerZTan, farisebri jirkvlisa da zrdis

hormonebTan, aseve mas gavlena aqvs glukozis metabolizmze; amas garda,

leptinskavSiri aqvs hematopoezTan, imunur da Zvlovan sistemasTan.

isawvdis informacias Tavis tvins cximovani qsovilis raodenobis Sesaxeb.

mas xatovnad cximovani qsovilis “xmasac” uwodeben. aqve unda aRiniSnos,

17  

rom misi moqmedeba xorcieldeba uaryofiTi ukukavSiris principiT.

leptinis funqciaa gansazRvrul doneze sxeulis cximovani maragis

SenarCuneba. mocirkulire leptinis done mWidro kavSirSia cximovani

qsovilis maragTan [38], rac gulisxmobs, rom cximovani qsovilis masis

mateba zrdis leptinis gamomuSavebas, Sesabamisad ki iTrgunebasakvebis

miReba da piriqiT. leptinis makodirebeli genis an misi receptoris

mutaciis dros, virTagvebsa da adamianebSi aRiniSneba morbiduli simsuqnis

adreuli Camoyalibeba [40-44]. dRemde leptinis ukmarobiT gamowveuli

monogenuri simsuqnis mxolod ramdenime SemTxvevaadafiqsirebuli, rac

sakmaod kargad eqvemdebareba rekombinantuli leptiniT mkurnalobas [45-46].

virTagvebis wonis regulaciaSi leptinis roli uaryofiTi ukaukavSiris

ciklSi kargad aris Seswavlili, rasac ver vityviT adamianebze. bolomde

yvelaferi naTeli ar aris. aRsaniSnavia, rom simsuqnis mqone pirebis

umetesobas leptinis done momatebuli aqvs, Tumca es momateba cximovani

masis daklebas ar iwvevs [47-49]. amavdroulad, simsuqnis mqone pirebisTvis

egzogenurad leptinis Seyvana ar amcirebs wonas, es ki miuTiTebs imaze,

rom simsuqnis mqone pirebi leptinis gavlenis mimarT rezistentulni arian

[50].

yovelive zemoTqmuli imaze metyvelebs, rom leptinis ZiriTadi funqcia

mxolod wonis matebis SeferxebaSi ar mdgomareobs. savaraudoa, rom

aRniSnuli sistema ufro cximovani qsovilis maragis Seqmnas ganapirobebs,

vidre misxarjvas. swored amitom, rigi mkvlevaris azriT, leptinis

ZiriTadi fiziologiuri moqmedebaar aris “maZRrobis signalis”

gadacemasimsuqnis prevenciisaTvis.aramed “SimSilis signalis” gadacemaa,

raTa energiis deficitis dros organizmis dasacavad SeinarCunos sakmarisi

cximis maragi [51].

leptinisa da misi receptoris ukmarobisdrosSeiniSnebaerTnairi

fenotipi.esgamoxatuleba gacilebiT ufro naklebia leptinis receptoris

ukmarobis SemTxvevaSi[52]. aseve, leptinis receptoris deficiti SedarebiT

ufro gavrcelebulia da morbiduli simsuqnis yvela SemTxvevis

daaxloebiT 3%-sSeadgens.

leptinis funqciebidan pirvelad aRweres misi gavlena wonis regulaciaze;

adamianebSi misi done mniSvnelovnad korelirebs smi-sa da cximovan

masasTan [40-43]. leptinis sekrecia xdeba adipocitebis mier pirdapir

sisxlis mimoqcevis sistemaSi [42-46]; mas tvinSi miaqvs informacia

organizmSi arsebuli cximovani masis Sesaxeb (sur 1). es hipoTeza

dadasturda kvleviT, sadac ob/ob leptinis deficitis mqone virTagvebSi

leptinis Seyvanam miRebuli sakvebis raodenobis Semcireba da energiis

xarjvis gazrdagamoiwvia [46-49]. normalur virTagvebSicki, msgavsi

Sedegiiqna miRebuli, Tumca, gacilebiT sustad gamoxatuli vidre ob/ob

virTagvebis SemTxvevaSi [47-50].

suraTi 1: leptini centralur nervul sistemaze moqmedebs an pirdapir an

garkveuli centrebis aqtivaciis gziT. is amcirebs sakvebis miRebas, zrdis

energiis xarjvas, gavlenas axdens glukozis da cximis metabolizmze da

cvlis neiroendokrinul aqtivobas.

aRmoCenidan Zalian male moxda leptinis receptorebis klonireba da

aRniSnuli receptorebisgamovlena qorionul wnulsa da hipoTalamusSi; es

is regionebia, romelic monawileobs madis regulaciaSi, sakvebis miRebasa

18  

19  

da sxeulis masis normalizaciaSi [51-55]. Semdgom moxda im gzebis aRmoCenac,

romliTac leptini axorcilebda Tavis moqmedebas cns-ze.dReisTvis

cnobilia, rom leptini Tavis tvinSi urTierTqmedebs TiTqmis yvela

neiropeptidTan, romelic CarTulia energiis regulaciasa da

gansakuTrebiT kvebiT procesSi. hipoTalamusis rkalisebribirTvi (hrb)

leptinis ZiriTadi samizne ubania [56-57]. hrb-Si gvxvdeba neironebis ori

klasi: pirveli klasi warmodgenilia proopiomelanokortiniTa (pomk) da

kokain/amfetamin-dakavSirebuli transkriptiT, rac amcirebs sakvebis

miRebas, maSin roca meore klasi warmodgnilia ori peptidiT: neiropeptidi

γ(npγ)da AgRP (agouti‐related protein), romlebic astimulireben kvebiT qcevas [58-

59]. leptinis receptorebi didi raodenobiT gvxvdeba orive klasis

neironebze, rac mas saSualebas aZlevs reciprokulad areguliros orive

procesi, rogorc sakvebis miRebis Semcireba, ise misi stimulacia.

hipoTalamusis rkalisebr birTvSi leptini ainhibirebs neiropeptid Y-s (npγ)

sekrecias [60] da paraventrikulur birTvze zrdis kortikotropin

rilizing hormonis eqskrecias [61]. leptinis sapasuxo reaqciaSi CarTulia

sxva gzebic: glukagonis-msgavsi-peptidi 1-is (gmp‐1) sistema, pre-

opiomelanokortinis sistema, neironebi, sadac xdeba oreqsinebis an

hipokretinebis eqspresia, kokain- da amfetamin-maregulirebel transkripti

da galanini [62].

leptinis receptori aris erTSriani cila, romelic struqturulad klasi

I citokinebis receptorebis ojaxis msgavsia [63, 64]. arsebobs leptinis

receptoris (ObR)  ramdenime gansxvavebuli izoforma [63], TiToeuli

damaxasiTebeli ujredSida domeniT. swored ujredSida domenis sigrZis

mixedviT izoformebi iyofa mokle da grZel izoformad. mokle izoformas

(ObRa, ObRb, ObRc, ObRd, ObRe da ObRf) aqvs SezRuduli sasignalo unari, maSin

roca grZeli izoforma ObRb, savaraudod receptoris ZiriTadi sasignalo

formaa [63, 65, 66]. mokle izoformaObRa da ObRc didi raodenobiT gvxvdeba

tvinis mikrosisxlZarRvebze, rac warmoadgens hemato-encefalur bariers da

ZiriTad rols asruleben cns-sken leptinis transportSi [67]. savaraudod,

mokle izoforma leptinis transports imonawileobs, Tumca misi moqmedeba

20  

jerjerobiT kvlav ucnobia [68]. receptoris grZeli izoforma, ObRbdidi

odenobiT gvxvdeba hipoTalamusSi da swored misi meSveobiT leptini

axorcielebs Tavis moqmedebas energiis homeostazze[66, 69]. ObRb-s

membranuli eqspresia nawilobriv regulirdeba OB‐R genTan SeWiduli

ciliT[70].swored funqciuri ObRb-s ukmarisobaa pasuxismgebeli simsuqnesa

da metabolur sindromze, romelic nanaxia db/db virTagvebis modelSi [71].

mas Semdeg rac aRmoaCines, rom virTagvebis leptinis genis mutacia

ganapirobebda ob/ob  fenotips, daibadaaseTiSekiTxva: SeeZlo Tu ara

adamianebSi msgavs mutacias gamoewvia simsuqne?molekuluri skriningis

monacemebis Tanaxmad, leptinis makodirebeli geni simsuqnis mqone pirebis

umetes nawilSi normis farglebSia [72-76]. 2000 wlamde leptinis genis

mutaciiT mxolod ori ojaxi iyo gamovlenili - leptinis Tandayolili

deficitiT [77-79].yvela maTgans aReniSneboda morbiduli simsuqnis

adreuli Camoyalibeba, Warbi cximovani masis miuxedavad leptinis Zalian

mcire done, gamoxatuli hiperfagia da hiperinsulinemia. adamianis

rekombinantuli leptiniT mkurnalobis Sedegad miaRwies wonis klebasa da

yvela metaboluri darRvevis gaumjobesebas [80]. am pacientebis heterozigot

ojaxis wevrebs ar aReniSneboda morbiduli simsuqne da maTi leptinis

donec normis farglebSi iyo.

1.2. rezistentoba leptinis mimarT

leptinis mimarT rezistentoba terminia, romelic organizmis mier

leptinis aRqmis darRvevas aRwers; simsuqnis mqone pirebSi is aseve

aRniSnavs leptinis momatebul dones. arsebobs rigi molekuluri

meqanizmebisa, romelic aRwers leptinis mimarT rezistentobis fenomens. is

moicavs molekuluri da funqciuri darRvevebis farTo speqtrs.

Gamoyofenleptinis mimarT rezistentobis ganviTarebis Semdeg meqanizmebs: a)

leptinis transportis darRveva sisxlidan tvinamde da b) leptinis

receptoris funqciisa da sasignalo Tvisebebis darRvevas. simsuqnisTvis

damaxasiaTebeli qronikulad momatebuli leptinis done amcirebs leptinis

21  

transports cns-ken da arRvevs leptinis receptoris sasignalo Tvisebebs.

AmisSedegad, leptinis mimarT rezistentoba zrdis sakvebiT-gamowveuli

simsuqnis ganviTarebas, rac, Tavis mxriv, zrdis leptinis dones da kidev

ufro auaresebs leptinis mimarT rezistentobas; yalibdeba wonis matebis

mankieri wre. aqedan gamomdinare, leptinis mimarT rezistentoba gvevlineba

simsuqnis gamomwvev rogorc mizezad, ise mis Sedegad [81, 82].

garkveulmakvlevebma aCvena, rom hematoencefaluri barieri leptinis mimarT

rezistentobis gaCenis sakvanZo ubania [83-85]. molekuluri masiT 16 kda,

leptini Zalin didiaimisaTvis, rom gaiaros transmembranuli barieri

difuziis gziT, amitomac tvinSi najeri satransporto sistemiT

transportirdeba.leptinis tranporti mTel cns-Sixdeba, Tumca

dakavSirebis yvelaze intensiur ubnad hipoTalamusis hrb-i gvevlineba. cns-

Si leptinis transportze ramodenime faqtorimoqmedebs. mag: α-adrenerguli

stimulacia aZlierebs transports [86], maSin roca hipertrigliceridemia

mniSvnelovnad aqveiTebs mas [87]. hipertrigliceridemia aRiniSneba SimSilis

dros. am SemTxvevaSi mowodebuli hipoTezis Tanaxmad, trigliceridebs aqvT

leptinis transportis inhibirebis unari, rac savaraudod sakvebis

deficitis dros organizmis damcavi meqanizmia. hipertrigliceridemia aseve

asocirdeba simsuqnesTan; am dros leptinis transportis darRveva

savaraudod dakavSirebulia leptinis mimarT periferiul rezistentobasTan

[83-85]. periferiuli rezistentoba, centraluris msgavsad, simsuqnis

ganviTarebis rogorc mizezi, ise Sedegia da gulisxmobs, rom savaraudod

erTdroulad gvxvdebaori tipis rezistentoba (periferiuli da

centraluri); rogorc ki es ori tipis rezistentoba Camoyalibdeba, maSinve

iqmneba wonis matebis mankieri wre [83-85].

Teoriulad leptinis mimarT rezistentoba SeiZleba leptinis sasignalo

gzebis sxvadasxva doneebze ganviTardes [89].es doneebia: receptoris done,

SemakavSirebel cilasTan dakavSirebis darRveva, hematoencefaluri

barieris gavliTtransportis darRveva da post-receptoruli defeqtebi.

22  

leptinis mimarT rezistentoba SesaZloa iyos receptoris defeqtis

Sedegi; es defeqti iwvevs leptinis SekavSirebis darRvevas mis

receptorTan. adamianebSi aseTi defeqti sakmaod iSviaTia [89-91]. am mutaciis

mxolod erTi SemTxvevaa aRwerili [88]. ufunqcio receptori sicocxlis

pirvelive TveSi morbiduli simsuqnis Camoyalibebas, hiperfagias,

pubertuli ganviTarebis Seferxebas da zrdis hormonisa da Tireotropuli

hormonis sekreciis darRvevasiwvevs. am mutaciis dros leptinis done

mkveTrad maRalia ojaxis sxva wevrebSi: ojaxis homozigot wevrebSi 500-dan

700 ng/ml-mde, xolo heterozigotebSi 145-dan 362 ng/ml-mde [88].

leptinis receptorTan dakavSirebuli mutaciebi aseve moicavs [89, 90, 92-

96], receptoris SemakavSirebeli an sasignalo Tvisebebis cvlilebebs.

Tumca, am kuTxiT kvlevebi ar moipoveba.

leptinis mimarT rezistentobis aseve SesaZlo meqanizmia, disbalansi

sisxlis SratSi mocirkulire leptinsa da mis SemakavSirebel cilas

Soris. Tu leptinis SemakavSirebeli cila sisxlSi Zalian didi

raodenobiTaa, maSin es aqveiTebs hormonis biologiur moqmedebas.naCvenebia,

rom adamianebSi SekavSirebuli leptinis Sefardeba Tavisufal leptinTan

gamxdar da simsuqnis mqone pirebSigansxvavebulia; Tavisufali leptinis

done dadebiTad korelirebs smi-Tan [97].

leptinis mimarT rezistentoba, aseve SesaZloa gamoiwvios leptinis

darRveulma transportma hematoencefaluri barieris gavliT. cnobilia,

rom am transportSi monawileobs leptinis receptoris mokle izoforma

[98-100], romelic gansakuTrebiT maRali sixSiriT qorionul wnulSi

gvxvdeba [99, 101]. virTagvebSi am saxis rezistentobis dros, leptinze

sapasuxo reaqcia ar warmoiqmneba, maSin roca organizmi egzogenur

leptinze reagirebs (102). adamianebSi naCvenebia, rom leptinis Sefardeba

Tavzurgtvinis siTxesa da Sratis leptins Soris qveiTdeba simsuqnis mqone

pirebSi [99, 100]. amitom leptinis Tavzurgtvinis siTxeSi Sesvlis sxvaoba

mniSvnelovania simsuqnis garkveuli formebis paTogenezis asaxsnelad; Tu

Sratis leptins ar ZaluZs miaRwios misi moqmedebis ubans, is ver gazrdis

leptinis koncentracias centralurad; Sedegad ki dairRveva samizne

ubanSisignalis gadacema.

leptinis mimarT rezistentoba SesaZloa gamoiwvios aseve post-

receptorulma defeqtma;

suraTi #: 2 leptinis mimarT rezistentobis sqematuri gamosaxuleba da

masSi sakvebi nivTierebebis mniSvneloba.

Warbi wonisa da simsuqnis mqone pirebs Sratis leptinis maRali done

aReniSneba.Tavisuflad mocirkulire leptinis didi raodenoba ar iwvevs

kaloriebis miRebis Semcirebasa da energiis xarjvis gazrdas, anu saqme

gvaqvs leptinis rezistentobasTan.wonis kleba asocirdeba leptinis donis

23  

24  

daqveiTebasTan, leptinis receptoris raodenobis momatebasTan da

mocirkulire Tavisufali leptinis koncentraciis SemcirebasTan.

1.3. leptinis genderuli dimorfizmi

adamianebSi leptinis aRmoCenisTanavecnobili gaxda, rom leptinis doneebs

Soris arsebobs genderuli dimorfizmi. leptinis done qalebSi 2-3-jer

ufro maRalia, vidremsgavsi smi-is mqone mamakacebSi [2, 5]. am gansxvavebas,

SesaZloa safuZvlad udevs gansxvavebuli sxeulis agebuleba; qalebs,

rogorc wesi,cximovani qsovilis ufro maRali procenti da kanqveSa

cximovani qsovili/visceraluri cximis ufro maRali Tanafardoba

aReniSneba. rogorc cnobilia, Sratis leptini mWidrodaa dakavSirebuli

cximovan masasTan da kanqveSa cximTan [103-108]. SesaZloa qalebisTvis

damaxasiaTebeli Warbi cximovani masa da gansakuTrebiT kanqveSa cximi,

ganapirobebs leptinis SedarebiT maRal dones.sainteresoa is faqti, rom

smi-is koreqciisas [109, 110, 111], cximovani masis [112-114] da kanqveSa cximovani

qsovilis [112] daqveiTebis Semdegac, leptinis done mainc gansxvavebulia da

qalebSikvlav maRali rCeba. leptinis donis genderuli sxvaoba

dabadebisTanaveSeiniSneba. [115-118]; gansxvaveba gansakuTrebiT TvalsaCinoa

pubertatis asakSi [118-123].leptinis donis aseTi sxvaoba gogonebsa da

biWebSi nawilobriv aixsneba pubertatis dros gansxvavebuli sxeulis

agebulebiT: gogonebSi ufro metia cximovani qsovili, xolo vaJebSi

sWarbobs kunTovani masa, gansakuTrebiT gviani pubertatis dros.

adamianebSiSeiniSneba leptinis sekreciis progresuli zrda, romelic

kulminacias sqesobrivi momwifebis periodSiaRwevs. gogonebSi, leptinis

done progresulad izrdeba 5-dan 15 wlamde, maSin roca biWebSi, leptinis

donis zrda 5-dan 10 wlamdexdeba, xolo 13 wlis asakisTvis

daqveiTebasiwyebs. amas adasturebs kvleva, romelSic xdebodaleptinis

donis kvleva vaJebSi.kvlevis Tanaxmad leptinis done yvelaze maRal

maCvenebels pubertatis dawyebis momentSiaRwevs, xolo adreuli pubertatis

Semdeg prepubertul dones ubrundeba [124]. ganviTarebis es cvlileba,

25  

ganapirobebda biWebSi Sratis testosteronis, xolo gogonebSi

estradiolis donis matebas. SesaZloa, rom leptini aris is metaboluri

barometri, romelic cns-s atyobinebs, rom organizmi mzadaa pubertuli

ganviTarebis dawyebisTvis.

rigi kvlevebis Tanaxmad, leptinis genderul sxvaobaSi cximovani qsovilis

garda sxva faqtorebsac eniWeba mniSvneloba, mag: rogoricaa sasqeso

steroidebi. es damtkicebulia in  vitro  eqsperimentebiTa da adamianebze

Catarebuli sxva kvlevebis monacemebiT. leptinis genderuli sxvaoba

aixsneba sasqeso hormonebis gansxvavebuli moqmedebiT, gansakuTrebiT,

testosteronis mainhibirebeli efeqtiT, rac emateba sxeulis agebulebis

gansxvavebebs, kerZod,qalebSi meti kanqveSa cximia, romelic met leptins

gamoimuSavebs [125].

naCvenebia, rom in  vitro, estrogenebi astimulireben adipocitebidanleptinis

sekrecias [126, 127]; es efeqti, mxolod qalebis cximovan ujredebSia nanaxi

[128]. amasTan aRsaniSnavia, rom leptinis done qveiTdeba ovareqtomirebul

virTagvebSi da sawyis maCvenebels estradioliT CanacvlebiTi mkurnalobis

Semdeg ubrundeba [127, 130]. adamianebSi, egzogenuri

folikulmastimulirebeli hormonis Seyvana IVF‐s (in vitro ganayofierebis)

dros estrogenTan erTad zrdis leptinis dones [131, 132].

estrogenebisgan gansxvavebiT, androgenebs leptinze mainhibirebeli

moqmedebaaqvs. testosteroni adamianis cximovani ujredebidan Trgunavs

leptinis eqspresias da sekrecias [129]. virTagvebSi testosteronis Seyvana

amcirebs leptinis eqspresias [133]. aTletebis mier anaboluri androgenuli

steroidebis moxmareba mniSvnelovnad amcirebs leptinis dones [134], maSin

roca, amave aTletebSi an biWebSi naadrevi pubertatiT testosteronis

produqciis supresia, gonadotropin-rilizing hormonis agonistis SeyvaniT,

piriqiT, zrdis leptinis dones [134, 135]. hipogonadur mamakacebs aReniSneba

leptinis momatebuli done [136], romelic testosteronis SeyvaniT mcirdeba

[137].

26  

1.4. leptinisa da naxirwylovani cvlis kavSiri

leptinsa da insulins Soris arsebuli kavSiri SemTxveviTi aRmoCenis

Sedegia.sxeulis cximovani qsovilis masis da miuxedavad uzmod Sratis

leptinsa da insulins Soris korelacia gamovlinda [138, 139,140-142]. am

korelaciis Semdeg daibada SekiTxva -arsebobs Tu ara mizez-Sedegobrivi

kavSiri, da Tu arsebobs, romeli mimarTulebiT? Ddasazustebeli iyo

regulirdeboda Tu ara leptinis sekrecia insuliniT, Tu leptini axdenda

zegavlenas insulinis sekreciasa da efeqtebze.

mraval wyaroze dayrdnobiT, SegviZlia vTqvaT, rom insulins SeuZlia

leptinis eqspresiis regulireba. izolirebul adipocitebze Catarebuli

kvlevebis Tanaxmad, in  vitro,  insulini astimulirebs leptinis m-rnm-is

eqspresiasa da sekrecias, rogorc virTagvebis, ise adamianis adipocitebSi

[143-147]. amas garda, virTagvebze Catarebulma eqsperimentebma aCvena, rom

insulini iwvevs cximovan qsovilSi ob m-rnm-is gazrdas [143, 148-149] da

plazmis leptinis donis matebas [150; 151]. im virTagvebSi, romelTac

aReniSneboda insulinis deficiti, streptozotocinis zegavlenis Sedegad

leptinis donec mniSvnelovnad daqveiTebuli hqonda: rodesac am

streptozotociniT namkurnalev cxovelebs ukeTebdnen insulinis ineqciebs,

leptinis sekrecia kvlav izrdeboda [148, 151, 152]. analogiurad, insulinis

deficitis mqone diabetian virTagvebSic plazmis leptinis Semcirebuli

done izrdeba insuliniT mkurnalobis sapasuxod [152].

adamianebze Catarebul eqsperimentebSi, hiperinsulinemia iwvevs leptinis

koncentraciis matebas, magram mxolod garkveuli periodis Semdeg [143, 151-

153] da ara momentalurad (varaudia postprandialur hiperleptinemiaze) [138,

153, 154, 155]. RogorcSaqriani diabetitipi 1, aseve tipi 2 dros,

insulinoTerapia zrdis Sratis leptinis dones [140, 156].aseve

dafiqsirebulia insulinomis erTi SemTxveva leptinis sagrZnoblad maRali

doniT; insulinomis qirurgiuli mkurnalobis Sedegad Semcirda rogorc

insulinis, ise leptinis done [157]; am SemTxvevamac kidev erTxel gausva

xazi, rom qronikuli hiperinsulinemia zrdis leptinis eqspresias.

27  

mosazreba, imis Taobaze, rom leptini insulinis sekreciisa da aqtivobis

modulatoria, rac insulinisa da glukozis donis daqveiTebas iwvevs, sul

ufro popularuli xdeba da mtkicdeba mravlobiTi kvlevebiTa da

eqsperimentebiT. hiperglikemiis, hiperinsulinemiisa da

insulinrezistentobis mqone ob/ob virTagvebis leptiniT mkurnalobam

SesaZloa moawesrigos yvela aRniSnuli metaboluri darRveva; Tanac imaze

gacilebiT ufro adre, vidre wonis kleba daiwyeba [46, 60, 158]. amas

adasturebs eqsperimenti, sadac nakveb da mSier virTagvebs egzogenurad

Seuyvanes leptini; pirvel jgufSi (nakvebi virTagvebi) leptinis Seyvanam

plazmis insulinis donis daqveiTeba da masTan asocirebuli hiperglikemia

gamoiwvia [159, 160]; meore jgufSi (mSieri virTagvebi) ki leptinis daniSvnam,

rogorc glukozis, ise insulinis donis daqveiTeba gamoiwvia [161, 162].

savaraudod am SemTxvevaSi leptini gavlenas axdens insulinis funqciasa

da sekreciaze.cxovelebSi, leptinis unari daTrgunos insulini SesaZloa

iyos simpaTikur inervaciaze misi gamaaqtivebeli moqmedebis Sedegi [163].

aRsaniSnaviais faqti, rom leptinis funqciuri receptorebi nanaxia

pankreasis β ujredebze [164]. SesaZloa swored es receptorebi

ganapirobebdnen insulinis sekreciis daqveiTebas leptinis administrirebis

sapasuxod.bazaluri da glukoziT stimulirebuli insulinis sekreciis

inhibireba pankreasis kunZulebze nanaxia leptinis an maRali

koncentraciis, an prolongirebuli moqmedebis Sedegad [159, 165-172]. Tumca,

sxva kvlevebma sapirispiro Sedegebi gamoavlina; rogorc Cans insulinis

gamoyofaze leptinis moqmedeba sakmaod specifiuria, rasac adasturebs is

faqti, rom leptinis deficitis mqone db/db  da  ft/ft  virTagvebisqsovilebSi,

aranairi pasuxi ar vlindeboda [159].

savaraudod, leptini moqmedebs insulinis sekreciis fosfolipaza

C/proteinkinaza C  gzebis regulaciis doneze. am gzaze aRwerilia leptinis

sxvadasxva safexurzemoqmedeba: a) ujredSida Ca++ koncentraciis daqveiTeba

da atf-mgrZnobiare K+ arxebis gaaqtiveba [166, 169, 173]; b) fosfolipaza C-Ti

ganpirobebuli insulinis sekreciis inhibireba, romelic Zlierdeba ob/ob

virTagvebSi [167, 174]; da g) Ca++ damokidebuli mediatori fosfolipaza C-s

28  

sasignalo gzis meore fazaSi, proteinkinaza C-s daqveiTeba [167, 170].

leptinis supresiuli moqmedeba insulinze SesaZloa nawilobriv

gamowveuli iyos fosfodiesTeraza 3B-s aqtivaciiT gziT [171, 175], rac

iwvevs c-amf-is supresias da gmp-1-iT stimulirebuli insulinis sekreciis

inhibirebas. bolo periodSi, nanaxia pankreasis β uredebze insulinis genis

transkrifciaze leptinis pirdapiri zegavlena, rac gamoixateba

preproinsulinis m-rnm-is 50%-iT daqveiTebiT [168, 176]. savaraudod, leptini

ujredis SigniT sxvadasxva doneebze moqmedebs, dawyebuli transkrifciidan

- membranis ganvladobamde, raTa gamoiwvios insulinis rogorc sinTezis,

ise sekreciis inhibireba.

pankreasisβ ujredebis garda, leptinis receptorebi RviZlSi, ConCxis

kunTebsa da cximovan ujredebze (adipocitebSi) vlindeba; es faqti ki

imazemetyvelebs, rom leptinma SesaZloa zegavlena moaxdinos insulinis

samizne am sam klasikur qsovilze (insulindamokidebuli qsovili) da aseve

imoqmedos am qsovilebSi insulinis sapasuxo reaqciaze.

In vivo kvlevebidan Cans leptinis gavlena glukozis utilizaciaze.leptinis

centraluri an i/v infuzia virTagvebSi zrdis RviZlismier da periferiul

mgrZnobelobas insulinze, Sedegad ki izrdeba glukozis utilizacia [161,

177-180]. ob/ob virTagvebis leptiniT mkurnalobis sapasuxod,

viTardebanormoglikemia [9]. imisTvis, rom gaerkviaT TuriTi iyo

gamowveuli misi es efeqti - wonis klebisa Tu pirdapir leptinis

hopoglikemiuri efeqtiT (mag: periferiaze insulinis mimarT mgrZnobelobis

gazrda), Catarda eqsperimenti virTagvebze.ob/ob  virTagvebi or jgufad

daiyo; erT jgufs leptiniT mkurnalobdnen, meores ki - kvebis SezRudviT;

wonis klebis garda orive jgufSiinsulinisa da glukozis donis

daqveiTeba aRiniSna. Tumca, leptiniT namkurnalev jgufSi 60%-iT ufro

meti efeqti miiRes [181].sxva kvlevaSiki Seadares virTagvebSi visceraluri

simsuqnis Semcirebis gavlena insulinis moqmedebaze; virTagvebi

gansxvavebuli mkurnalobis mixedviT sam jgufaddaiyo: leptini, β3-

adrenoreceptoris agonisti an kvebis SezRudva. samive jgufSi insulinis

29  

RviZlismieri aqtivoba erTnairad gaizarda, Tumca insulinis periferiuli

aqtivobis mniSvnelovani gazrda mxolod leptinis mkurnalobis sapasuxod

SeiniSna [180]. am eqsperimentebidan SegviZlia davaskvnaT, rom leptini

hipoglikemiur moqmedebas avlens, nawilobriv damoukideblad misi wonisa

da cximovani masis daqveiTebis efeqtisgan. amasTan, leptinis moqmedeba

glukozis metabolimze, nawilobriv insulinis efeqtze ar aris

damokidebuli, rac STZ-(streptazotocini)-inducirebul diabetian

virTagvebzeCatarebulma kvlevam aCvena; am kvlevaSi leptiniT mkurnalobam

glukoza normaSi moiyvana da gaaumjobesa insulinis mimarT mgrZnobeloba

insulinis gamoyenebis gareSec [179].

leptinis receptorebi adamianis hepatocitebzecgvxvdeba; SesaZloa leptini

am ujredebSic insulin-damokidebuli aqtivobebis modulatorad gvevlineba

[182]. leptini insulinis sasignalo moqmedebis sawinaaRmdego moqmedebas

avlens, irs-1-isinsulin-damokidebuli Tirozin-fosforilirebis

daqveiTebis gziT [182]; is zrdis fosfoenolpurivat-karboqsikinazas [183,

184] da amcirebs glukokinazis eqspresias [183]; Sedegad izrdeba

glukoneogenezi da qveiTdeba glukogenolizi [183, 184].

periferiul qsovilze leptinis mier insulinis biologiur efeqtze

zegavlenis moqmedebis Sesaswavlad mravali kvlevaCatarda. rigi kvlevebis

Tanaxmad, leptins SeuZlia insulinis aqtivobis gazrda (glukozis

STanTqma da/an lipidebis sinTezi) adipocitebsa [160, 177, 185-187] da

kunTovan ujredebSi [177, 188-191] Tumca, sxva kvlevebma leptinis es efeqti

ver daadastura.

1.5. leptini da Saqriani diabeti tipi 2

ramdenime wlis win pirvelad daisva SekiTxva, Tu ramdenad mniSvnelovania

leptini Saqriani diabetitipi 2 –s ganviTarebaSi [192, 193]. sxvadasxva

kvlevebis Tanaxmad, hiperleptinemias SeuZlia daarRvios insulinis

30  

produqcia da periferiaze gamoiwvios an gaaZlieros insulinis mimarT

rezistentoba. Camoyalibda simsuqnis mqone pirebSi insulinrezistentobis/

Saqriani diabetitipi 2 –s ganviTarebis hipoTeza: simsuqnis dros leptinis

maRali done iwvevs hiperglikemias, romlis mizezicaa pankreasis β

ujredebSi glukoziT gamowveuli insulinis sekreciis supresia.

periferiuli insulinrezistentoba, romelic SesaZloa aseve

hiperleptinemiiT iyos gamowveuli, kidev ufro aRrmavebs glukozisadmi

tolerantobis darRvevas, leptiniT-gamowveuli insulinis sekreciis

supresia β ujredebze wydeba da viTardeba hiperinsulinemia. sxva SesaZlo

hipoTezaa: hiperleptinemia iwvevs receptoris mgrZnobelobis moSlas,

irRvevaβ ujredebze leptinis receptoris signali da Sedegad yalibdeba

qronikuli hiperinsulinemia da ganwyoba Saqriani diabetis ganviTarebisadmi

[172].

sxva mxriv, leptins SesaZloa hqondes Saqriani diabetis ganviTarebis

sawinaaRmdegod mimarTuli damcavi moqmedeba, vinaidan is zrdis

periferiaze insulinis mgrZnobelobas da amcirebs sxvadasxva

qsovilebSitrigliceridebis dagrovebas [194, 195].

dReisaTvis arc erTi kvleva ar amtkicebs, rom Saqriani diabeti tipi 2-is

an glukozis mimarT tolerantobis darRvevaSi raime kavSiri aqvs leptinis

an misi receptoris genis mutacias. adamianis ob genis an misi

gamaaqtivebeli faqtoris skriningisasSaqriani diabetitipi 2-

iTdaavadebulebSi aranairi mutacia ar gamovlinda [74, 76]. msgavsi smi-iTa

da cximovani masis mqone Saqriani diabetiT daavadebul da janmrTel

individebSi, leptinis dones Soris gansxvaveba praqtikulad ar SeiniSneba

[109, 197-199]. aseve msgavsia leptinis korelacia Saqriani diabetiT

daavadebul da janmrTel individebSi sxeulis agebulebasTan, insulinTan

da genderul dimorfizmTan[196, 156, 199].

Catarebuli kvlevebidan savaraudoa, rom leptini ainhibirebs insulinis

sekrecias pankreasis β ujredebis doneze; amavdroulad is zrdis

insulinis aqtivobas da glukozis utilizacias. adipocitebis mier

31  

leptinis sekrecia mWidrodaa damokidebuli insulinze. adamianebSi,

leptinis da insulinis done erTmaneTTanaadakavSirebuli, Tumca, kvlav

sadavoa is faqti, SeuZlia Tu ara insulins leptinis regulacia. nanaxia

leptinis donis cvlileba insulinis sapasuxod, Tumca es efeqti garkveuli

periodis SemdegSeiniSneba. savaraudod, insulinis es mastimulirebeli

moqmedeba leptinis sekreciaze nawilobriv insulinis adipocitebze

tropuli moqmedebis Sedegia.

1.6. leptini da kardiometaboluri darRvevebis riski

bolo wlebSi leptinis sekrecia da misi koncentraciis Seswavla sakmaod

aqtualuria simsuqnisa da Saqriani diabetitipi 2-iTdaavadebul pacientebSi;

Sedegad, momravlda leptinze Catarebuli kvlevebis ricxvic. arsebobs

monacemebi, rom Sratis leptinis done izrdeba simsuqnis mqone pirebsa da

Saqriani diabetiT daavadebulebSi. eqsperimentuli kvlevis SedegebiT

hiperleptinemiam SesaZloa pirdapir an meoradad imoqmedos gul-

sisxlZarRvTa daavadebis ganviTarebaze [200].garkveuli kvlevebis Tanaxmad

mniSvnelovani kavSiri gamovlinda Sratis leptinis donesa da

insulinrezistentoba/anTebis markerebs Soris, rac imazemetyvelebs, rom

leptini SesaZloa gvevlinebodes gul-sisxlZarRvTa daavadebebis risk-

faqtorad. Tumca, arsebobs kvlevebi, sadac leptinis korelacia ar

gamovlinda leptinis donesa da gulis koronarul daavadebas Soris [201,

202]. urTierTsapirispiro Sedegebis gamo Kajikawa  da Tanaavt. Caatares

kvleva, romlic ufro klinikuri kuTxiT mimdinareobda. am kvlevis erT-

erTi mizani iyo leptinis kavSiris gamovlena metaboluri sindromis da

gulis koronaruli daavadebis riskTan, sxvadasxva koronaruli risk-

faqtorebis mqonepacientebSi. kvlevaSi monawileoba miiRo 104-ma pacientma,

visac ukve dasmuli hqonda metaboluri sindromis diagnozi, an

aReniSneboda sul mcire erTi koronaruli risk-faqtori. kvlevis Sedegebis

Tanaxmad, yvela pacientSi, leptinma dadebiTi korelacia aCvena welis

garSemowerilobasTan, smi-Tan da insulinrezistentobis ideqsTan. leptinis

32  

yvelaze maRali cifri aramwevel qalebSidafiqsirda. metaboluri

sindromis jgufSi leptinis done ufro maRaliiyo; aseve ufro maRali iyo

uzmod insulinis done da Homa‐IR-indeqsi (P<0,01). multivariaciulma

analizma gamoavlina, rom leptini dadebiTad korelirebs metabolur

sindromTan. rac Seexeba gulis koronarul daavadebas, leptinis donis

mxriv aranairi mniSvnelovani sxvaoba ar gamovlinda pacientebSi gulis

koronaruli daavadebiT da mis gareSe (leptini 1,79 ±0,12 vs 1,91 ± 0,10).

Kajikawa da Tanaavt. mier Catarebuli kvlevis Tanaxmad leptini dadebiTad

korelirebs metabolur sindromTan. miuxedavad imisa, rombolo wlebSi

Catarebuli ramdenime kvlevis Tanaxmad leptini xels uwyobs

aTerosklerozis da kardiovaskuluri daavadebebis ganviTarebas simsuqnis

mqone pacientebSi, am kvlevam msgavsi Sedegi ver gamoavlina da Sesabamisad

ver hpova dasabuTeba im mosazrebam, romlis Tanaxmadac leptini SesaZloa

pirdapir asocirdebodes gulis koronarul daavadebasTan [203], Tumca,

metabolur sindromTan korelacia aCvenebs, rom meoradad leptini,

SesaZloa zrdis kardiometaboluri darRvevebis ganviTarebis risks.

adipokinebis rolis gamosakvlevad, Warbi wonisa da simsuqnis mqone

pacientebSi, .metabolur sindromiT da mis gareSe dainteresdnen Maria

Gnacińska da Tanaavt. maT mier Catarebul kvlevaSi monawileobda 55

pacienti (38 – metaboluri sindromiT da 17 – metaboluri sindromis

gareSe). kvlevis Sedegebidan gamomdinare orive jgufis pacientebSi Sratis

leptinis done msgavsi iyo.

Marie-He´le`ne Gannage´-Yared da Tanaavt. kvlevis Tanaxmad leptini

dakavSirebulia insulinis mgrZnobelobasTan, damoukideblad asakisa da

smi-sa. amave kvlevis Tanaxmad gamovlinda korelacia leptinsa da smi-s

Soris, Tumca leptinis korelacia lipidur speqtrTan sakmaod sustad iyo

gamoxatuli. smi-is gaTvaliswinebis Semdeg, leptinsa da lipidebs Soris

korelacia mTlianad gaqra, insulinis mimarT mgrZnobelobis raodenobrivi

indeqsis mniSvneloba ki ar Secvlila. msgavsi Sedegebi miiRes Baratta-s da

Tanaavt. mier CatarebulkvlevaSi [204] leptinisa da lipidebs Soris

33  

korelaciuri kavSiris gamokvlevis dros. WOSCOPS kvlevam aCvena insulinis

mimarT mgrZnobelobasa da leptins Soris mWidro kavSiri, smi-sgan

damoukideblad. rac SesaZloa xsnis im faqts, rom leptini gulis

koronaruli daavadebis damoukidebeli risk faqtoria[205].

Erik Ingelsson-ma da Tanaavt. gamoikvlies 362 pacienti, raTa ganesazRvraT

leptinis jvaredin-damokidebuleba kardiometabolur risk-faqtorebTan.

maTi Sedegebis Tanaxmad leptinis koncentracia mniSvnelovnad maRali iyo

qalebSi (P<0,0001). multivariabelur modelSi, leptini dadebiTad

korelirebda smi-YTan da welis garSemowerilobasTan. leptinis

koncentracia metaboluri sindromis komponentebis ricxvTan ufro maRali

iyo, vidre sxva adipokinebisa. am kvlevaSi gamovlinda leptinis korelacia

yvela gamokvleul maxasiaTebelTan, garda Tambaqos mwevelebisa. kvlevis

Tanaxmad, leptinis koncentracia izrdeboda metaboluri sindromis

komponentebis raodenobis zrdasTan erTad.

Wildman da Tanaavt. kvlevis Tanaxmad menopauzis mqonesaSualo asakis

qalebSi, leptinis gazrdili done asocirdeboda maRali simkvrivis

lipoproteinebis donis daqveiTebasTan da diastoluri wnevis, glukozis

donisa da insulinrezistentobis matebasTan [206]. msgavsi Sedegebi miiRes

Langenberg-ma da Tanaavtorebma. maTi grZelvadiani kvlevis Tanaxmad, leptini

asocirdeboda metaboluri sindromis umetes komponentebTan sawyis etapze;

Tumca,maTi kvlevis Tanaxmad leptinis aRniSnuli kavSiri metaboluri

sindromis komponentebTan, ar unda yofiliyo am drosganviTarebuli gulis

koronaruli daavadebiT sikvdilobis xelSemwyobi faqtori[207]. aseve,

arsebobs mtkicebuleba, rom leptinis kavSiri insulinrezistentobasTan ar

aris damokidebuli cximovan masaze [208, 209]. leptinsa da

insulinrezistentobas Soris arsebuli zusti meqanizmi da maTi

kompleqsuri urTierTdamokidebuleba sxva kardiometabolur risk-

faqtorebTan, bolomde naTeli ar aris [210].

Huang KCda Tanaavt. kvleva moicavda mozardebSi (diabetis gareSe) plazmis

leptinis kavSiris gamovlenas sxvadasxva anTropometrul maCveneblebTan,

34  

smi-Tan, lipidebTan da insulinrezistentobasTan. maTMmier Catarebuli

kvlevis Tanaxmad, plazmis leptinis done mniSvnelovnad maRali iyo

gogonebSi (17.45+/-10.13 ng/ml) vaJebTan SedarebiT (8.81+/-6.71 ng/ml,  P<0.001). 

plazmis leptinis done dadebiTad korelirebda smi-Tan, welis

garSemowerilobasTan, weli/TeZos TanafardobasTan, cximovan masasTan,

cximovani masisprocentul maCvenebelTan da trigliceridebTan.

insulinrezistentobis indeqsi dadebiTad korelirebda smi-Tan, welis

garSemowerilobasTan, weli/TeZos TanafardobasTan, cximovan masasTan,

cximovani masis procentul maCvenebelTan, trigliceridebTan da leptinTan.

multivariaciuli xazobrivi regresiis modelis gamoyenebiT, aRmoCnda, rom

plazmis leptinis done mniSvnelovan kavSirSirCeba

insulinrezistentobasTan, Tundac mas Semdeg rac daregulirda asakisTvis,

sqesisTvis, smi, cximovani masisa da trigliceridebisTvis. kvlevidan

gamomdinare plazmis leptinis done SesaZloa metaboluri sindromis

darRvevebisa da kardiovaskuluri daavadebebis Camoyalibebis prediqtori

iyos [211]. 

arsebuli samecniero literatura, kvlevis Sedegebi bolomde ver

adasturebs leptinis mWidro korelacias metabolur sindromTan da mis

calkeul komponentebTan. aseve bolomde naTeli ar aris, leptinis, rogorc

kardiometaboluri darRvevis prediqtoris roli da is mosazreba, rom es

hormoni zrdis metaboluri darRvevebis risks. amas garda, gamoiTqva

mosazreba hiperleptinemiis, rogorc metaboluri sindromis axali

komponentis damatebisa da ganxilvis Taobaze. vinaidan arsebobs monacemebi

imis Taobaze, rom leptinis siWarbis mqone pirebs metaboluri sindromi

gacilebiT ufro adreul etapzeuviTardebaT.

taivanSi Catarda kvleva, romelSic ikvlevdnen leptinis korelacias

kardiometabolur risk-faqtorebTan da hiperleptinemias, rogorc

metaboluri sindromis prediqtors. kvlevaSi 957 adamiani monawileobda,

upiratesad mamakacebi. kvlevis Tanaxmad, leptinis done orive sqesSi

korelirebda gul-sisxlZarRvTa daavadebis gazrdil riskTan. uzmod

glukozis garda, leptinis momatebuli done asocirdeboda metaboluri

35  

sindromis zrdasTan. asakis gaTvaliswinebis Semdeg, SeiniSneboda kavSiri

leptinis donesa da metabolur sindroms Soris. mxolod asakTan an

Tambaqos moxmarebis gaTvaliswinebis Semdeg, is pirebi visac aReniSneboda

leptinis ufro maRali done, yvelaze metad hqondaT gazrdili metaboluri

sindromis ganviTarebis riski. smi-is gaTvaliswinebis Semdegac metaboluri

sindromis riski kvlav mniSvnelovnad maRali rCeboda im mamakacebSi, visac

leptinis ufro maRali done aReniSneboda. kvlevis erT-erTi mniSvnelovani

Sedegi iyo daskvna, rom mamakacebsa da qalebSi leptinis gazrdili done

metaboluri sindromis prediqtoriiyo [211].

1.7. leptini da Zvlis mineraluri simkvrive

axlo warsulSi simsuqnesa da osteoporozs Soris kavSiri ar iyo cnobili,

Tumca uaxlesi kvlevebis Sedegad aRmoCnda, rom am or daavadebas aqvs rigi

saerTo genetikuri da garemo faqtorebi. arsebobs damadasturebeli masala,

rom sxeulis cximovani qsovili SesaZloa dadebiTad moqmedebdes Zvalze,

Tumca sapirispiro kvlevebis Sedegebi ar adasturebs cximovani qsovilis

Zvalze damcav efeqts [213].

cnobilia, rom motexilobis riskis saukeTeso ganmsazRvreli faqtori

Zvlovani qsovilis masaa, romelic izomeba Zvlis mineraluri simkvriviT

(Zms). mravalricxovani kvlevebi adasturebs, rom didi wona an maRali smi

dadebiT korelaciaSia Zms-sTan da rom wonis kleba Zvlis masis kargvas

iwvevs. aRniSnuli korelacia SeiniSneba, rogorc qalebSi, ise mamakacebSi,

aseve zrdasrulebSi, bavSvebsa da mozardebSi. mravalwliani kvlevebis

Sedegad dadginda, rom Zms-s cvlilebebi dadebiT korelaciaSia iyo

cximovani masis cvlilebasTan [215, 216]; aseve kvleva EPIC‐ma aCvena, rom im

pirebs, visTanac ufro “swrafad” mcirdeboda Zvlis simkvrive, hqondaT

mniSvnelovnad naklebi cximovani qsovilis masa,im pirebTan SedarebiT,

visTanac “nela” mimdinareobda Zvlis masis Semcireba [217]. Lau da

36  

Tanaavtorebis Tanaxmad mamakacebs, romelTac aReniSneboda vertebruli

deformaciis mZime forma, hqondaT cximovani qsovilis gacilebiT dabali

Semcveloba, sakontrolo jgufTan SedarebiT [218].

aRniSnuli monacemebis sapirispirod, rigi kvlevebis Tanaxmad, cximovani

qsovili SesaZloa srulebiT ar moqmedebdes Zvlis masis damcavad. aziel

da kavkasiel qalebSi Catarebuli farTomasStaburi kvleviT, cximovani

qsovilis masa uaryofiTad korelirebda Zvlovan masasTan, rac miuTiTebda

Zvalze cximovani qsovilis uaryofiT gavlenaze. msgavsi Sedegi dadasturda

ramodenime farTomasStaburi kvleviTac [214].

Zms-sa da cximovan masas Soris uaryofiT kavSirze metyvelebs kvlevebi,

romlebSic Seswavlilia garemo faqtorebis da sxvadasxva medikamentebis

gavlena Zvlovan masaze. mag. cnobilia, rom fizikuri datvirTva zrdis

Zvlovan masas da paralelurad amcirebs cximovani qsovilis masas

[219].dadgenilia, rom kalciumiT mdidari sakvebi pubertatis asakSi zrdis

Zvlis pikur masas, xandazmulebSi amcirebs Zvlis danakargs da

motexilobis risks. amasTan erTad, kalciumi aumjobesebs wonisa da

cximovani qsovilis klebas, Tumca, amis dasadastureblad mravalwliani

kvlevebia saWiro [220]. menopauza aseve dakavSirebulia Zvlovani masis

gazrdil danakargebTan, cximovani masis zrdasTan da kunTuri masis

SemcirebasTan. aseve dadgenilia, rom medikamentebisrigi uaryofiTad

moqmedebs Zvlovan masaze da amasTan zrdis sxeulis masas mag:

gonadotropin-rilizing hormoni prostatis kibos mkurnalobisas, an

glukokortikoidebi [214].

aRniSnuli gansxvavebuliSedegebisavaraudod ganpirobebulia sxvadasxva

faqtoriT, rogoricaa sqesi, asaki, eTnikuriwarmomavloba, kvlevis dizaini,

analizis meTodebi da sxva.

arsebobs cximovani qsovilis Zvalze moqmedebis ramdenimesavaraudo

meqanizmi, romelic xsnis cximovan da Zvlovan qsovils Soris kavSirs. erT-

erTi aRniSnuli meqanizmi SesaZloa dakavSirebli iyos cximovan qsovilTan

da mis mier gamomuSavebul biologiurad aqtiur nivTierebebTan. leptini,

37  

cximovani qsovilis mier gamomuSavebuli hormoni, SesaZloa monawileobdes

Zvlis metabolizmSi. amasTan,cnobilia, rom adipocitebi da osteoblastebi

erTi progenitorisgan viTardebian, mezenqimuri Rerovani ujredisgan; In vitro

kvlevebma gamoavlina, rom leptini SesaZloa pirdapir moqmedebdes Zvlis

tvinis mezenqimur Rerovan ujredebze, raTa gaaZlieros maTi diferenciacia

osteoblastebad da daTrgunos maTi diferenciacia adipocitebad.

diferenciaciis dros maT Soris balansi damokidebulia ramdenime

meqanizmze, ramac SesaZloa aseve gansazRvros cximovani qsovilis saboloo

zegavlena Zvalze [221].

leptinis Zvlis metabolizmze moqmedebis zusti meqanizmi bolomde

cnobili ar aris. literaturis monacemebi arasrulyofili da sadavoa.

savaraudod leptinis Zvalze moqmedeba xorcieldeba ori meqanizmiT. I

meqanizmi – “arapirdapiri”, SemoTavazebulia Ducy da Tanaavtorebis mier. am

meqanizmis mixedviT cximovani ujredebis mier gamomuSavebuli leptini

sisxlZarRvovani endoTeluri ujredis ObRa receptoris meSveobiT gadis

hematoencefalur bariers, sadac aaqtiurebs hipoTalamusis ObRb

receptors. es signalebi, Tavis mxriv, astimulireben e.w. HOBIF-is

(hipoTalamusis osteoblastebis mainhibirebeli faqtori) eqspresias.

gamomuSavebuli HOBIF aqveiTebs osteoblastebis matriqs-warmomqmnel

unars. am avtorebma aRmoaCines didi wonis mqone Ob(Lep)-/- virTagvebSi

anomaliurad didi Zvlovani masis savaraudo mizezi. kerZod gamoavlines,

rom leptinis intracerebroventrikuluri ineqciebi iwvevda Zvlovani masis

Semcirebas. aqedan gamomdinare, Ducy da Tanaavtorebis varaudiT leptini

astimulirebs tvinSiHOBIF-is gamomuSavebas.

aRniSnul meqanizmSi CarTuli meore centraluri rgoli aris NPY da

misiY2 receptori, romelsac, Tavis mxriv, SeuZlia HOBIF-is

stimulacia.NPYaris hipoTalamusis mier gamomuSavebuli peptidi, romelic

sakvebis miRebas, energiis homeostazs da Zvlis remodelirebas

aregulirebs. leptini ainhibirebs NPYgenis eqspresias hipoTalamusSi.

plazmis leptinis daqveiTeba aZlierebs NPYeqspresias, astimulirebs

38  

sakvebis miRebas, ainhibirebs energiis danaxarjs da xels uwyobs simsuqnisa

da masTan dakavSirebuli fenotipis ganviTarebas. NPY‐is efeqti

regulirdeba Y‐  receptoruli sistemiT, romelic eqspresirdeba

hipoTalamusSi da Sedgeba 5 gansxvavebuli receptorisgan (Y1,  Y2,  Y4,  Y5, 

Y6).CamoTvlilTagan yvelaze ukeT Seswavlilia Y2 receptori.

hipoTalamusSi NPY2 deficitis mqone virTagvebs aReniSnebodaT

momatebuli Zvlovani masa, maSin roca amis gamomwvevi sxva endokrinuli

mizezi ar arsebobda. aRniSnuli miuTiTebs, rom es receptorebi

aregulireben Zvlis homeostazs avtonomiuri funqciis Secvlis gziT.

amgvarad, Y2 an leptinis, arqona aqveiTebs HOBIF–s da aZlierebs

osteoblastebis produqcias. Elefteriou et al. aRmoaCines, rom NPY-deficitis

mqone virTagvebs aReniSnebodaT Zvlis normaluri masa, gansxvavebiT NPY2-

deficitis mqone virTagvebisgan. aseve gamovlinda, rom NPY4-deficitis

mqone virTagvebs aReniSnebaT Zvlis normaluri masa, maSin rocaNPY2 da

NPY4-is erTdrouli gamoTiSva mniSvnelovnad zrdis Zvlovan masas,

mxolod NPY2-deficitis mqone virTagvebTan SedarebiT. Zvlis

gaZlierebuli formireba NPY2 da NPY4-s erTdrouli gaTiSvis SemTxvevaSi

miuTiTebs NPY2 da NPY4-s receptorul gzebs Soris sinergiul

damokidebulebaze [214].

amasTan, simsuqneze leptinis moqmedeba ganpirobebulia im neironuli

gzebiT, romelic moicavs proopiomelanokortiniT (pomk) warmodgenil

katabolur gzebs. leptini astimulirebs pomk neironebs raTa gamomuSavdes

α-melanokortin mastimulirebeli hormoni (α-mmh).α-mmh-is da melanokortin

3da 4-is kombinacia iwvevs sakvebis naklebi raodenobiT miRebas da energiis

danaxarjis gazrdas. amasTan, leptini ainhibirebsAgRP‐is(agouti‐related 

protein)aqtivobas, romelic aris melanokortin 3 da 4-is receptoris

endogenuri antagonisti. yovelive amis Sedegad izrdeba melanokortin 3 da

4-is receptoris signali da mcirdeba mada. simsuqneze zemoqmedebis garda,

melanokortin-sasignalo gza SesaZloa iwvevdes Zvlis rezorbcias da ara

39  

formirebas. Mc4r gaTiSuli Tagvebi avlenen Zvlis did masas Zvlis

rezorbciis Semcirebis xarjze [222].

II meqanizmi – “pirdapiri”anu osteotrofuli efeqti - gulisxmobs

Rerovani ujredebidan osteoblastebis diferenciaciisTvis xelis

Sewyobasa da osteoklastebis warmoqmnis daTrgunvas. leptini

astimulirebs IGF-1-is (Insulin‐like  growth  factor‐1)produqcias, romelic, Tavis

mxriv, axdens: a) osteoblastebis proliferaciis stimulacias, ris

Sedegadac izrdeba osteoblasturi xazis ujredebis mdgradoba

apoptozisadmi; b) osteoklastebis warmoqmnis supresias, osteoblastebis

Rerovani ujredebidan naklebi RANKL-is (NF-kappaB Ligand) warmoqmnis

Sedegad; g) OPG (Osteoprotegerin) stimulacias, romelic iwvevs

osteoklastebis supresias.

amgvarad, leptini Zvlis remodelirebis mniSvnelovani regulatoria. misi

gavlena Zvalze kompleqsuria. kerZod, adamianebSi Catarebul kvlevebSi

miRebulia rogorc uaryofiTi, aseve dadebiTi kavSiri leptinsa da Zms-s

Soris an leptinis gavlena Zvlovan qsovilze srulebiT ar vlindeba.

1.8. kvebis sxvadasxvastilis gavlena leptinze

arsebobs mosazreba, rom trigliceridebis maRali done iwvevs leptinis

gadaadgilebis dabrkolebas hematoencefaluri barieris gavliT[223].

saintereso iqneboda imis gamokvleva, Tu ra Sedegi eqneboda

trigliceridebis donis daqveiTebas. Teoriulad aRar dabrkoldeboda

leptinis transporti hipoTalamusamde, Sesabamisad moxdeboda wonis

daregulireba madis daTrgunvis da energiis danaxarjis gazrdis Sedegad.

aRniSnulidan gamomdinare gadavwyviteT gagvesazRvra naxSirwylebis da

cximebis SezRudvis gavlena trigliceridebis doneze da Sesabamisad

leptinis koncentraciaze simsuqnis mqone pacientebSi. Catarebulma in 

vivokvlevebma virTagvebze, aCvena, rom rZem, sadac cximis 98%

trigliceridebis saxiT iyo warmodgenili, dauyovnebliv Seaferxa

40  

leptinis gadasvla sisxlidan tvinSi. msgavsi Sedegi ar dafiqsirebula

ucximo rZis miRebis SemTxvevaSi. aseve ar gamovlenila msgavsi efeqti

soios cximis miRebis Semdeg, rac gvafiqrebinebs imas, rom mcenareul

trigliceridebs da esenciur Tavisufal cximovan mJavebs aseve ar aqvT

leptinis transportirebis Seferxebis unari [224].

milanis universitetSi Catarebuli kvlevis Tanaxmad leptinis done

mniSvnelovnad Semcirda dabalkaloriuli dietis, fizikuri datvirTvis da

Sesabamisad wonis klebisa da smi-is daqveiTebis Sedegad. meore kvlevis

Tanaxmadac, sxeulis 10%-iT daqveiTebam - leptinis donis TiTqmis 50%-iT

Semcireba gamoiwvia. msgavsi saxis kvlevebi mravalia da Sedegebic msgavsia.

leptinis Semcireba xdeba rogorc cximebis ise naxSirwylebis SezRudvis

xarjze. Tundac normaluri wonis mqone pacientebSi, leptinis done

izrdeba cximiani sakvebis didi raodenobiT miRebis fonze, xolo

SezRudvis SemTxvevaSi ki - qveiTdeba [225].

Tavi 2: gamokvlevis masalebi da meTodebi

2.1. gamokvlevis masalis zogadi daxasiaTeba

kvleva mimdinareobda S.p.s. “janmrTeli cxovreba”-s (amJamad S.p.s.

“endokrinologiis erovnuli instituti” –s saxeliT cnobili) bazaze 2009

wlis ivnisidan 2010 wlis dekembris CaTvliT.

41  

CarTvis kriteriumi iyo: mdedrobiTi sqesi, asaki ≥ 20 welze, kvlevaSi

monawileobaze Tanxmoba, dadasturebuli xelmoweriT. gamoricxvis

kriteriumebs warmoadgenda: asaki < 20 welze, anamnezSi iseTi qronikuli

daavadebis arseboba, romelic imoqmedebda maT metabolur funqciebze, mag:

farisebri jirkvlis funqciis darRveva, qronikuli hepatiti, cirozi,

hipoTalamusis daavadebebi, Saqriani diabetis dadasturebuli diagnozi;

kvlevaSi ar erTvebodnen pacientebi, vinc kvlevis dawyebamde 6 Tvis adre

imyofeboda dabalkaloriul dietaze (<1800 kkal) an mkurnalobda simsuqnis

sawinaaRmdego farmakologiuri preparatebiT, an itarebda metabolizmze

mmoqmed sxva mkurnalobas, an Catarebuli hqonda bariatriuli qirurgiuli

Careva.aseve kvlevidan gamoricxvis kriteriums warmoadgenda orsuloba da

laqtacia. TiToeuli pacienti, vinc akmayofilebda kvlevaSi CarTvis

kriteriumebs da ar aReniSneboda kvlevidan gamoricxvis kriteriumi avsebda

specializirebul kiTxvars; pacienti iyo uzmod gamokvlevebis dawyebamde

minimum 10 saaTis manZilze; maT utardeboda fizikuri gamokvleva da venuri

sisxlis nimuSis aReba Semdeg maCveneblebze: Sratis leptini, bazaluri da

postprandialuri insulini, glukozisadmi tolerantobis gansazRvris

testi, lipiduri speqtri (saerTo qolesterini, trigliceridebi, maRali

simkvrivis lipoproteinebi da dabali simkvrivis lipoproteinebi). venuri

sisxlis aRebis maqsimaluri dro iyo 11:00. yvela pacients Cautarda

ormagenergetikuli rentgenuli absorbciometriiT sxeulis agebulebis

gansazRvra.

kvlevis pirobebi daakmayofila 149 pacientma, romelTaasakobrivi zRvari

20-70 wlamde meryeobda.

2.2. kvlevis kiTxvari:

pacientebis gamokiTxva xdeboda specialuri kiTxvaris saSualebiT.

kiTxvari iyo martivi, ise rom pacients Tavad SeeZlo misi Sevseba. kiTxari

Sedgeboda 1 gverdis da 10 kiTxvisgan. kiTxvaris mizani iyoSemdegi saxis

informacis miReba: demografiuli (mag: asaki, sqesi da a.S.), cxovrebis

stili (mag: Tambaqo, alkoholi, sxva mavne Cvevebi da a.S.), daavadebis

42  

anamnezi da medikamentebi, fiziologiuri statusi (orsuloba, laqtacia,

uzmod yofnis periodi da a.S.).

2.3. fizikaluri gamokvleva:

2.3.1. sasicocxlo maCveneblebis (arteriuli wneva, pulsi)gansazRvra:

arteriuli wnevis gansazRvramde pacientiminimum 5 wuTi imyofeboda

mjdomare, mosvenebul mdgomareobaSi. pacients esazRvreboda wneva orive

xelze, daaxloebiT 2 wuTis intervaliT. kvlevisTvis irCeoda dominanturi

xeli. dominantur xelze pacients damatebiT esazRvreboda wneva 2-jer, 2

wuTiani intervalis dacviT. kvlevisTvis viyenebdiT sami gazomviT miRebul

saSualo ariTmetikul cifrs. arteriuli wnevis gasazomad viyenebdiT

avtomatur spigmomanometrs – Microlife BPA80. pacients pulsi esazRvreboda 1

wuTis manZilze.

2.3.2. wona, simaRle, sxeulis masis indeqsi, welis garSemoweriloba:

pacientebis awonva da simaRlis gansazRvra xdeboda fexsacmelebis,

qurTukisa da mZime tanisamosis gareSe. pacientebis asawonad viyenebdiT

saswors – ТВЕС; wonis sazom erTeulad viyenebdiTkilogramebs (kg).

sasworis awonvis maqsimaluri zRvari a 200 kg-s Seadgend. simaRlis

gansazRvrisTvis viyenebdiT simaRlis meqanikur sazoms – Seca 240; simaRlis

sazom erTeulad viyenebdiT metrs (m). sxeulis masis indeqsis (smi) (Quetelet 

indeqss) gamosaTvlelad viyenebdiT formulas (226): wona (kg)/simaRlis² (m²).

smi-is mixedviT gamovyaviT sami jgufi. jgufebi ixileT cxrilSi #1.

cxrili #1

jgufi s.m.i.-is maCvenebeli maxasiaTebeli

I 18.5 – 24.9 normaluri wona

II 25 – 29.9 Warbi wona

III > 30 simsuqne

43  

welis garSemowerilobas vsazRvravdiT TeZos Zvlis wvetebsa da me-12 neknis

qvemo sazRvars Soris Sua wertilSi. welis garSemowerilobis sazom

erTeulad viyenebdiT sm-s. jandacvis saerTaSoriso organizaciis

monacemebis Tanaxmad maRali welis garSemoweriloba asocirdeba

kardiometaboluri daavadebis gzrdil rikTan [212].

2.3.3. sxeuliskompoziciis gansazRvra:

sxeuliskompoziciis Seswavla da qsovilovani gadanawileba ganisazRvra

ormagenergetikuli rentgenuli absorbciometriiT (DXA). DXA-smeSveobiT

isazRvreba sxeulis cximovani, kunTovani da Zvlovani masa.DXA

dafuZnebulia rentgenis orfotoniani sxivis absorbciometriis

principze.Zvlis mineraluri simkvrivis Sefaseba warmoebs welis malebSi,

proqsimalur barZaySi, winamxarSi.gamokvlevis Casatareblad viyenebdiT

Lunar Prodigy Primo, General Electric, 2008. 

2.4. venuri sisxlis nimuSi:

venuri sisxlis nimuSis aReba xdeboda 10-12 saaTis SimSilis Semdeg dilis

9:00-11:00 saaTis SualedSi; aRebuli nimuSis nawili inaxeboda 4ºC-ze.

TiToeuli pacientisTvis vsazRvravdiT saerTo qolesterinis (qol.),

trigliceridebis (tg), maRali simkvrivis lipoprotein-qolesterinis (msl),

dabali simkvrivis lipoprotein-qolesterinis (dsl), uzmod glukozis,

Sratis leptinis, bazaluri insulinisdones.xdeboda insulinrezistentobis

indeqsis (HOMA‐IR) gamoTvla Semdegi formuliT: uzmod bazaluri insulinis

done (mU/mL) + uzmod plazmis glukoza (mmol/L) gayofili 22,5 [227]. 

venuri sisxlis nimuSis aRebis Semdeg, pacientebs utardeboda glukozis

mimarT tolerantobis gansazRvris testi (gtt). testis dawyebidan 2 saaTSi

44  

kidev erTxel viRebdiT venuri sisxlis nimuSs postprandialuri insulinis

gansazRvrisTvis, romelsac vinaxavdiT 4ºC-ze.

glukozis gansazRvrisTvis viyenebdiTglukozooqsidazur meTods.

glukozis sazom erTeulad viyenebdiT mg/dl-s.

glukozisadmi tolerantobis gansazRvris testis Casatareblad 75 gr.

glukoza ixsneboda 200 mloTaxis temperaturis wyalSi da pacients is 5

wuTis manZilzeunda mieRo. Ddalevidan 2 saaTSi kvlav vsazRvravdiT

glukozis dones.Sedegebis interpretaciisTvis, viyenebdiT janmos

rekomendaciebs (cxrili #2) [228].

cxrili #2 gtotinterpretaciis janmos rekomendaciebi

maCvenebeli norma

(mg/dl)

normidan gadaxra

(mg/dl)

uzmod glukoza < 110 > 110

datvirTvidan 2 saaTSi < 140 > 140

lipiduri profili moicavda saerTo qolesterinis, trigliceridebis,

maRali simkvrivis lipoproteinebisa da dabali simkvrivis

lipoproteinebisgansazRvras. normisa da normidan gadaxris maCvenebeli

motanilia cxrilSi #3.

saerTo qolesterinis gansazRvrisaTvis viyenebdiT “CHOD-PAP” meTods

(qolesterinis fermentuli kalorimetriuli testi lipidebis gamwmendi

faqtoriT [LCF]). am meTodis meSveobiT qolesterinis gansazRvra xdeboda

fermentuli hidrolizis da oqsidaciis Sedegad. indikatori yalibdeboda

wyalbadis peroqsidis da 4-aminofenazonisgan, fenolisa da peroqsidazis

Tanaarsebobisas. saerTo qolesterinis sazom erTeulad viyenebdiT mg/dl.

evropis aTerosklerozis asociaciis rekomendaciiT qolesterinis done

45  

unda iyos < 200 mg/dl-ze. saerTo qolesterins vsazRvravdiT “human”-is

firmis “Cholesterol liquicolor”test nakrebiT.

trigliceridebs vsazRvravdiT “GPO-PAP” meTodiT (trigliceridebis

fermentuli kalorimetriuli testi lipidebis gamwmendi faqtoriT [LCF]).

am meTodis meSveobiT trigliceridebis gansazRvra xdeboda lipaziT

fermentuli hidrolizis saSualebiT. indikatori yalibdeboda wyalbadis

peroqsidis, 4-aminoantipirinis da 4-qlorofenolidan peroqsidazis

katalizuri zemoqmedebis Sedegad. trigliceridebis sazom erTeulad

viyenebdiT mg/dl-s. (229). trigliceridebis dones vsazRvravdiT “human”-is

firmis “Triglycerides liquicolor –mono”test nakrebiT.

maRali simkvrivis lipoproteinebis gansazRvrisTvis viyenebdiT

“CHOLESTEROL liquicolor”test nakrebs. qilomikronebis, Zalian dabali

sikvrivis lipoproteinebis da dabali simkvrivis lipoproteinebisdaleqva

xdeboda fosforismJavis da magniumis qloridis damatebiT.

centrifugirebis Semdeg, siTxe Seicavda maRali simkvrivis

lipoproteinebis fraqciebs. msl-is sazom erTeulad viyenebdiT mg/dl-s.

dabali simkvrivis lipoproteinebis gamosaTvlelad viyenebdiT saerTo

qolsterinis, msl-is koncentraciisa da trigliceridebis koncentracias.

dsl-is gansazRvrisTvis viyenebdiT Friedewald et al. mier mowodebul formulas

[229]: qolesterini (mg/dl) – trigliceridebi (mg/dl)/5 - maRali simkvrivis

lipoproteinebi (mg/dl). mis sazom erTeulad aseve viyenebdiT mg/dl-s.

cxrili # 3: lipiduri profilis norma da darRveva

norma (mg/dl) normidan gadaxra

(mg/dl)

saerTo

qolesterini

< 200 > 200

trigliceridebi < 150 > 150

46  

maRali simkvrivis

lipoproteinebi

> 40 mamakacebisTvis

> 50 qalebisTvis

< 40 mamakacebisTvis

< 50 qalebisTvis

dabali simkvrivis

lipoproteinebi

< 100 > 100

bioqimiuri analizebi Sesrulda germanuli warmoebis “humani”s fotometrze

Humalizer 2000. 

Sratis leptinis dones vsazRvravdiT DRG firmis ELISA nakrebiT, rac aris

fermentiT moniSnuli imunosorbentuli kvleva dafuZnebuli sendviCis

principze.kvlevis arsi SemdegSimdgomareobs: mikrosinjara ifareba

monoklonuri antisxeuliT, romelic mimarTulia leptinis molekulis

antigenuri ubnisken. Semdeg isxmeva pacientis sisxlis nimuSi, romelsac

emateba is koniugatis xsnari, romelic Seicavs fermentiT moniSnul

antisxeuls. Sedegad warmoiqmneba sendviC-kompleqsi.mikrosinjaris

gamorecxvis Semdeg rCeba mxolod SekavSirebuli leptini. substratis

dasxmis Semdeg miRebuli Seferilobis intensivoba pirdapirproporciulia

pacientis sisxlis SratSi leptinis koncentraciisa. leptinis sazom

erTeulad viyenebdiT ng/ml-s.

Sratis insulinis dones vsazRvravdiT DRG firmis ELISA nakrebiT, rac

aris fermentiT moniSnuli imunosorbentuli kvleva dafuZnebuli sendviCis

principze.kvlevis arsi SemdegSmdgomareobs: mikrosinjara ifareba

monoklonuri antisxeuliT, romelic mimarTulia insulinis molekulis

antigenuri ubnisken. Semdeg isxmeva pacientis sisxlis nimuSi, romelsac

emateba is koniugatis xsnari, romelic Seicavs fermentiT moniSnul

antisxeuls, romelic aris anti-insulinuri antisxeuli, koniugirebuli

biotinTan. Sedegad warmoiqmneba sendviC-kompleqsi.mikrosinjaris

gamorecxvis Semdeg rCeba mxolod SekavSirebuli koniugati. meore

inkubaciuri safexuris dros, streptavidin peroqsidazis fermentuli

kompleqsi ukavSirdeba biotin-anti-insulinur antisxeulebs. SekavSirebuli

47  

kompleqsis raodenoba proporciulia nimuSSi insulinis

koncentraciisa.substratis dasxmis Semdeg miRebuli Seferilobis

intensivoba pirdapirproporciulia pacientis sisxlis SratSi insulinis

koncentraciisa.insulinis sazom erTeulad viyenebdiT mU/L-s (merT/l).

cxrili #4

norma (μIU/ml) Hhiperinsulinemia(mU/L)

bazaluri insulini < 12,5 > 12,5

postprandialuriinsulin < 25 > 25

yvela hormonuli kvleva Catarebulia humanis warmoebis aparatze – ELISYS 

UNO.

2.5. pacientebis ganawileba jgufebad

pacintebis jgufebad ganawileba moxda ori parametris mixedviT:

1. sxeulis masis indeqsi; da

2. asaki. 

aRniSnulidan gamomdinare, smi-is mixedviT pacientebis dayofa moxda sam

jgufad:

I jgufi – pacientebi normaluri woniT (smi 18.5 – 24.9 kg/m2);

II jgufi – pacientebi Warbi woniT (smi 25 – 29.9 kg/m2);

III jgufi – pacientebi simsuqniT (smi> 30 kg/m2).

asakis mixedviT pacientebis ganawileba moxda or jgufad:

I jgufi – pacientebi 20-39 wlis asakiT;

II jgufi – pacientebi 40-70 wlis asakiT.

48  

yvela pacients ganesazRvra zemoxsenebuli maCveneblebi, romelic Semdeg

damuSavda jgufebis mixedviT.  

2.6. dietoTerapiis zegavlena leptinis doneze

arsebobsmonacemebi, rom trigliceridebis maRali done iwvevs leptinis

gadaadgilebis dabrkolebas hematoencefaluri barieris gavliT.

saintereso iqneboda imis gamokvleva, Tu ra Sedegi eqneboda

trigliceridebis donis daqveiTebas. Teoriulad aRarunda

dabrkolebuliyo leptinis transporti hipoTalamusamde, Sesabamisad

moxdeboda wonis daregulireba madis daTrgunvis da energiis danaxarjis

gazrdis Sedegad.aRniSnulidan gamomdinare gadavwyviteT gagvesazRvra

naxSirwylebis da cximebis SezRudvis gavlena trigliceridebis doneze da

Sesabamisad leptinis koncentraciaze, simsuqnis mqone pacientebSi.

sub-kvlevaSi CarTvis kriteriums warmoadgenda pacientis Tanxmoba,

bolomde mieRo monawileoba kvlevaSi, mdedrobiTi sqesi, simsuqne,

trigliceridebis done >151 mg/dl da <500 mg/dl da uzmod glikemia <110

mg/dl. gamoricxvis kriteriums warmoadgenda wina 6 Tvis manZilze

dabalkaloriuli dietiT mkurnaloba, Saqris damwevi, lipidebis

damaqveiTebeli an/da sxva metabolizmze moqmedi preparatebis moxamreba,

anamnezSi kvlevis dawyebamde 6 Tvis manZilze.

44 pacienti randomulad ganawilda or jgufSi. pacientTa asaki meryeobda

23-dan 48 wlamde. pirveli jgufi iRebda naxSirwylebiT Rarib dietas,

xolo meore jgufi – cximebiT Rarib dietas. kvlevis xangrZlivobam 12

kvira Seadgina. TiToeul jgufs, rogorc kvlevis dawyebis, ise 12 kviris

TavzeganesazRvra Semdegi parametrebi: wona, smi, trigliceridebis done,

Sratis leptinis koncentracia.

TiToeuli pacientisaTvis SemuSavdaindividualuri dieta im jgufisTvis

damaxasiaTebeli Taviseburebebis gaTvaliswinebiT, romelSic isini

49  

randomulad iyvnenganawilebulebi.kaloraJis mxriv SezRudva ar

dawesebula.

pirveli jgufi iRebda energiis 60%-s cximebis, 30%-s cilebis da 10%-s

naxSirwylebis gziT.

meore jgufSi energiis 20% miReba xdeboda cilebiT, 25% cximiT, xolo 55%

naxSirwylebiT. aseve mkacrad iyo gansazRvruli, rom aRniSnul jgufSi

najeri cximebi yofiliyo <10%-ze da miRebuli qolesterinis raodenoba <

300 mg-ze.

2.7. masalis statistikuri analizi:

monacemebis mowodeba moxda saSualo±standartuli gadaxriT (sd) mudmivi

variabelisaTvis da n (%)variabelisaTvis. klinikuri maxasiaTeblebis

Sedareba xdeboda erTgzis ANOVA-Ti mudmivi variabelisaTvis da Chi‐sqaure 

anFisher-is zusti testi variabelisaTvis. Spearman-is korelaciiT

ganvsazRvreTkavSiri leptinis donesa da kardiometabolur risk-faqtorebs

Soris.variabelobis analizis (ANOVA) gamoyenebiT moxda kvebis sxvadasxva

stilis (naxSirwylebis da cximebis SezRudva) gavlenis Seswavla wonis

klebaze, trigliceridebisa da leptinis doneze, kvlevis dawyebisa da 12

kviris Tavze.statistikuri analizisTvis gamoviyeneT SPSS 20.0 versia (SPSS, 

Inc.,  Chicago,  IL).  P‐value  < 0.05 iqna gamoyenebuli, rogorc statistikurad

sarwmuno.

50  

Tavi 3: gamokvlevis Sedegebi

 

kvlevaSi CaerTo 149mdedrobiTi sqesis pacienti.

kvlevaSi CarTuli pirebis saerTo maxasiaTeblebida standartuli gadaxra

mocemulia cxrilSi #: 5.

cxrili #:5 saerTo populaciis daxasiaTeba

sakvlevi komponentebi saerTo populacia

n = 149

asaki (weli) 31.58 ± 10.37

51  

wona (kg) 87.78 ± 17.2

simaRle (sm) 165.9 ± 5.7

smi (kg/m2) 31.86 ± 6.39

welis garS. (sm) 102.52 ± 18.31

sistoluri wneva

(mm.vwy.sv)

124.39 ± 12.67

diastoluri wneva

(mm.vwy.sv)

81.48 ± 10.78

leptini (ng/ml) 67.76 ± 31.71

insulin(merT/l) 13.87 ± 7.83

glukoza (mg/dl) 93.47 ± 10.10

HOMA‐IR 3.27 ± 2.2

saerTo qolest.(mg/dl) 206.14 ± 20.6

trigliceridebi (mg/dl) 195.42  ± 22.75

HDL‐C (mg/dl) 69.89 ± 4.59

LDL‐C (mg/dl) 105.17 ± 10.64

cximi% 47.34 ± 6.62

cximi (kg) 39.97 ± 11.93

ara-cximov. qs. (kg) 42.97 ± 6.35

Zvlovani masa (kg) 2.91 ± 0.41

zeda kidurebi (kg) 43.85 ± 7.38

qveda kidurebi (kg) 50.12 ± 7.41

torsi (kg) 48.24 ± 6.88

androiduli (kg) 52.21 ± 7.62

ginoiduri (kg) 53.11 ± 5.86

smi-is mixedviT dayofil jgufebSi pacientebi ganawilda Semdegnairad:

I jgufi (normaluri wonis mqone pacientebi – smi 18.5 – 24.9 kg/m2) –N - 19

(12.7%); II jgufi (Warbi wonis mqone pacientebi - smi 25 – 29.9 kg/m2) – N - 41

(27.52%); III jgufi (simsuqnis mqone pacientebi - smi> 30 kg/m2) –N - 89 (59.7%)

(ix. grafiki #1).

grafiki #1: pacientebis ganawileba jgufebad smi-is mixedviT.

52  

53  

ganisazRvra leptinis korelacia yvela sakvlev maxasiaTebelTan, rogorc

sakvlev populaciaSi, ise dayofil jgufebSi. saSualo maCveneblebi da

standartuli gadaxra mocemulia cxrilSi #6.

cxrili #6: saSualo da standartuli gadaxra smi-is mixedviT Seqmnil

jgufebSi:

sakvlevi komponentebi Ijgufi

(normaluri

wona)

n = 19

IIjgufi

(Warbi wona)

n = 41

IIIjgufi

(simsuqne)

n = 89

asaki (weli) 25.32 ± 5.49  29 ± 7.48  34.11 ±  11.45

wona (kg) 63.51 ± 6.84  77.62 ± 6.15  97.65 ± 14.04

simaRle (sm) 166.21 ± 5.93  167.68 ± 5.18  165.01 ± 5.74

smi (kg/m2) 22.57 ± 1.39  27.5 ± 1.52  35.86 ± 4.86

welis garS. (sm) 75.74 ± 8.25  92.78 ± 8.65  112.72 ± 14.54

sistoluri wneva

(mm.vwy.sv)

113.68 ± 5.74  117.93 ± 8.73  129.65 ± 12.5

diastoluri wneva

(mm.vwy.sv)

71.84 ± 6.5  76.32 ± 8.28  85.91 ± 10.16

leptini(ng/ml) 67.74 ± 29.35  54.38 ± 27.89  80.84 ± 26.05

insulini(merT/l) 9.51 ± 4.54  12.48 ± 4.67  15.09 ± 8.91

glukoza(mg/dl) 89 ± 7.22  93.80 ± 8.82  94.27 ± 10.97

HOMA‐IR 2.07 ± 0.99  2.9 ± 1.13  3.6 ± 2.56

saerTo qolest.(mg/dl) 199.57 ± 15.29  200.88 ± 14.98  209.97 ± 22.95

54  

trigliceridebi(mg/dl) 168.13 ± 18.68  190.47 ± 25.31  213.25 ± 21.68

HDL‐C (mg/dl) 70.52 ± 4.49  69.49 ± 4.55  69.93 ± 4.66

LDL‐C (mg/dl) 101.74 ± 10.76  102.67 ± 11.92  107.08 ± 9.64

cximi% 37.95 ± 5.86  43.57 ± 4.58  51.12 ± 4.12

cximi (kg) 22.90 ± 4.8  32.01 ± 5.09  47.37 ± 8.66

ara-cximov. qs. (kg) 37.15 ± 4.47  41.18 ± 3.43  45.06 ± 6.73

Zvlovani masa (kg) 2.76 ± 0.44  2.38 ± 0.34  2.02 ± 0.37

zeda kidurebi (kg) 34.51 ± 6.97  39.9 ± 5.27  47.71 ± 5.27

qveda kidurebi (kg) 41.52 ± 7.55  46.15 ± 5.41  53.83 ± 5.48

torsi (kg) 38.29 ± 5.88  44.74 ± 5.33  52.01 ± 4.25

androiduli (kg) 41.43 ± 7.35  48.33 ± 6.11  56.35 ± 4.48

ginoiduri (kg) 46.63 ± 5.46  50.14 ± 4.37  55.90 ± 4.69

srulsakvlev populaciaSi leptinis statistikurad mniSvnelovani dadebiTi

korelacia aRiniSna wonasTan, smi-Tan, welis garSemowerilobasTan,

sistolur da diastolur wnevasTan, trigliceridebis da dabali

simkvrivis lipoprotein-qolesterinis donesTan,cximovani masis procentTan,

cximis raodenobasTan zeda da qveda kidurebsa da torsSi, (grafiki #2).

grafiki #2: srul sakvlev populaciaSileptinis dadebiTi korelacia - smi

(r=0.53, p<0.001), wona (r=0.49, p<0.001), welis garSemoweriloba (r=0.47, p<0.001),

saerTo cximis procenti (r=0.55, p<0.001), sistoluri da diastoluri wneva

(r=0.36, p<0.001 da r=0.3, p<0.001), trigliceridebida dabali simkvrivis

lipoprotein-qolseterini (r=0.09, p<0.05 da r=0.23, p<0.01).

korelaciuri kavSiri Seicvala jgufebis mixedviT.

I jgufSi leptinis dadebiTi korelacia darCa sistolur arteriul

wnevasTan, uzmod glikemiasa da cximovani masis procentul maCvenebelTan.

 

grafiki 3: leptinis dadebiTi korelacia normaluri wonis mqone

pacientebis jgufSi. pacientebis jgufSi, normaluri woniT, leptinis

dadebiTi korelacia aRiniSneboda sistolur wnevasTan (r=0.58, p<0.001),

Zvlis mineralur simkvrivesTan (r=0.14, p=0.05) saerTo cximis procentTan

55  

(r=0.07, p=0.004), torsis (r=0.03, p=0.02) da androidul areSi Calagebul

cximovan masasTan (r=0.15, p=0.05).  

II jgufSi leptinma dadebiTi korelacia aCvena mxolod smi-Tan, dabali

simkvrivis lipoprotein – qolesterinTan, trigliceridebTan, xolo

uaryofiTi korelacia ki - Zvlis mineralur simkvrivesTan.aseve dadebiTi

iyo leptinis korelacia cximis saerTo procentul SemcvelobasTan (r=0.2, 

p=0.001), cximovani qsovilis masasTan  (r=0.11, p=0.05), torsisa (r=0.19, p=0.05) da

androidul areSi Calagebul cximovan qsovilTan (r=0.18, p=0.05).

 

grafiki 4: leptinis korelacia Warbi wonis mqone pacientebis jgufSi.

Warbi wonis SemTxvevaSi, leptinis dadebiTi korelacia dafiqsirda

trigliceridebTan(r=0.17, p=0.05) da dabali simkvrivis lipoprotein-

qolesterinTan(r=0.37, p=0.02). 

III jgufSi leptinis korelacia dadebiTi iyo wonasTan, smi-Tan,

trigliceridebTan, dabali simkvrivis lipoprotein - qolesterinTan,

cximovani masis procentTan, cximovani qsovilis saerTo masasTan, cximovan

qsovilTan zeda kidurebSi da torsis zonaSi da androidul zonaSi

Calagebul cximTan; gamovlinda leptinis uaryofiTi korelacia Zvlis

mineralur simkvrivesTan, racmeore jgufTan SedarebiT ufro metad iyo

gamoxatuli.

56  

 

grafiki 5: leptinis korelacia simsuqnis mqone pacientebis jgufSi.

simsuqnis SemTxvevaSi, leptinis dadebiTi korelacia dafiqsirda smi-Tan

(r=0.22, p=0.04),trigliceridebTan(r=0.33, p=0.001), cximovani qsovilis saerTo

masasTan (r=0.25, p=0.001), cximovan qsovilTan zeda kidurebis (r=0.33, p<0.001),

torsis (r=0.22, p=0.03) da androidul nawilSi (r=0.31, p=0.003). 

leptinis yvelaze dabali koncentracia iyo I jgufSi, xolo yvelaze

maRali – III jgufSi.

leptinis korelacia sakvlev maxasiaTeblebTan smi-is mixedviT dayofil

jgufebSi mocemulia cxrilSi #7

cxrili #7: leptinis korelacia sakvlev maxasiaTeblebTan smi-is mixedviT

dayofil jgufebSi (p < 0.05 ; p< 0.01**) 

r 

sakvlevi komponentebi Ijgufi

(normaluri

wona)

n = 19

IIjgufi

(Warbi wona)

n = 41

IIIjgufi

(simsuqne)

n = 89

asaki (weli) -0.43 0.03 -0.05

wona (kg) 0.26 0.08 0.39**

simaRle (sm) 0.14 -0.13 -0.05

57  

58  

smi (kg/m2) 0.19 0.28 0.22*

welis garS. (sm) 0.27 -0.02 0.17

sistoluri wneva

(mm.vwy.sv)

0.58** -0.08 0.14

diastoluri wneva

(mm.vwy.sv)

0.4 -0.17 0.07

insulini(merT/l) 0.13 -0.16 0.16

glukoza (mg/dl) 0.2 0.17 0.11

HOMA‐IR 0.05 -0.1 0.17

saerTo qolest.(mg/dl) -0.32 -0.12 -0.16

trigliceridebi(mg/dl) 0.31 0.17* 0.33**

HDL‐C (mg/dl) -0.13 0.27 0.27

LDL‐C (mg/dl) -0.29 0.37* 0.42**

cximi% 0.07* 0.2** 0.25**

cximi (kg) 0.48 0.11* 0.26**

ara-cximov. qs. (kg) -0.15 -0.27 0.04

Zvlovani masa (kg) 0.14* -0.07* -0.29**

zeda kidurebi (kg) 0.43 0.14 0.33**

qveda kidurebi (kg) 0.33 0.19 0.16

torsi (kg) 0.03* 0.19* 0.22*

androiduli (kg) 0.15* 0.18* 0.31*

ginoiduri (kg) 0.34 0.25 0.15

asakobrivi sxvaobis mixedviT jgufebi Semdegnairad ganawilda: 20-39 wlis

asaki – N - 119 qali; 40-70 wlis asaki – N - 30 qali (grafiki #6).

grafiki #6: pacientebis ganawileba asakis mixedviT.

 

 

saSualo maCveneblebi da standartuli gadaxra asakis mixedviT dayofili

jgufebisTvis mocemulia cxrilSi #3.

cxrili #8: saSualo da standartuli gadaxra asakis mixedviT dayofil

jgufebSi:

sakvlevi komponentebi Ijgufi

(asaki 20-39

weli)

n = 199

IIjgufi

(asaki 40-70

weli)

n = 30

asaki (weli) 27.34 ± 6  48.43 ± 5.86 

59  

60  

wona (kg) 85.59 ± 16.99  96.48 ± 15.44 

simaRle (sm) 166.11 ± 5.58  165.07 ± 6.19 

smi (kg/m2) 30.98 ± 6.25  35.37 ± 5.80 

welis garS. (sm) 100.13 ± 18.15  111.97 ± 15.97 

sistoluri wneva

(mm.vwy.sv)

121.59 ± 10.61  135.5 ± 14.16 

diastoluri wneva

(mm.vwy.sv)

79.33 ± 9.61  90 ± 11.06 

leptini(ng/ml) 65.83 ± 31.49  75.43 ± 31.95 

insulini(merT/l) 13.39 ± 7.45  15.72 ± 9.14 

glukoza(mg/dl) 92.34 ± 9.04  97.93 ± 12.73 

HOMA‐IR 3.05 ± 1.76  4.1 ± 3.34 

saerTo qolest.(mg/dl) 203.04 ± 18.18  218.47 ± 24.98 

trigliceridebi(mg/dl) 192.73 ± 21.77  206.08 ± 23.80 

HDL‐C (mg/dl) 69.92 ± 4.69  69.75 ± 4.2 

LDL‐C (mg/dl) 103.66 ± 10.79  111.1 ± 7.66 

cximi% 47 ± 6.9  48.65 ± 5.3 

cximi (kg) 38.78 ± 12.07  44.65 ± 10.25 

ara-cximov. qs. (kg) 42.16 ± 6.17  46.17 ± 6.13 

Zvlovani masa (kg) 2.90 ± 0.42  2.35 ± 0.36 

zeda kidurebi (kg) 43.17 ± 7.45  46.54 ± 6.57 

qveda kidurebi (kg) 50.02 ± 7.76  50.54 ± 5.94 

torsi (kg) 47.83 ± 7.08  49.85 ± 5.87 

androiduli (kg) 51.61 ± 7.67  54.61 ± 7.06 

ginoiduri (kg) 53.21 ± 6.09  52.73 ± 4.97 

aRniSnul or jgufs Soris leptinis done ufro maRali iyo II jgufSi.

Tumca, regresiuli analizis mixedviT asaki ar aRmoCnda leptinis

mniSvnelovaniganmsazRvreli faqtori.rodesacmoxda leptinis Seswavla

wonasTan mimarTebaSi, analizis Sedegad asaki dadebiT korelaciaSi

aRmoCnda wonasTan.

orive asakobriv jgufSi gamovlinda leptinis dadebiTi korelacia

wonasTan, smi-Tan, welis garSemowerilobasTan, saerTo cximovan masasTan.

amas garda, 20-39 wlis jgufSi leptinis dadebiTi korelacia damatebiT

aRiniSna sistolur da diastolur arteriul wnevasTan, uzmod

glukozasTan, dabali simkvrivis lipoprotein – qolesterinTan, Zvlovan

masasTan, xolo 40-70 wlis jgufSi – trigliceridebTan.

 

61  

 

grafiki 7: leptinis korelacia 20-40 wlis asakisgan Sedgenil jgufSi.

aRniSnul jgufSi leptinis dadebiTi korelacia aRiniSna wonasTan (r=0.48, 

p<0.001), smi-Tan (r=0.53, p<0.001), welis garSemowerilobasTan (r=0.45, p<0.001),

sistolur da diastolur wnevasTan pressure (r=0.37, p<0.001 da  r=0.33, p<0.001,

Sesabamisad), uzmod glukozasTan(r=0.24, p=0.001), dabali simkvrivis

lipoprotein - qolesterinsa (r=0.21, p=0.02) da saerTo cximovani masis

procentTan(r=0.56, p<0.001).

 

 

 

grafiki 8: leptinis korelacia 40-70 wlis asakisgan Sedgenil jgufSi.

aRniSnul jgufSi leptinis dadebiTi korelacia aRiniSna wonasTan (r=0.47, 

p=0.001), smi-Tan (r=0.48, p=0.001), welis garSemowerilobasTan (r=0.49, p=0.01), 

trigliceridebsa (r=0.24, p<0.001) da saerTo cximovani masis procentTan

(r=0.48, p=0.01).

leptinis detaluri korelacia asakis mixedviT dayofil jgufebSi

mocemulia cxrilSi #9.

cxrili #9: leptinis korelacia sakvlev maxasiaTeblebTan asakis mixedviT

dayofil jgufebSi (p < 0.05 ; p< 0.01**) 

r 

sakvlevi komponentebi Ijgufi

(asaki 20-39

weli)

IIjgufi

(asaki 40-70

weli)

62  

63  

n = 199 n = 30

asaki (weli) 0.06 0.09

wona (kg) 0.48** 0.47**

simaRle (sm) -0.13 -0.02

smi (kg/m2) 0.53** 0.48**

welis garS. (sm) 0.45** 0.49**

sistoluri wneva

(mm.vwy.sv)

0.37** 0.26

diastoluri wneva

(mm.vwy.sv)

0.33** 0.12

insulini(merT/l) 0.13 0.33

glukoza (mg/dl) 0.24** 0.03

HOMA‐IR 0.16 0.29

saerTo qolest.(mg/dl) 0.01 -0.25

trigliceridebi(mg/dl) 0.09 0.24**

HDL‐C (mg/dl) 0.11 0.53

LDL‐C (mg/dl) 0.21* 0.2**

cximi% 0.56** 0.48**

cximi (kg) 0.54** 0.52**

ara-cximov. qs. (kg) 0.17 0.22

Zvlovani masa (kg) 0.25* -0.26**

64  

zeda kidurebi (kg) 0.52** 0.57**

qveda kidurebi (kg) 0.49** 0.36*

torsi (kg) 0.55** 0.44**

androiduli (kg) 0.55** 0.51**

ginoiduri (kg) 0.49 0.16

gamovlinda uaryofiTi korelacia Sratis leptinsa da Zvlis mineralur

simkvrives Soris40-70 wlis asakis jgufSi. 20-39 wlis jgufSi leptinis

korelacia Zvlis mienralur simkvrivesTan iyo dadebiTi.mas Semdeg rac

gaviTvaliswineT asakis faqtori, smi da wona, kvlav SenarCunda aRniSnuli

uaryofiTi korelacia. korelacia gansakuTrebiT Zlieri iyo asakisa da smi-

is matebasTan erTad.

dietoTerapiisgavlena Sratis leptinis doneze:

sakvlevi populaciis sawyisi maxasiaTeblebi mocemulia cxrilSi 1.

cxrili #10: sakvlevi populaciis daxasiaTeba:

cximebiT Raribi

dieta

(n=22) 

naxSirwylebiT

Raribi dieta

(n=22)

asaki (w) 33.2 ± 14.3 34.4 ± 11.2

wona (kg) 87.5 ± 19.3 86.9 ± 14.3

smi(kg/m2) 33.2 ± 5.2 34.6 ± 4.9

trigliceridebi

(mg/dl)

202± 51 199± 57

leptini(ng/ml) 78.84 ± 24.05 80.84 ± 19.05

12 kviris Semdeg dafiqsirda wonis mniSvnelovani kleba orive jgufSi,

Tumca naxSirwylebiT Raribi dietis dros wonis klebis intensivoba ufro

metad iyo gamoxatuli (-8.9 kg), cximis SezRudvasTan SedarebiT (-6.1 kg) (ix.

grafiki 9).

grafiki #9: naxSirwylebis an cximebis SezRudvis efeqti wonis (kg)

klebaze:

msgavsi Sedegi dafiqsirda trigliceridebis daqveiTebis mxriv

(naxSirwylebiT Raribi - (-37%) da cximebiT Raribi – (-21%) Sesabamisad)

(grafiki 10).

grafiki #10: naxSirwylebis an cximebis SezRudvis efeqti trigliceridebis

(mg/dl) donis daqveiTebaze:

65  

rogorc mosalodneli iyo, kilogramebis ufro meti raodenobiT daklebis

SemTxvevaSi, leptinis donec metad daqveiTda naxSirwylebiT Raribi dietis

fonze da Seadgenda – (-32%), xolo cximebiT Raribi dietis fonze – (-19%).

(grafiki 11).

grafiki #11: naxSirwylebis an cximebis SezRudvis efeqti leptinis (ng/ml)

koncentraciis daqveiTebaze:

66  

grafiki #12: leptinisa da trigliceridebis urTierTkavSiri:

 

 

67  

68  

Tavi 4: gamokvlevis Sedegebis ganxilva

aRniSnuli kvlevis mizani iyo Sratis leptinis korelaciis dadgena

kardiometaboluri daavadebis risk-faqtorebTan; aseve leptinis donis

Sedareba smi-sa da asakis mixedviT dayofil jgufebSi.

kvlevis monacemebis Tanaxmad, gamovlinda, rom leptinis koncentracia

yvelaze maRali iyo simsuqnis mqone pacientebis jgufSi, leptinis yvelaze

Zlieri dadebiTi korelacia aRiniSna rogorc mTeli sxeulis cximovan

masasTan, ise regionebis mixedviT dayofil cximovan masasTan,

gansakuTrebiT cximovani qsovilis ganawilebis androidul tipTan, misi

done izrdeboda asakTan erTad, igi dadebiTad korelirebda

trigliceridebTan. aseve gamovlinda, leptinis uaryofiTi korelacia Zvlis

mineralur simkvrivesTan.

Cveni kvlevis Tanaxmad leptinis done daqveiTda rogorc cximiT Raribi

dietis, ise naxSirwylebiT Raribi kvebis dros, Tumca am ukanasknelis

SemTxvevaSi leptinis daqveiTeba ufro mniSvnelovnad iyo gamoxatuli.

4.1. leptini, wona, smi da cximovani qsovili:

simsuqne aris disbalansi miRebul da gacemul energias Soris, rac

gamowveulia, umoZrao cxovrebis wesisa da gadaWarbebuli da

daubalansebeli kvebiTi Cvevebis urTierTkavSiriT. Sedegad izrdeba

cximovani qsovilis masa.

leptinis koncentracia yvelaze maRali iyo simsuqnis mqone pacientebis

jgufSi;Liuzzi A. da Tanaavtorebis, iseve rogorc Adami GF da Tanaavtorebis

mier Catarebuli kvlevebis monacemebi emTxveva Cvens mier miRebul Sedegebs

leptinis dadebiT korelaciasTan dakavSirebiT smi-Tan [231, 232].

69  

leptinis genis eqspresia dakavSirebulia gacximovnebis xarisxTan, amitom

msoflioSi Catarebuli kvlevebis umetesoba amtkicebs leptinis dadebiT

korelacias smi-Tan da wonasTan.

simsuqne xasiaTdeba cximovani qsovilis gazrdili masiT, romelic

ganpirobebulia, adipocitis rogorc hipertrofiiT, aseve hiperplaziiT

[226]. saqarTveloSi pirvelad ganisazRvra korelacia smi-s, welis

garSemowerilobasa da leptins Soris. rogorc mosalodneli iyo leptinis

done pirdapir kavSirSi iyo smi-sa da welis garSemowerilobasTan.

rogorc mravali kvlevidan viciT, erTnairi smi-is mqone orive sqesis

warmomadgenlebSi - leptinis koncentracia ufro maRalia qalebSi,

mamakacebTan SedarebiT. es aixsneba cximovani qsovilis ufro meti

procentuli SemcvelobiT qalebSi da kanqveSa/visceraluri cximis ufro

maRali proporciuli TanafardobiT. Cveni kvlevis SezRudva iyo masSi

mxolod qalebis monawileoba, winaaRmdeg SemTxvevaSi zustad

ganvsazRvravdiT aris Tu ara sxvaoba qarTvel mamakacebsa da qalebs Soris

erTnairi smi-iT.

jer kidev 1998 wels Cas Lek Cesk-is mier daweril publikaciaSi aRniSnulia,

rom arsebobs dadebiTi korelacia smi-sa da leptinis dones Soris, rac

savaraudod aris leptinis produqciis an aRqmis unaris darRveva. amis gamo

leptinis egzogenuri Seyvana aseT SemTxvevebSi araefeqturia.

leptinis yvelaze Zlieri dadebiTi korelacia aRiniSna rogorc mTeli

sxeulis cximovan masasTan, ise regionebis mixedviT dayofil cximovan

masasTan, gansakuTrebiT androidul cximovan qsovilTan; wonasa da smi-Tan

korelaciis garda, Cven gamovikvlieT leptinis kavSiri cximovan masasTan,

cximisagan Tavisufal masasa da Zlovan masasTan. msgavsi detaluri

gamokvleva sakmaod mniSvnelovania. vinaidan smi mWidrod korelirebs

cximovan masasTan, Tumca am meTodiT ver xerxdeba kunTovani da cximovani

qsovilis gamoyofa. Cveni kvlevis farglebSi gamovikvlieT sxeulis

agebuleba DXA-Ti.marTaliaumniSvnelo, magram mainc gamovlinda

sxvaobacximis ganawilebis androidul da ginoidur models Soris.

70  

pacientebis 50,8%-s aReniSneboda cximovani qsovilis ganawileba

androiduli tipiT, rac gulisxmobs cximis upiratesad muclis areSi

Calagebas; abdominuri simsuqne ki ufro metad aris dakavSirebuli

kardiometaboluri darRvevebis gazrdil riskTan.

Cveni kvlevis Sedegad leptini dadebiTad korelirebda cximovan

masasTan.korelacia ar gamovlinda leptinsa da kunTovan masas Soris.

msgavsi Sedegebi dafiqsirda García-Lorda P.da Tanaavt. mier Catarebul

kvlevaSic, romelic aseve mxolod qalTa populacias ikvlevda [233].

MehabirS.-isa da Tanaavt. mier Catarebuli kvlevis Tanaxmad

multivariaciuli analizis Sedegad gamovlinda, rom Warbi wonis mqone

qalebs leptinis koncentracia hqondaT 2-jer, xolo simsuqnis mqone qalebs

3-jer maRali, normalur smi-is mqone qalebTan SedarebiT. aRniSnulSi

cximovani masisCarTvis Semdeg, gairkva, rom rac ufro maRali iyo cximovani

qsovilis procentuli Semadgenloba, miT ufro maRali iyo leptinis done.

Cveni kvlevisgan gansxvavebiT MehabirS.-isa da Tanaavt. kvlevaSi

monawileobda mxolod aramweveli, postmenopauzis asakis qalebi [234].

Jurimae T.-sa da Tanaavtorebis kvlevaSic leptinma yvelaze Zlieri dadebiTi

korelacia gamoavlina sxeulis wonasa da smi-Tan. amasTan, simsuqnis mqone

pacientebSi cximovani qsovilis masa, gansakuTrebiT mxrebisa da bicefsebis

areSi mniSvnelovnad korelirebda leptinTan, rac ar dafiqsirda Cvens

kvlevaSi [235]. 

4.2. leptini da asaki:

Cven mier Catarebul kvlevaSi leptinis done izrdeboda asakTan erTad;

leptinis donis zrda asakTan erTad aseve aRiniSna Andreasson A.da

Tanaavtorebis mier Catarebul kvlevebSi [245].Cvens kvlevaSi leptinis

71  

dadebiTi korelacia smi-Tan orive asakobriv jgufSi aRiniSna.msgavsi

Sedegebi aCvena aseve LoÈnnqvist Fda Tanaavt. kvlevamac[41].

Liuzzi Amier Catarebul kvlevaSileptinis done pirdapir korelirebda smi-

Tan da cximovan masasTan asakisa da sqesisgan damoukideblad.

asakis mateba dakavSirebulia iseT ujredul procesebTan, rogoricaa

oqsidaciuri stresi da anTeba, rac kidev ufro Zlierdeba simsuqnis

SemTxvevaSi.oqsidaciuri stresisa da anTebis mateba, Tavis mxriv, aRrmavebs

leptinis mimarT rezistentobas da iwvevs energiis homeostazis

disregulacias. Zhang G. da Tanaavt. mier virTagvebze Catarebuli kvlevebi

cxadyofs, rom asakis matebasTan erTad hopoTalamusis garkveuli“anTebiTi

gzebi” aqtiurdeba.rodesac moaxdines hipoTalamusis aRniSnuli “anTebiTi

gzebis”pirdapiri blokada, aRniSnulma virTagvebze “gamaaxalgazrdaveblad”

imoqmeda.gadaWarbebuli kveba zrdis hipoTalamusze endoTeliumis

retikulumis stress da Sesabamisad aaqtiurebs anTebiT IKKbeta/NF‐kappa  B

gzebs, rac, Tavis mxriv, zrdis leptinis mimarT rezistentobas da simsuqnes

virTagvebSi. jerjerobiT ucnobia hipoTalamusze leptinis signalis

gaZliereba iwvevs Tu ara sicocxlis gaxangrZlivebazemsgavs cvlilebebs

[236].Aanalogiuri Sinaarsis kvlevebi adamianebze ar Catarebula, Tumca

leptinis mimarT rezistentoba SesaZloa marTlac warmoadgendes simsuqnesa

da asaks Soris kavSirs. Cveni kvlevis mier miRebuli Sedegi, asakis

matebasTan erTad leptinis koncentraciis mzardi xasiaTis sarwmuno

korelaciis Sesaxeb esadageba msoflioSi am mimarTulebiT Catarebul

sxvadasxva kvlevas. samwuxarod mocemuli kvlevis farglebSi ver

SeviswavleT leptinis donis koreqciisa da asakis korelacia.

4.3. leptini da trigliceridebis done;

imis gaTvaliswinebiT, rom leptini aregulirebs wonas, leptinis

darRveuli sinTezi, signali an mgrZnobeloba, Sesabamisad gamoiwvevs

energiis homeostazisa da sxeulis agebulebis mimarT garkveulgadaxrebs.

72  

naTelia, rom hiperleptinemia simsuqnis gamoxatulebis maxasiaTebelia,

rogorc adamianebSi, ise cxovelebSi, rac aris leptinis mimarT

rezistentobis mizezi. magram xom ar aris hiperleptinemia hormonis is

saWiro done, romelic inarCunebs mis mgrZnobelobas da energiis

homeostazs?simsuqnismqone pirebis mxolod daaxloebiT 10%-s aReniSneba

leptini fiziologiur normebSi. miuxedavad amisa, leptinis mimarT

rezistentobis zusti meqanizmi kvlav ucnobia.

sxva kvlevebis msgavsad, Cvens kvlevaSic gamovlinda sakvlev populaciaSi

leptinis maRali mocirkulire done, rac miuTiTebs leptinis mimarT

rezistentobaze [237]. bunebrivia, rom vinaidan leptinis genis eqspresia

xdeba cximovan ujredebze, rac ufro metad iqneba gamoxatuli gacximovneba,

miT maRali iqneba leptinis koncentracia. Cvens kvlevaSi umetes pacients

aReniSneboda sawyisad leptinis sakmaod maRali koncentracia.aseve

gamovlinda hipertrigliceridemia, rac SesaZloa iyos axsna leptinis

momatebuli koncentraciisa; trigliceridebis momatebuli done Trgunavs

leptinis transports sisxlidan tvinamde da zrdis leptinis mimarT

rezistentobas. Cvens kvlevaSi rogorc naxSirwylebiT, ise cximebiT Rarib

kvebas hqonda kargi efeqti trigliceridebis da leptinis

daqveiTebaze.mocemuli kvlevis Sedegebi eTanxmeba Catarebul kvlevebs,

sadac aseve naCvenebia, rom trigliceridebis donis daqveiTebam TiTqmis

gaanaxevra mocirkulire leptinis done da gansakuTrebiT es kleba ufro

mniSvnelovani iyo naxSirwylebiT Raribi dietis fonze. sainteresoa is

faqti, rom cximovani cvlis maregulirebeli hormonis rezistentoba ukeT

qveiTdeba naxSirwylebis SezRudvis fonze. am fenomenis axsna, savaraudod

aris naxSirwylovani cvlis fonze wonis meti kleba, Sesabamisad meti

cximovani masis daqveiTeba da leptinis naklebi gamomuSaveba.

Cveni da kidev mravali kvlevis Tanaxmad leptinis done izrdeba wonis

matebasa da simsuqnesTan erTad.amis damamtkicebelia, normaluri wonis

mqone cxovelebisTvis leptinis egzogenuri Seyvanis sapasuxod aRniSnuli

wonis mateba.msgavsi Sedegi iqna miRebuli wonis deficitis mqone

adamianebTan leptinis egzogenuri Seyvanis Sedegad. aRniSnuli miuTiTebs

73  

imaze, rom Tu ar aris darRveuli leptinis transporti hipoTalamusamde,

misi moqmedeba Tavisuflad xorcieldeba, rac realobaSi ar xdeba

simsuqnis mqone pacientebTan. simsuqne aseve dakavSirebulia

trigliceridebis maRal donesTan, rac leptinis signalis Semaferxebeli

SeiZleba gaxdes. naTelia, rom Tu moxdeba trigliceridebis daqveiTeba,

gaizrdeba leptinis mimarT mgrZnobeloba, leptini Seuferxeblad

Seasrulebs mis anti-simsuqnis hormonis funqcias da xels Seuwyobs

metaboluri darRvevebis gaumjobesebasa da wonis klebas. MMantzoros C.da

Tanaavt. mier Catarebuli kvlevis Tanaxmadac naxSirwylebis SezRudvas

sakveb racionSi da wonis klebas sakmaod mniSvnelovani efeqti aqvs

trigliceridebisa da leptinis daqveiTebis mxriv [237]. aseve

trigliceridebis damaqveiTebeli preparatebic aumjobeseben leptinis

transports hipoTalamusamde.

4.5. leptini da Zvlis mineraluri simkvrive

Cvens kvlevaSi gamovlinda leptinis uaryofiTi korelacia Zvlis

mineralur simkvrivesTan.aRniSnulis Tanaxmad leptinis donis gazrda

dakavSirebuli iyo Zvlis mineraluri simkvrivis daqveiTebasTan. vinaidan

leptinis gazrdili done dadebiTad korelirebs wonasa da smi-sTan,

aRniSnuli Sedegi ewinaaRmdegeba ramdenime wlis win farTod gavrcelebul

mosazrebas imis Taobaze, rom zedmeti wona icavs Zvlovan qsovils

gamofitvisgan.

dReisaTvis monacemebi leptinisa da Zvlis mineraluri simkvrivis kavSirze

gansxvavebulia.Yamauchi  et  al.mier 2001 wels Catarebuli kvlevidan

gamovlinda, rom leptini dadebiTad korelirebda Zvlis mineralur

simkvrivesTan. regresiuli analizis meTodiT korelacia kvlav

mniSvnelovani darCa, rogorc mTliani sxeulis, ise barZayis yelis Zms-sTan,

mas Semdeg rac moxda sxeulis cximovani cvlisa da asakis gaTvaliswineba

statistikuri damuSavebis dros [238]. Cveni kvlevis Sedegebi msgavsia Thomas 

et  al –is mier 2001 wels Catarebuli kvlevisa, Tumca aRniSnuli avtoris

74  

Tanaxmad leptini dadebiTad korelirebda Zms-sTan mxolod qalebSi da ara

mamakacebSi [239]. Sato et al-is mier Catarebul kvlevaSi ki leptini dadebiTad

korelirebda Zms-sTan mamakacebSic, Tumca wonis CarTvis Semdeg korelacia

daikarga.aRniSnul kvlevebSi monawileobdnen pacientebi sxeulis

normaluri masiT,romelTac ar aReniSneboda leptinis mimarT rezistentoba.

savaraudod, swored es iyo mizezi imisa, romleptini asocirdeboda Zvlis

mineraluri simkvrivis gazrdasTan [240].

Cveni kvlevis SemTxvevaSi, pacientebis umetesobas aReniSneboda leptinis

mimarT rezistentoba.leptinis mimarT rezistentobis gamo SesaZloa

iTrguneba leptinis dadebiTi efeqti Zvalze. aqedan gamomdinare, leptini

SesaZloa astimulirebs Zvlis formirebas mxolod axalgazrda asakSi da

normaluri smi-is dros, rodesac misi done normis farglebSia. Cveni

kvlevis Tanaxmad leptinis done dadebiTad korelirebda Zvlis mineralur

simkvrivesTan axalgazrda da normaluri wonis mqone pirebSi.

msgavsi Sedegebi gamovlinda ramdenime kvlevis mixedviTac, sadac Warbi

wona asocirdeboda Zvlis mineraluri simkvrivis daqveiTebasa da

motexilobis gazrdil riskTan.

savaraudod aRniSnulis mizezi aris leptinis Zvalze moqmedebis

specifiuroba, rac iTvaliswinebs sqess, Zvlis Semadgenlobis Taviseburebas

da ConCxis gansazRvrul nawilebze mis sxvadasxva moqmedebas.

mravalricxovani kvlevebis Sedegad dadginda leptinis rogorc uaryofiTi,

ise dadebiTi zegavlena Zvalze. Cveni kvleva erT-erTi maTgania, sadac

gamovlinda leptinis gazrdili donis uaryofiTi gavlena Zvlis mineralur

simkvriveze.vinaidan Sedegebi arasrulfasovani da sadavoa, meti

farTomasStaburi kvlevaa saWiro imisTvis, rom naTlad ganisazRvros

leptinis efeqti Zvlovan qsovilze.

4.6. kvebis sxvadasxva stilisgavlena leptinze

75  

leptinis donis daqveiTeba gamoiwvia, rogorc cximiT Raribma, ise

naxSirwylebiT Raribma kvebam, Tumca am ukanasknelis dros leptinis

daqveiTeba ufro mniSvnelovani iyo.

aRniSnuli Sedegis gaTvaliswinebiT, SesaZlebelia eqimebisTvis praqtikuli

rekomendaciebis micema. kerZod, Tu romeli kvebis reJimia ufro efeqturi

rogorc trigliceridebis, ise leptinis donis daqveiTebis TvalsazrisiT.

savaraudoa, rom wonis daqveiTebam Tavdapirvelad gamoiwvia

trigliceridebis daqveiTeba. aRniSnulis Sedegad sisxlidan tvinamde

leptinis gadaadgilebis gaumjobesda da Sesabamisad leptinma Tavisuflad

ganaxorciela wonis klebis efeqti, madis daqveiTebisa da energiis

danaxarjis gazrdis Sedegad.

Cvens kvlevaSi kvebis orive stilma mniSvnelovani SedegebiaCvena, rogorc

wonis klebis, ise trigliceridebisa da leptinis donis daqveiTebis

TvalsazrisiT.

Tumca, kvlevis Sedegad dafiqsirda, rom naxSirwylebis SezRudva

gacilebiT ukeT moqmedebs wonis klebaze, trigliceridebis donis

daqveiTebasa da leptinis koncentraciis Semcirebaze, vidre cximebiT

Raribi dieta.

sxvadasxva kvlevebis Sedegebi cxadyofen, rom dietas aqvs mniSvnelovani

gavlena leptinis koncentraciaze. Kratz M. da Tanaavt, iseve rogorc

Pelleymounter MA.da Tanaavt. Tanaxmad mniSvneloba aqvs ara martocximebis

raodenobas, aramed cximovani mJavebis tipsac. energiis raodenobac aseve

mniSvnelovnad asocirdeba hormonTan [241, 47]. Martin LJ da Tanaavt. Tanaxmad

naxSirwylebis miReba aseve mniSvnelovnad aregulirebs leptinis dones,

rac SesaZloa insulinis sekreciis cvlilebis mizezi iyos.dadasturebulia,

rom naxSirwylebiT mdidari sakvebi ufro metad zrdis postprandialuri

leptinis koncentracias, vidre cximiani sakvebi [242]. vinaidan simsuqne

mniSvnelovani etiologiuri faqtoria metaboluri sindromis, Saqriani

diabetisa da gul-sisxlZarRvTa daavadebebisTvis, kvebis Taviseburebebs

76  

sakmaod didi mniSvneloba aqvT simsuqnisa da aRniSnuli qronikuli

daavadebebis marTvaSi. Jensen MK. da Tanaavt. mier 2006 wels

CatarebulikvlevebiTaa dadasturebuli, rom ujredisiT mdidari sakvebis

didi odenobiT miReba zrdis leptinis mimarT mgrZnobelobas da

akontrolebs leptinis sekrecias. Sesabamisad SesaZlebelia, rom leptinis

pasuxi gansxvavebuli iyos sxvadasxva tipis naxSirwylebis dros [243].

sqesi da sxeulis cximovani qsovili ori mniSvnelovani faqtoria, rac

leptinis koncentraciazemoqmedebs. Cveni kvlevis SemTxvevaSi mdedrobiTi

sqesi da simsuqne aris zustad is ori faqtori rac asocirdeba

hiperleptinemiasTan.

Cvens kvlevaSi ar momxdara cilebis zegavlenis gamokvleva leptinis

koncentraciaze.Weigle DS mier mowodebuli publikaciis Tanaxmad, cilovani

kveba zrdis maZRrobis grZnobas da leptinis koncentracias centralur

nervul sistemaSi, iseve rogorc leptinis mimarT mgrZnobelobas, rac xels

uwyobs wonis SenarCunebas da klebasac ki [244].vinaidan cilovan kvebas

xangrZlivi periodiT SesaZloa hqondes janmrTelobaze sxvadasxva

uaryofiTi zegavlena, Cven aRniSnuli jgufis gamokvleva am etapze ar

CavTvaleT mizanSewonilad.

Semdgomi kvlevebia saWiro imisTvis, rom dadgindes Tu trigliceridebis

maregulirebeli romeli preparati, kvebis stili annutrientebis kombinacia

ukeT moqmedebs metaboluri darRvevebis gaumjobesebaze Warbi wonisa da

simsuqnis mqone pacientebSi.Tumca kidev erTxelaa aRsaniSnavi, rom

leptinis koncentracia mniSvnelovnad damokidebulia kvebasa da dietaze.

daskvnebi

77  

1. Sratis leptini dadebiTad korelirebs kardiometabolur risk-

faqtorebTan, kerZod, welis garSemowerilobasTan, sistolur da

diastolur arteriul wnevasTan, trigliceridebis donesTan;

2. Sratis leptini dadebiTad korelirebs cximovani qsovilis

raodenobasTan da misi gadanawilebis androidul tipTan, rac

SesaZloa metyvelebdes leptinis kavSirze dislipidemiasTan da

Sesabamisad gul-sisxlZarRvTa daavadebis gazrdil riskTan;

3. hiperleptinemia SesaZloa iyos normaluri wonis populaciaSi kardio-

vaskuluri riskis prediqtori;

4. dafiqsirda Sratis leptinis uaryofiTi korelaciuri kavSiri Zvlis

mineralur simkvrivesTan;

5. kvebis racionSi naxSirwylebiT mdidari sakvebis SezRudvis sapasuxod

gemovlinda leptinis donis ufro mkveTri daqveiTeba, cximebiT Rarib

dietasTan SedarebiT.

praqtikuli rekomendaciebi:

78  

1. Warbi wonisa da simsuqnis mqone pacientebSi leptinis gamokvleva

gvexmareba metaboluri darRvevebis adreul diagnostikasa da

profilaqtikuri RonisZiebebis droul gatarebaSi; es xels Seuwyobs

simsuqnesa da metabolur sindromTan dakavSirebuli garTulebebis

Semcirebas;

2. leptinis uaryofiTi kavSiri Zvlis mineralur simkvrivesTan,

SesaZloa iyos momavalSi motexilobebis prediqtori;

3. leptinis daqveiTebisTvis mizanSewonilia naxSirwylebis SezRudva

kvebis racionSi. wonis klebis Sedegad qveiTdeba trigliceridebis

done da leptinis koncentraciac, rac kidev ufro metad uwyobs xels

wonis klebas da kardiometaboluri darRvevebis gamosworebas an maTi

ganviTarebis Tavidan acilebas.

 

 

 

 

 

 

 

 

 

 

 

 

 

gamoyenebuli literatura:

79  

 

1. World health organization data, 2011

2. "Obesity: preventing and managing the global epidemic. World Health Organ Tech Rep Ser 2000; 894

3. Eckle RH, Grundy SM, Zimmet PZ. The metabolism syndrome. Lancet. 2005;365(9468):1415–28. doi: 10.1016/S0140-6736(05)66378-7

4. Al-Quaiz, Al-Joharah M. Current concepts in the management of obesity. An evidenced based review. Saudi Med J 2001; 22: 205-10.

5. Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who

have been reared apart. N Engl J Med. 1990;322:1483–1487. 6. Bouchard C, Tremblay A. Genetic influences on the response of Body fat and Fat

Distribution to positive and negative energy balances in human identical twins. J Nutr. 1997;127:943S–947S

7. Stanley S, Wynne K, McGowan B, Bloom S. Hormonal regulation of food intake. Physiol Rev 2005; 85: 1131-58.

8. Havel PJ. Peripheral signals conveying metabolic information to the brain: Short-term and long-term regulation of food intake and energy homeostasis. Exp Biol Med 2001; 226: 963-77

9. Adil Omar Saeed Bahathiq* Relationship of Leptin Hormones with Body Mass Index and Waist Circumference in Saudi Female Population of the Makkah Community; The Open Obesity Journal, 2010, 2, 95-100

10. Fasshauer M, Paschke R. Regulation of adipocytokines and insulin resistance. Diabetologia 2003; 46: 1594–1603.

11. Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and Insulin Resistance. J Clin Endocrinol Metab 2004; 89: 447–452

12. Ronti T, Lupattelli G, Monnarino E. The endocrine function of adipose tissue: an update. Clin Endocrinol 2006; 64: 355–365

13. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89: 2548–2556..

14. Mohamed-Ali V, Pinkney JH, Coppack SW. Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord 1998; 22: 1045–1058.

15. Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 2001; 60: 349–356

80  

16. Huang KC, Lin RC, Kormas N. et al. Plasma leptin is associated with insulin resistance independent of age, body mass index, fat mass, lipids, and pubertal development in nondiabetic adolescents. Int J Obes Relat Metab Disord. 2004;28(4):470–5. doi: 10.1038/sj.ijo.0802531;

17. Moreno LA, Pineda I, Rodriguez G. et al. Leptin and metabolic syndrome in obese and non-obese children. Horm Metab Res. 2002;34(7):394–9. doi: 10.1055/s-2002-33472;

18. Hodge AM, Boyko EJ, de Courten M. et al. Leptin and other components of the Metabolic Syndrome in Mauritius--a factor analysis. Int J Obes Relat Metab Disord. 2001;25(1):126–31. doi: 10.1038/sj.ijo.0801522

19. Sudhaa Sharma, Vishal R. Tandon,Shagun Mahajan,Vivek Mahajan, Annil Mahajan; Obesity: Friend or foe for osteoporosis; J Midlife Health. 2014 Jan-Mar; 5(1): 6–9

20. Considine RV, Sinha MK, Heiman ML. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334(5):292–5. doi: 10.1056/NEJM199602013340503

21. Beltowski J. Role of leptin in blood pressure regulation and arterial hypertension. J Hypertens. 2006;24(5):789–801. doi: 10.1097/01.hjh.0000222743.06584.66. [PubMed] [Cross Ref]

22. Soderberg S, Zimmet P, Tuomilehto J. et al. Leptin predicts the development of diabetes in Mauritian men, but not women: a population-based study. Int J Obes (Lond) 2007;31(7):1126–33. doi: 10.1038/sj.ijo.0803561.

23. Ruhl CE, Everhart JE. Leptin concentrations in the United States: relations with demographic and anthropometric measures. Am J Clin Nutr. 2001;74(3):295–301. [PubMed]

24. Zimmet P, Hodge A, Nicolson M. et al. Serum leptin concentration, obesity, and insulin resistance in Western Samoans: cross sectional study. BMJ. 1996;313(7063):965–9. [PMC free article] [PubMed]

25. Widjaja A, Stratton IM, Horn R. et al. UKPDS 20: plasma leptin, obesity, and plasma insulin in type 2 diabetic subjects. J Clin Endocrinol Metab. 1997;82(2):654–7. doi: 10.1210/jc.82.2.654. [PubMed] [Cross Ref]

26. Franks PW, Brage S, Luan J. et al. Leptin predicts a worsening of the features of the metabolic syndrome independently of obesity. Obes Res. 2005;13(8):1476–84. doi: 10.1038/oby.2005.178. [PubMed] [Cross Ref]

27. Leyva F, Godsland IF, Ghatei M. et al. Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk. Arterioscler Thromb Vasc Biol. 1998;18(6):928–33. [PubMed]

28. Valle M, Gascon F, Martos R. et al. Relationship between high plasma leptin concentrations and metabolic syndrome in obese pre-pubertal children. Int J Obes Relat Metab Disord. 2003;27(1):13–8. doi: 10.1038/sj.ijo.0802154. [PubMed] [Cross Ref]

81  

29. Huang KC, Lin RC, Kormas N. et al. Plasma leptin is associated with insulin resistance independent of age, body mass index, fat mass, lipids, and pubertal development in nondiabetic adolescents. Int J Obes Relat Metab Disord. 2004;28(4):470–5. doi: 10.1038/sj.ijo.0802531. [PubMed] [Cross Ref]

30. Moreno LA, Pineda I, Rodriguez G. et al. Leptin and metabolic syndrome in obese and non-obese children. Horm Metab Res. 2002;34(7):394–9. doi: 10.1055/s-2002-33472. [PubMed] [Cross Ref]

31. Hodge AM, Boyko EJ, de Courten M. et al. Leptin and other components of the Metabolic Syndrome in Mauritius--a factor analysis. Int J Obes Relat Metab Disord. 2001;25(1):126–31. doi: 10.1038/sj.ijo.0801522. [PubMed] [Cross Ref]

32. LoÈnnqvist F, Arner P, Nordfors L & Schalling M. Overexpression of the obese (ob) gene

in adipose tissue of human obese subjects. Nature Medicine 1995 1 950±953. 33. Hamilton BS, Paglia D, Kwan AY & Deitel M. Increased obese mRNA expression in

omental fat cells from massively obese humans. Nature Medicine 1995 1 953±956

34. Koerner A, Kratzsch J, Kiess W. Adipocytokines: leptin.the classical, resistin.the controversical, adiponectin.the promising, and more to come. Best Pract Res Clin Endocrinol Metab. 2005;19:525–546.

35. Brzozowski T, Konturek PC, Konturek SJ, Brzozowska I, Pawlik T. Role of

prostaglandins in gastroprotection and gastric adaptation. J Physiol Pharmacol. 2005;56 Suppl 5:33–

55.

36. Nawrot-PorabkaK, JaworekJ, Leja-SzpakA, PalonekM, SzklarczykJ, KonturekSJ,

PawlikWW. Leptin is able to stimulate pancreatic enzyme secretion via activation of duodeno-

pancreatic reflex and CCK release. J Physiol Pharmacol. 2004;55 Suppl 2:47–57.

37. Konturek PC, Brzozowski T, Burnat G, Kwiecien S, Pawlik T, Hahn EG, Konturek SJ.

Role of brain-gut axis in healing of gastric ulcers. J Physiol Pharmacol. 2004;55:179–192

38. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L & Friedman JM. Positional cloning

of the mouse obese gene and its human homologue. Nature 1994 372 425±431.

39. Considine RV, Sinha MK, Heiman ML, Kriauciunas, Stephens TW, Nyce MR et al.

Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England

Journal of Medicine 1996 334 292±295.

40. Considine RV, Sinha MK, Heiman ML, Kriauciunas, Stephens TW, Nyce MR et al.

Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England

Journal of Medicine 1996 334 292±295. 41. LoÈnnqvist F, Arner P, Nordfors L & SchAl-Shoumer ing M. Overexpression of the

obese (ob) gene in adipose tissue of human obese subjects. Nature Medicine 1995 1 950±953.

42. Hamilton BS, Paglia D, Kwan AY & Deitel M. Increased obese mRNA expression in

omental fat cells from massively obese humans. Nature Medicine 1995 1 953±956.

82  

43. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Yet al. Leptin levels in

human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced

subjects. Nature Medicine 1995 1 1155±1161.

44. Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat.

Proceedings of the Royal Society 1953 140578±592.

45. Coleman DL. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia

1973 9 294±298.

46. Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto M et al. Human Obese

gene expression ± adipocyte-speci®c expression and regional differences in the adipose tissue.

Diabetes 1995 44 855±858.

47. Pelleymounter M, Cullen M, Baker M, Hecht R,Winters D, Boone T et al. Effects of the

obese gene product on body weight regulation in ob/ob mice. Science 1995 269 540±543;

48. Halaas J, Gajiwala K, Maffei M, Cohen SL, Chait BT, Rabinowitz D et al. Weight-

reducing effects of the plasma protein encoded by the obese gene. Science 1995 269 543±546.

49. Camp®eld LA, Smith FJ, Guisez Y, Devos R & Burn P. Recombinant mouse OB

protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995

269 546±549.

50. Ozata M, Ozdemir IC & Licinio J. Human leptin de®ciency caused by a missense

mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction

indicate new targets for leptin action, greater central than peripheral resistance to the effects of

leptin, and spontaneous correction of leptin-mediated defects. Journal of Clinical Endocrinology and

Metabolism 1999 84 3686±3695.

51. Tartaglia LA, Dembski M,Weng X, Deng N, Culpepper J, Devos R et al. Identi®cation

and expression cloning of a leptin receptor, OB-R. Cell 1995 83 1263±1271.

52. Matsuoka N, Ogawa Y, Hosoda K, Matsuda J, Masuzaki H, Miyawaki T et al. Human

leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or

association of sequence variants with obesity. Diabetologia 1997 40 1204±1210.

53. Schwartz MW, Seeley RJ, Camp®eld LA, Burn P & Baskin DG. Identi®cation of leptin

action in rat hypothalamus. Journal of Clinical Investigation 1996 98 1101±1106.

54. Considine RV, Considine EL, Williams CJ, Nyce MR, Zhang P, Opentanova I et al.

Mutation screening and identi®cation of a sequence variation in the human OB gene coding region.

Biochemical and Biophysical Research Communications 1996 220 735±739.

55. Maffei M, Stoffel M, Barone M, Moon B, Dammerman M, Ravussin E et al. Absence of

mutations in the human OB gene in obese/diabetic subjects. Diabetes 1996 45 679±682.

56. Niki T, Mori H, Tamori Y, Kishimoto-Hashiramoto M, Ueno H, Araki S et al. Human

obese gene: molecular screening in Japanese and Asian Indian NIDDM patients associated with

obesity. Diabetes 1996 45 675±678.

57. Shigemoto M, Nishi S, Ogawa Y, Isse N, Matsuoka N, Tanaka T et al. Molecular

screening of both the promoter and the protein coding regions in the human ob gene in Japanese

83  

obese subjects with non-insulin-dependent diabetes mellitus. European Journal of Endocrinology

1997 137 511±513.

58. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ et al.

Congenital leptin de®ciency is associated with severe early-onset obesity in humans. Nature 1997

387 903± 908

59. StephensTW, BasinskiM, BristowPK, Bue-Vallesky JM, Burgett SG, Craft L et al. The

role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 1995 377

530±532

60. Schwartz MW, Seeley RJ, Camp®eld LA, Burn P & Baskin DG. Identi®cation of leptin

action in rat hypothalamus. Journal of Clinical Investigation 1996 98 1101±1106

61. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL & Kalra PS. Interacting appetite-regulating

pathways in the hypothalamic regulation of body weight. Endocrine Reviews 1999 20 68±100

62. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI. et al. Abnormal

splicing of the leptin receptor in diabetic mice. Nature. 1996;379(6566):632–635.

63. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ. et al. Evidence that the

diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in

db/db mice. Cell. 1996;84(3):491–495.

64. Bjørbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and

short isoforms of the leptin receptor. J Biol Chem 1997;272:32686–32695.

65. Fei H, Okano HJ, Li C et al. Anatomic localization of alternatively spliced leptin

receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci USA 1997;94:7001–7005.

66. Hileman SM, Pierroz DD, Masuzaki H et al. Characterizaton of short isoforms of the

leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity.

Endocrinology 2002;143:775–783.

67. Banks WA, Niehoff ML, Martin D, Farrell CL. Leptin transport across the blood-brain

barrier of the Koletsky rat is not mediated by a product of the leptin receptor gene. Brain Res

2002;950:130–136.

68. Elmquist JK, Bjørbaek C, Ahima RS, Flier JS, Saper CB. Distributions of leptin receptor

mRNA isoforms in the rat brain. J Comp Neurol 1998;395:535–547.

69. Couturier C, Sarkis C, Séron K et al. Silencing of OB-RGRP in mouse hypothalamic

arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity. Proc Natl

AcadSci USA 2007;104:19476–19481.

70. White DW, Tartaglia LA. Leptin and OB-R: body weight regulation by a cytokine

receptor. Cytokine Growth Factor Rev 1996;7:303–309.

71. Considine RV, Considine EL, Williams CJ, Nyce MR, Magosin SA, Bauer TL et al.

Evidence against either a premature stop codon or the absence of obese gene mRNA in human

obesity. Journal of Clinical Investigation 1995 95 2986±2988.

72. Considine RV, Considine EL, Williams CJ, Nyce MR, Zhang P, Opentanova I et al.

Mutation screening and identi®cation of a sequence variation in the human OB gene coding region.

Biochemical and Biophysical Research Communications 1996 220 735±739.

84  

73. Maffei M, Stoffel M, Barone M, Moon B, Dammerman M, Ravussin E et al. Absence of

mutations in the human OB gene in obese/diabetic subjects. Diabetes 1996 45 679±682.

74. Niki T, Mori H, Tamori Y, Kishimoto-Hashiramoto M, Ueno H, Araki S et al. Human

obese gene: molecular screening in Japanese and Asian Indian NIDDM patients associated with

obesity. Diabetes 1996 45 675±678.

75. Shigemoto M, Nishi S, Ogawa Y, Isse N, Matsuoka N, Tanaka T et al. Molecular

screening of both the promoter and the protein coding regions in the human ob gene in Japanese

obese subjects with non-insulin-dependent diabetes mellitus. European Journal of Endocrinology

1997 137 511±513.

76. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ et al.

Congenital leptin de®ciency is associated with severe early-onset obesity in humans. Nature 1997

387 903± 908.

77. Strobel A, Issad T, Camoin L, Ozata M & Strosberg AD. A leptin missense mutation

associated with hypogonadism and morbid obesity. Nature Genetics 1998 18 213±215.

78. Ozata M, Ozdemir IC & Licinio J. Human leptin de®ciency caused by a missense

mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction

indicate new targets for leptin action, greater central than peripheral resistance to the effects of

leptin, and spontaneous correction of leptin-mediated defects. Journal of Clinical Endocrinology and

Metabolism 1999 84 3686±3695

79. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM et al. Effects

of recombinant leptin therapy in a child with congenital leptin de®ciency. New England Journal of

Medicine 1999 341 879±884

80. Myers MG, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance.

Annu Rev Physiol 2008;70: 537–556.

81. Scarpace PJ, Zhang Y. Leptin resistance: a prediposing factor for diet-induced obesity.

Am J Physiol Regul Integr Comp Physiol 2009;296:R493–R500.

82. Banks WA. Is obesity a disease of the bloodbrain barrier? Physiological, pathological, and

evolutionary considerations. Curr Pharm Des 2003;9:801–809.

83. Banks WA. Blood-brain barrier and energy balance. Obesity (Silver Spring)

2006;14(Suppl 5):234S–237S.

84. Banks WA. The blood-brain barrier as a cause of obesity. Curr Pharm Des 2008;14:

1606–1614.

85. Banks WA. Enhanced leptin transport across the blood-brain barrier by alpha 1-adrenergic

agents. Brain Res 2001;899:209–217.

86. Banks WA, Coon AB, Robinson SM et al. Triglycerides induce leptin resistance at the

blood-brain barrier. Diabetes 2004;53:1253–1260.

87. CleÂment K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D et al. A mutation in the

human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998 392 398±401.

88. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL & Considine RV. Leptin: the tale of an

obesity gene. Diabetes 1996 45 1455± 1462.

85  

89. Considine RV, Considine EL,Williams CJ, Hyde TM & Caro JF. The hypothalamic leptin

receptor in humans: identi®cation of incidental sequence polymorphisms and absence of the db/db

mouse and fa/fa rat mutations. Diabetes 1996 19 992±994.

90. Rolland V, CleÂment K, Dugail I, Guy-Grand B, Basdevant A, Froguel P et al. Leptin

receptor gene in a large cohort of massively obese subjects: no indication of the fa/fa rat mutation.

Detection of an intronic variant with no association with obesity. Obesity Research 1998 6 122±127

91. Thompson DB, Ravussin E, Bennett PH & Bogardus C. Structure and sequence variation

at the human leptin receptor gene in lean and obese Pima Indians. Human and Molecular Genetics

1997 6 675±679

92. Chung WK, Power-Kehoe L, Chua M, Chu F, Aronne L, Huma Z et al. Exonic and

intronic sequence variation in the human leptin receptor gene (LEPR). Diabetes 1997 46

1509±1511.

93. Echwald SM, Sorensen TD, Sorensen TI, Tybjaerg-Hansen A, Andersen T, Chung WK et

al. Amino acid variants in the human leptin receptor: lack of association to juvenile onset obesity.

Biochemical and Biophysical Research Communications 1997 233 248±252.

94. Matsuoka N, Ogawa Y, Hosoda K, Matsuda J, Masuzaki H, Miyawaki T et al. Human

leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or

association of sequence variants with obesity. Diabetologia 1997 40 1204±1210.

95. Francke S, CleÂment K, Dina C, Inoue H, Behn P, Vatin V et al. Genetic studies of the

leptin receptor gene in morbidly obese French Caucasian families. Human Genetics 1997 100 491±

496.

96. Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD et al. Leptin

receptor gene variation and obesity: lack of association in awhite British male population. Human

and Molecular Genetics 1997 6 869±876.

97. Banks WA, Kastin AJ, Huang W, Jaspan JB & Maness LM. Leptin enters the brain by a

saturable system independent of insulin. Peptides 1996 17 305±311.

98. Schwartz M, Peskind E, Raskind M, Boyko EJ & Porte D. Cerebrospinal ¯uid leptin

levels: relationship to plasma level and to adiposity in humans. Nature Medicine 1996 2 589±593

99. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH et al.

Decreased cerebrospinal-¯uid/serum leptin ratio in obesity: a possible mechanism for leptin

resistance. Lancet 1996 348 159±161.

100. Tartaglia LA, Dembski M,Weng X, Deng N, Culpepper J, Devos R et al. Identi®cation and

expression cloning of a leptin receptor,OB-R. Cell 1995 83 1263±1271.

101. Van Heek M, Compton DS, France CF, Tedesco RP, Fauzi AB, Graziano MP et al. Diet-induced

obese mice develop peripheral, but not central, resistance to leptin. Journal of Clinical Investigation

1997 99 385±390. 102. Vettor R, Vicennati V, Gambineri A, Pagano C, Calzoni F & Pasquali R. Leptin and the

hypothalamic±pituitary±adrenal axis activity in women with different obesity phenotypes. International Journal of Obesity 1997 21 708±711.

86  

103. RamachandranA, SnehalathaC, VijayV, SatyavaniK, LathaE&HaffnerS. Plasmaleptininnon-diabeticAsianIndians: associationwithabdominaladiposity. Diabetic Medicine 1997 14 937±941.

104. Wauters M, Mertens I, Considine R, Leeuw ID & Van Gaal L. Are leptin levels dependent on body fat distribution in obese men and women? Eating and Weight Disorders 1998 3 124±130.

105. HubeF, LietzU, IgelM, JensenPB, TornqvistH, JoostH-Getal. Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Hormone and Metabolic Research 1996 28 690±693.

106. MontagueCT, PrinsJB, SandersL, DigbyJE&O'RahillyS. Depotandsex-speci®cdifferencesinhumanleptinmRNAexpression. Diabetes 1997 46 342±347.

107. LefebvreA-M, LavilleM, VegaN, RiouJ-P, VanGaalL, AuwerxJetal. Depot-speci®c differences in adipose tissue gene expression in lean and obese subjects. Diabetes 1998 47 98±103.

108. SchwartzM, PeskindE, RaskindM, BoykoEJ&PorteD. Cerebrospinal ¯uidleptinlevels: relationshiptoplasmalevelsandtoadiposityinhumans. Nature Medicine 1996 2 589±593, 51

109. Dagogo-Jack S, Fanelli C, Paramore D, Brothers J & Landt M. Plasma leptin and insulin relationships in obese and nonobese humans. Diabetes 1996 45 695±698. 52.

110. HavelPJ, Kasim-KarakasS, DubucGR, MuellerW&PhinneySD. Gender differences in plasma leptin concentrations. Nature Medicine 1996 2 949±950.,

111. Rosenbaum M, Nicholson M, Hirsch J, Heyms®eld SB, Gallagher D, Chu F et al. Effects of gender, body composition and menopause on plasma concentrations of leptin. Journal of Clinical Endocrinology and Metabolism 1996 81 3424±3427.

112. Saad MF, Damani S, Gingerich RL, Riad-Gabriel MG, Khan A, Boyadjian R et al. Sexual dimorphism in plasma leptin concentration. Journal of Clinical Endocrinology and Metabolismn 1997 82 579±584.

113. Couillard C, Mauriege P, Prud'homme D, Nadeau A, Tremblay A, Bouchard C et al. Plasma leptin concentrations: gender differences and associations with metabolic risk factors for cardiovascular disease. Diabetologia 1997 40 1178±1184

114. Tome MA, Lage M, Camina JP, Garcia-Mayor RV, Dieguez C & Casanueva FF. Sex-based differences in serum leptin concentrations from umbilical cord blood at delivery. European Journal of Endocrinology 1997 137 655±658.

115. Hassink SG, de Lancey E, Sheslow DV, Smith-Kirwin SM, O'Connor DM, Considine RVet al. Placental leptin: an important new growth factor in intrauterine and neonatal development? Pediatrics 1997 100 124 (e1).

116. Matsuda J, Yokota I, Iida M, Murakami T, Naito E, Ito M et al. Serum leptin concentration in cord blood: relationship to birth weight and gender. Journal of Clinical Endocrinology and Metabolism 1997 82 1642±1644.

117. Garcia-Mayor RV, Andrade MA, Rios M, Lage M, Dieguez C & Casanueva FF. Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary±gonadal hormones and pubertal stage. Journal of Clinical Endocrinology and Metabolism 1997 82 2849±2855.

118. Blum WF, Englaro P, Hanitsch S, Juul A, Hertel NT, MuÈ ller J et al. Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. Journal of Clinical Endocrinology and Metabolism 1997 82 2904±2910.

119. Falorni A, Bini V, Molinari D, Papi F, Celi F, Di Stefano G et al. Leptin serum levels in normal weight and obese children and adolescents: relationship with age, sex, pubertal development, body mass index, and insulin. International Journal of Obesity 1997 21 881±890.

120. Roemmich JN, Clark PA, Berr SS, Mai V, Mantzoros CS, Flier JS et al. Gender differences in leptin levels during puberty are related to the subcutaneous fat depot and sex steroids. American Journal of Physiology 1998 275 E543±E551.

87  

121. Wabitsch M, Blum WF, Muche R, Braun M, Hube F, Rascher W et al. Contribution of androgens to the gender difference in leptin production in obese children and adolescents. Journal of Clinical Investigation 1997 100 808±813.

122. Lahlou N, Landais P, De Boissieu D & BougneÁres P-F. Circulating leptin in normal children and during the dynamic phase of juvenile obesity. Relation to body fatness, energy metabolism, caloric intake, and sexual dimorphism. Diabetes 1997 46 989± 993.

123. Mantzoros CS, Flier JS & Rogol AD. A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. Journal of Clinical Endocrinology and Metabolism 1997 82 1066±1070.

124. Machteld Wauters, Human leptin: from an adipocyte hormone to an endocrine mediator; European Journal of Endocrinology (2000) 143 293±311

125. Sivan E, Whittaker P, Sinha D, Homko CJ, Lin M, Reece EA et al. Leptin in human pregnancy: the relationship with gestational hormones. American Journal of Obstetrics and Gynecology 1998 179 1128±1132.

126. Kristensen K, Pedersen SB & Richelsen B. Regulation of leptin by steroid hormones in rat adipose tissue. Biochemical and Biophysical Research Communications 1999 259 624±630.

127. Lahlou N, Landais P, De Boissieu D & BougneÁres P-F. Circulating leptin in normal children and during the dynamic phase of juvenile obesity. Relation to body fatness, energy metabolism, caloric intake, and sexual dimorphism. Diabetes 1997 46 989± 993.

128. Wabitsch M, Blum WF, Muche R, Braun M, Hube F, Rascher Wet al. Contribution of androgens to the gender difference in leptin production in obese children and adolescents. Journal of Clinical Investigation 1997 100 808±813.

129. Shimizu H, Shimomura Y, Nakanishi Y, Futawatari T, Ohtani K, Sato N et al. Estrogen increases in vivo leptin production in rats and human subjects. Journal of Endocrinology 1997 154 285±292

130. Mannucci E, Ognibene A, Becorpi A, Cremasco F, Pellegrini S, Ottanelli S et al. Relationship between leptin and oestrogens in healthy women. European Journal of Endocrinology 1998 139 198±201.

131. BuÈ tzow TL, Moilanen JM, Lehtovirta M, Tuomi T, Hovatta O, Siegberg R et al. Serum and follicular ¯uid leptin during in vitro fertilization: relationship among leptin increase, body fat mass, and reduced ovarian response. Journal of Clinical Endocrinology and Metabolism 1999 84 3135±3139.

132. Wu-Peng S, Rosenbaum M, Nicolson M, Chua SC & Leibel RL. Effects of exogenous gonadal steroids on leptin homeostasis in rats. Obesity Research 1999 7 586±592.

133. Hislop M, Ratanjee B, Soule S & Marais A. Effects of anabolicandrogenic steroid use or gonadal testosterone suppression on serum leptin concentration in men. European Journal of Endocrinology 1999 141 40±46.

88  

134. Palmert MR, Radovick S & Boepple PA. The impact of reversible gonadal sex steroid suppression on serum leptin concentrations in children with central precocious puberty. Journal of Clinical Endocrinology and Metabolism 1998 83 1091±1096

135. Behre HM, Simoni M & Nieschlag E. Strong association between serum levels of leptin and testosterone in men. Clinical Endocrinology 1997 47 237±240

136. JockenhoÈvel F, Blum WF, Vogel E, Englaro P, MuÈ ller-Wieland D, Reinwein D et al. Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men. Journal of Clinical Endocrinology and Metabolism 1997 82 2510±2513.

137. Saad MF, Damani S, Gingerich RL, Riad-Gabriel MG, Khan A, Boyadjian R et al. Sexual dimorphism in plasma leptin concentration. Journal of Clinical Endocrinology and Metabolism 1997 82 579±584.

138. Couillard C, Mauriege P, Prud'homme D, Nadeau A, Tremblay A, Bouchard C et al. Plasma leptin concentrations: gender differences and associations with metabolic risk factors for cardiovascular disease. Diabetologia 1997 40 1178±1184.

139. Ryan AS & Elahi D. The effects of acute hyperglycemia and hyperinsulinemia on plasma leptin levels: its relationships with body fat, visceral adiposity, and age in women. Journal of Clinical Endocrinology and Metabolism 1996 81 4433±4438.

140. Schwartz MW, Prigeon RL, Kahn SE, Nicholson M, Moore J, Morawiecki A et al. Evidence that plasma leptin and insulin levels are associated with body adiposity via different mechanisms. Diabetes Care 1997 20 1476±1481.

141. Widjaja A, Stratton IM, Horn R, Holman RR, Turner R & Brabant G. UKPDS 20: Plasma leptin, obesity, and plasma insulin in type 2 diabetic subjects. Journal of Clinical Endocrinology and Metabolism 1997 82 654±657.

142. Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B et al. Transient increase in obese gene expression after food intake or insulin administration. Nature 1995 377 527±529.

143. Rentsch J & Chiesi M. Regulation of ob gene mRNA levels in cultured adipocytes. FEBS Letters 1996 379 55±59.

144. Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R et al. Acute and chronic effect of insulin on leptin production in humans ± studies in vivo and in vitro. Diabetes 1996 45 699±701.

145. Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E et al. Insulin and cortisol promote leptin production in cultured human fat cells. Diabetes 1996 45 1435±1438.

146. Hardie L, Guilhot N & Trayhurn P. Regulation of leptin production in cultured mature white adipocytes. Hormone and Metabolic Research 1996 28 685±689.

89  

147. MacDougald OA, Hwang C-S, Fan H & Lane MD. Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adipocytes. PNAS 1995 92 9034±9037.

148. Cusin I, Sainsbury A, Doyle P, Rohner-Jeanrenaud F & Jeanrenaud B. The ob gene and insulin: a relationship leading to clues to the understanding of obesity. Diabetes 1995 44 1467± 1470.

149. Hardie LJ, Rayner DV, Holmes S & Trayhurn P. Circulating leptin levels are modulated by fasting, cold exposure and insulin administration in lean but not Zucker (fa/fa) rats as measured by ELISA. Biochemical and Biophysical Research Communications 1996 223 660±665.

150. Patel B, Koenig J, Kaplan L & Hooi S. Increase in plasma leptin and Lep mRNA concentrations by food intake is dependent on insulin. Metabolism 1998 47 603±607.

151. Sivitz WI, Walsh S, Morgan D, Donohoue P, Haynes W & Leibel R. Plasma leptin in diabetic and insulin-treated diabetic and normal rats. Metabolism 1998 47 584±591

152. Boden G, Chen X, Kolaczynski J & Polansky M. Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. Journal of Clinical Investigation 1997 100 1107±1113.

153. Larsson H, Elmstahl S & AhreÂn B. Plasma leptin levels correlate to islet function independently of body fat in postmenopausal women. Diabetes 1996 45 1580±1584

154. Vidal H, Auboeuf D, De Vos P, Staels B, Riou JP, Auwerx J et al. The expression of ob gene is not acutely regulated by insulin and fasting in human abdominal subcutaneous adipose tissue. Journal of Clinical Investigation 1996 98 251±255.

155. Nagasaka S, Ishikawa S, Nakamura T, Kawakami A, Rokkaku K, Hayashi H et al. Association of endogenous insulin secretion and mode of therapy with body fat and serum leptin levels in diabetic subjects. Metabolism 1998 47 1391±1396.

156. Korbonits M, Trainer PJ, Little JA, Edwards R, Kopelman PG, Besser GM et al. Leptin levels do not change acutely with food administration in normal or obese subjects, but are negatively correlated with pituitary±adrenal activity. Clinical Endocrinology 1997 46 751±757.

157. Muzzin P, Eisensmith RC, Copeland KC & Woo SL. Correction of obesity and diabetes in genetically obese mice by leptin gene therapy. PNAS 1996 93 14804±14808.

158. Kulkarni RN, Wang Z-L, Wang R-M, Hurley JD, Smith DM, Ghatel MA et al. Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. Journal of Clinical Investigation 1997 100 2729±2736.

159. Harris RB. Acute and chronic effects of leptin on glucose utilization in lean mice. Biochemical and Biophysical Research Communications 1998 245 502±509.

160. Sivitz WI, Walsh S, Morgan D, Thomas M & Haynes W. Effects of leptin on insulin sensitivity in normal rats. Endocrinology 1997 138 3395±3401.

90  

161. Mizuno A, Murakami T, Otani S, Kuwajima M & Shima K. Leptin affects pancreatic endocrine functions through the sympathetic nervous system. Endocrinology 1998 139 3863± 3870.

162. Considine RV & Caro JF. Pleiotropic cellular effects of leptin. Current Opinion in Endocrinology and Diabetes 1999 6 163±169.

163. Kieffer TJ, Heller RS & Habener JF. Leptin receptors expressed on pancreatic b-cells. Biochemical and Biophysical Research Communications 1996 224 522±527.

164. Emilsson V, Liu Y-L, Cawthorne M, Morton NM & Davenport M. Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 1997 46 313±316.

165. Kieffer TJ, Heller RS, Leech CA, Holz GG & Habener JF. Leptin suppression of insulin secretion by the activation of ATPsensitive K+ channels in pancreatic b-cells. Diabetes 1997 46 1087±1093.

166. Chen N-G, Swick AG & Romsos DR. Leptin constrains acetylcholine- induced insulin secretion from pancreatic islets of ob/ob mice. Journal of Clinical Investigation 1997 100 1174±1179.

167. Pallett AL, Morton NM, Cawthorne MA & Emilsson V. Leptin inhibits insulin secretion and reduces insulin mRNA levels in rat isolated pancreatic islets. Biochemical and Biophysical Research Communications 1997 238 267±270.

168. Fehmann H-C, Peiser C, Bode H-P, Stamm M, Staats P, Hedetoft C et al. Leptin: a potent inhibitor of insulin secretion. Peptides 1997 18 1267±1273.

169. Ookuma M, Ookuma K & York DA. Effects of leptin on insulin secretion from isolated rat pancreatic islets. Diabetes 1998 47 219±223.

170. Zhao AZ, Bornfeldt KE & Beavo JA. Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. Journal of Clinical Investigation 1998 102 869±873.

171. Seufert J, Kieffer TJ, Leech CA, Holz GG, MoritzW, Ricordi C et al. Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 1999 84 670±676.

172. Harvey J, McKenna F, Herson P, Spanswick D & Ashford M. Leptin activates ATP-sensitive potassium channels in the rat insulin-secreting cell line, CRI-G1. Journal of Physiology 1997 504 527±535.

173. Chen N-G & Romsos DR. Persistently enhanced sensitivity of pancreatic islets from ob/ob mice to PKC-stimulated insulin secretion. American Journal of Physiology 1997 272 E304±E311.

174. Poitout V, Rouault C, Guerre-Millo M, Briaud I & Reach G. Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans. Endocrinology 1998 139 822±826.

91  

175. Seufert J, Kieffer TJ & Habener JF. Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-de®cient ob/ob mice. PNAS 1999 96 674±679.

176. Kamohara S, Burcelin R, Halaas JL, Friedman JM & Charron MJ. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 1997 389 374±377.

177. Koyama K, Chen G,Wang M-Y, Lee Y, Shimabukuro M, Newgard CB et al. b-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy. Diabetes 1997 46 1276±1280.

178. Chinookoswong N, Wang J-L & Shi Z-Q. Leptin restores euglycemia and normalizes glucose turnover in insulin-de®cient diabetes in the rat. Diabetes 1999 48 1487±1492.

179. Barzilai N, She L, Liu L,Wang J, Hu M, Vuguin P et al. Decreased visceral adiposity accounts for leptin effect on hepatic but not peripheral insulin action. American Journal of Physiology 1999 277 E291±E298.

180. Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G et al. Speci®city of leptin action on elevated blood glucose levels and hypothalamic Neuropeptide Y gene expression in ob/ob mice. Diabetes 1996 45 531±535.

181. Cohen B, Novick D & Rubinstein M. Modulation of insulin activities by leptin. Science 1996 274 1185±1188.

182. Rossetti L, Massillon D, Barzilai N, Vuguin P, ChenW, HawkinsM et al. Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. Journal of Biological Chemistry 1997 272 27758±27763.

183. Liu L, Karkanias GB, Morales JC, Hawkins M, Barzilai N, Wang J et al. Intracerebroventricular leptin regulates hepatic but not peripheral glucose ¯uxes. Journal of Biological Chemistry 1998 273 31160±31167.

184. MuÈ ller G, Ertl J, Gerl M & Preibisch G. Leptin impairs metabolic actions of insulin in isolated rat adipocytes. Journal of Biological Chemistry 1997 272 10585±10593.

185. Williams LB, Ohannesian DW, Kogon BE, Jones R, Inman M, Huse J et al. Leptin increases basal and insulin-stimulated glucose uptake into human subcutaneous adipocytes. Diabetes 1998 47 A73.

186. Fukuda H, Iritani N, Sugimoto T & Ikeda H. Transcriptional regulation of fatty acid synthase gene by insulin/glucose, polyunsaturated fatty acid and leptin in hepatocytes and adipocytes in normal and genetically obese rats. European Journal of Biochemistry 1999 260 505±511.

187. Berti L, Kellerer M, Capp E & HaÈring H. Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes: evidence for a PI3-kinase mediated effect. Diabetologia 1997 40 606±609.

92  

188. Kellerer M, Koch M, Metzinger E, Mushack J, Capp E & HaÈring H. Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase- 2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabetologia 1997 40 1358±1362.

189. Ceddia R, William W & Curi R. Comparing effects of leptin and insulin on glucose metabolism in skeletal muscle: evidence for an effect of leptin on glucose uptake and decarboxylation. International Journal of Obesity 1999 23 75±82.

190. Muoio DM, Dohm GL, Tapscott EB & Coleman RA. Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice. American Journal of Physiology 1999 276 E913±E921

191. Zimmet P & Alberti K. Leptin: is it important in diabetes? Diabetic Medicine 1996 13 501±503.

192. Taylor SI, Barr V & Reitman M. Does leptin contribute to diabetes caused by obesity? Science 1996 274 1151±1152.

193. Shimabukuro M, Koyama K, Chen G, Wang M-Y, Trieu F, Lee Y et al. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. PNAS 1997 94 4637±4641.

194. Sarmiento U, Benson B, Kaufman S, Ross L, Qi M, Scully S et al. Morphologic and molecular changes induced by recombinant human leptin in the white and brown adipose tissues of C57BL/6 mice. Laboratory Investigation 1997 77 243±256.

195. Widjaja A, Stratton IM, Horn R, Holman RR, Turner R & Brabant G. UKPDS 20: Plasma leptin, obesity, and plasma insulin in type 2 diabetic subjects. Journal of Clinical Endocrinology and Metabolism 1997 82 654±657.

196. Haffner SM, Stern MP, Miettinen H, Wei M & Gingerich RL. Leptin concentrations in diabetic and nondiabetic Mexican± Americans. Diabetes 1996 45 822±824.

197. McGregor GP, Desaga JF, Ehlenz K, Fischer A, Heese F, Hegele A et al. Radioimmunological measurement of leptin in plasma of obese and diabetic human subjects. Endocrinology 1996 137 1501±1504.

198. De Courten M, Zimmet P, Hodge A, Collins V, Nicholson M, Staten M et al. Hyperleptinaemia: the missing link in the Metabolic Syndrome? Diabetic Medicine 1997 14 200±208.

199. Beltowski J. Leptin and atherosclerosis. Atherosclerosis 2006;189; 47-60 (review)].

200. Segal KR, Landt M. Relation between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes 1996;45;988-91;

201. Van Dielen FM, van’t Veer C. Increased leptin concentracions correlate with increased concentration of inflammatory markers in morbidly obese individuals. Int J Obes Relat Metab Disord 2001;25;1759-66

93  

202. Yutaka Kajikawa, Masae Ikeda; Association of Circulating Levels of Leptin and Adiponectin with Metabolic Syndrome and Coronary Heart Disease in Patients with Various Coronary Risk Factors; Int Heart J; 2011; 17-22

203. Yutaka Kajikawa, Masae Ikeda; Association of Circulating Levels of Leptin and Adiponectin with Metabolic Syndrome and Coronary Heart Disease in Patients with Various Coronary Risk Factors; Int Heart J; 2011; 17-22

204. Yutaka Kajikawa, Masae Ikeda; Association of Circulating Levels of Leptin and Adiponectin with Metabolic Syndrome and Coronary Heart Disease in Patients with Various Coronary Risk Factors; Int Heart J; 2011; 17-22

205. Yutaka Kajikawa, Masae Ikeda; Association of Circulating Levels of Leptin and Adiponectin with Metabolic Syndrome and Coronary Heart Disease in Patients with Various Coronary Risk Factors; Int Heart J; 2011; 17-22

206. Langenberg C, Bergstrom J, Scheidt-Nave C, Pfeilschifter J, Barrett-Connor E 2006 Cardiovascular death and the metabolic syndrome: role ofadiposity-signaling hormones and inflammatory markers. Diabetes Care29:1363–1369

207. Zimmet P, Hodge A, Nicolson M, Staten M, de Courten M, Moore J, Morawiecki A, Lubina J, Collier G, Alberti G, Dowse G 1996 Serum leptinconcentration, obesity, and insulin resistance in Western Samoans: cross sectionalstudy. BMJ 313:965–969;

208. Leyva F, Godsland IF, Ghatei M, Proudler AJ, Aldis S, Walton C, Bloom S, Stevenson JC 1998 Hyperleptinemia as a component of a metabolic syndromeof cardiovascular risk. Arterioscler Thromb Vasc Biol 18:928–933

209. Margetic S, Gazzola C, Pegg GG, Hill RA 2002 Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 26:1407–1433

210. Huang KC, Lin RC Plasma leptin is associated with insulin resistance independent of age, body mass index, fat mass, lipids, and pubertal development in nondiabetic adolescents;

211. Wen-Cheng Li, Serum leptin is associated with cardiometabolic risk and predicts metabolic syndrome in Taiwanese adults; Cardiovasc Diabetol. 2011; 10: 36. Published online 2011 April 28. doi: 10.1186/1475-2840-10-36.

213. RICCI TA, HEYMSFIELD SB, PIERSON RN JR, STAHL T, CHOWDHURY HA, SHAPSES SA: Moderate energy restriction increases bone resorption in obese postmenopausal women. Am J Clin Nutr 73: 347-352, 2001

214. Lan-Juan Zhao,Hui Jiang,Christopher J Papasian,Dev Maulik, Betty Drees, James Hamilton, Hong-Wen Deng; Correlation of Obesity and Osteoporosis: Effect of Fat Mass on the Determination of Osteoporosis; J Bone Miner Res. Jan 2008; 23(1): 17–29

215. Felson DT, Zhang Y, Hannan MT, Anderson JJ. Effects of weight and body mass index on bone

94  

mineral density in men and women: The Framingham study. J Bone Miner Res. 1993;8:567–573

216. Reid IR, Ames R, Evans MC, Sharpe S, Gamble G, France JT, Lim TM, Cundy TF. Determinants of total body and regional bone mineral density in normal postmenopausal women—a key role for fat mass. J Clin Endocrinol Metab. 1992;75:45–51

217. Riis BJ, Rodbro P, Christiansen C. The role of serum concentrations of sex steroids and bone turnover in the development and occurrence of postmenopausal osteoporosis. Calcif Tissue Int. 1986;38:318–322

218. Lau EM, Chan YH, Chan M, Woo J, Griffith J, Chan HH, Leung PC. Vertebral deformity in chinese men: Prevalence, risk factors, bone mineral density, and body composition measurements. Calcif Tissue Int. 2000;66:47–52

219. Reid IR, Legge M, Stapleton JP, Evans MC, Grey AB. Regular exercise dissociates fat mass and bone density in premenopausal women. J Clin Endocrinol Metab. 1995;80:1764–1768

220. Zemel MB. Role of calcium and dairy products in energy partitioning and weight management.Am J Clin Nutr. 2004;79:907S–912S

221. Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung UI, Kubota N, Terauchi Y, Harada Y, Azuma Y, Nakamura K, Kadowaki T, Kawaguchi H. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest. 2004;113:846–855

222. Wisse BE, Schwartz MW. Role of melanocortins in control of obesity. Lancet. 2001;358:857–859

223. Westman Eric, Mavropoulos John, Yancy Jr. William, Volek Jeff. A Review of Low-carbohydrate Ketogenic Diets. Current Atherosclerosis Reports; 2003

224. Banks William A, et. al. Triglycerides Induce Leptin Resistance at the Blood- Brain Barrier. Diabetes; 2004

225. Herbst, Sarah K., "The Association Between Triglyceride and Leptin Levels in Obese Subjects Following a Low-Carbohydrate or Low- Fat Diet" (2006). Honors Scholar Theses. Paper 15

226. World Health Organization. Physical status: The use and interpretation of anthropometry. Geneva, Switzerland: World Health Organization 1995. WHO Technical Report Series.

227. Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 1985; 28: 412–419. 14.

228. World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Geneva: World Health Organization, 1999;

95  

229. NHANES 2005–2006 Data Documentation Laboratory Assessment: Triglycerides, LDL-Cholesterol, and Apoliprotein (ApoB)

230. Gordon, T. et al., Amer. J. Med. 62, 707 (1977)

231. Liuzzi A, Savia G, Tagliaferri M, Lucantoni R, Berselli ME, Petroni ML, De Medici C, Viberti GC. Serum leptin concentration in moderate and severe obesity: relationship with clinical, anthropometric and metabolic factors. Int J Obes Relat Metab Disord. 1999; 23: 1066-1073;

232. Adami GF, Civalleri D, Cella F, Marinari G, Camerini G, Papadia F, Scopinaro N. Relationships of serum leptin to clinical and anthropometric findings in obese patients. Obes Surg. 2002; 12: 623-627 ;

233. García-Lorda P, Bulló M, Vilà R, del Mar Grasa M, Alemany M, Salas-Salvadó J. Leptin concentrations do not correlate with fat mass nor with metabolic risk factors in morbidly obese females. Diabetes Nutr Metab. 2001;14:329-36;

234. Mehabir S, Baer D, Johnson LL, Roth M, Campbell W, Clevidence B, Taylor PR; Body mass index, percent body fat, and regional body fat distribution in relation to leptin concentrations in healthy, non-smoking postmenopausal women in a feeding study; Nutrition Journal 2007, 6:3;

235. Jürimäe T1, Sudi K, Jürimäe J, Payerl D, Rüütel K.; Relationships between plasma leptin levels and body composition parameters measured by different methods in postmenopausal women. Am J Hum Biol. 2003 Sep-Oct;15(5):628-36.

236. Zhang G et al. Nature. 2013;497:211-216

237. Mantzoros Christos. The Role of Leptin in Human Obesity and Disease: A Review of Current Evidence. American College of Physicians-American Society of Internal Medicine; 1999

238. Yamauchi H, Uetsuka K, Okada T, Nakayama H, Doi K. Impaired liver regeneration after partial hepatectomy in db/ db mice. Exp Toxicol Pathol 2003;54(4):281–6.

239. Thomas T. Leptin: A potential mediator for protective effects of fat mass on bone tissue. Joint Bone Spine. 2003;70:18–21

240. SATO M, TAKEDA N, SARUI H, TAKAMI R, TAKAMI K, HAYASHI M, SASAKI A, KAWACHI S, YOSHINO K, YASUDA K: Association between serum leptin concentrations and bone mineral density, and biochemical markers of bone turnover in adult men. J Clin Endocrinol Metab 86: 5273-5276, 2001

241. Kratz M, von EA, Fobker M, Buyken A, Posny N, Schulte H, et al. The impact of dietary fat composition on serum leptin concentrations in healthy nonobese men and women. J Clin Endocrinol Metab 2002; 87(11): 5008-14.

242. Martin LJ, Siliart B, Lutz T A, Biourge V , Nguyen P, Dumon HJ. Postprandial response of plasma insulin, amylin and acylated ghrelin to various test meals in lean and obese cats. Br J Nutr 2010; 103(11): 1610-9

96  

243. Jensen MK, Koh-Banerjee P , Franz M, Sampson L, Gronbaek M, Rimm EB. Whole grains, bran, and germ in relation to homocysteine and markers of glycemic control, lipids, and inflammation 1. Am J Clin Nutr 2006; 83(2): 275-83

244. Weigle DS, Cummings DE, Newby PD, Breen PA, Frayo RS, Matthys CC, et al. Roles of leptin and ghrelin in the loss of body weight caused by a low fat, high carbohydrate diet. J Clin Endocrinol Metab 2003; 88(4): 1577-86;

245. Andreasson, A. N., Undén, AL., Elofsson, S., Brismar, K. Leptin and adiponectin: Distribution and associations with cardiovascular risk factors in men and women of the general population.Am J Hum Biol. 2012; 24: 595-601. doi: 10.1002/ajhb.22279