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7/29/2019 Mlinar B. Et Al.- Insulin Resistance Obesity and Metabolic Syndrome
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Biochemia Medica god. 16, br. 1, 2006. Biochemia Medica Vol. 16, No. 1, 2006
8
Molekularni mehanizmi inzulinske rezistencije, pretilosti i metabolikog sindroma
Molecular Mechanisms o Insulin Resistance, Obesity and Metabolic Syndrome
Barbara Mlinar1, Janja Marc1, Marija Peier2
1 Zavod za kliniku biokemiju, Farmaceutski akultet, Sveuilite u Ljubljani, Ljubljana, Slovenija1 Department o Clinical Biochemistry, Faculty o Pharmacy, University o Ljubljana, Slovenia;2 Zavod za endokrinologiju i metabolike bolesti, Kliniki bolniki centar Ljubljana, Ljubljana, Slovenija2 Department o Endocrinology and Metabolic Diseases, University Medical Center, Ljubljana, Slovenia
Saetak
Inzulinska rezistencija je stanje poremeene sposobnosti odgovora na djelo-
vanje inzulina. Najei osnovni uzrok je sredinja pretilost, iako je primarnainzulinska rezistencija mogua i u osoba s normalnom teinom. Suvino abdo-
minalno masno tkivo otputa poveane koliine aktora tumorske nekroze i
slobodnih masnih kiselina, to izravno utjee na inzulinsko signaliziranje, sma-
njuje preuzimanje glukoze u miiima, dovodi do pretjerane sinteze trigliceri-
da i izaziva glukoneogenezu u jetri. Ostali imbenici za koje se pretpostavlja
da igraju ulogu u inzulinskoj rezistenciji su adiponektin (snienje), leptin, IL-6
i neki drugi adipokini. Smatra se da je obina pretilost poligenog podrijetla
uz utjecaj "pretilogene" okoline povean unos hrane i nedostatak tjelesne
aktivnosti. Dananja visoka uestalost pretilosti mogla bi se objasniti evolucij-
skim pritiskom za odabir gena koji promiu pohranu masti za preivljenje u
vrijeme gladovanja. Inzulinska rezistencija je prisutna zajedno sa sredinjom
pretilosti, hipertenzijom i dislipidemijom, koje se skupno oznaavaju kao me-taboliki sindrom. Ove pojavnosti predstavljaju snane imbenike rizika za e-
ernu bolest tipa 2 i kardiovaskularnu bolest.
Kljune rijei: inzulinska rezistencija, pretilost, metaboliki sindrom, adipo-
kini
Abstract
Insulin resistance is a state o impaired responsiveness to insulin action. The
most common underlying cause is central obesity although primary insulinresistance in normal-weight individuals is also possible. Excess abdominal
adipose tissue has been shown to release increased amounts o tumor necro-
sis actor and ree att y acids, which directly afect insulin signaling, dimi-
nish glucose uptake in the muscle, drive exaggerated triglyceride synthesis
and induce gluconeogenesis in the liver. Other actors presumed to play a role
in insulin resistance are adiponectin (a decrease), leptin, IL-6 and some other
adipokines. Common obesity is thought to be o polygenic origin with inu-
ence o "obesogenic" environment, i.e. increased ood intake and the lack o
physical activity. Today's high prevalence o obesity could be explained by
evolutionary pressure or selection o genes promoting at storage to survi-
ve in starvation. Insulin resistance requently coexists with central obesity,
hypertension and dyslipidemia, which have collectively been denoted as me-tabolic syndrome. These maniestations represent strong risk actors or dia-
betes mellitus type 2 and cardiovascular disease.
Key words: insulin resistance, obesity, metabolic syndrome, adipokines
Pregledni lanak Rewiev
Pristiglo: 2. sijenja 2006. Received: January 2, 2006
Prihvaeno: 16. oujka 2006. Accepted: March, 16, 2006
UvodInzulinska rezistencija (IR) defnira se kao odgovor na inzu-
lin manji od normalnog, to dovodi do hiperinzulinemije
kako bi se odrali euglikemijski uvjeti (1). Stoga kompen-
zacijska hiperinzulinemija zbog pojaanog luenja -sta-
nica obvezatno popratno obiljeje uz IR. Glavne znaajke
IR su loe inhibirana glukoneogeneza, poremeeno preu-
zimanje glukoze u miiima i loe inhibirana lipoliza u
masnom tkivu. Kliniki biljezi IR su visceralna pretilost, crn-
kasta akantoza (2), akne, prekomjerna dlakavost (3), jetre-
na steatoza (1).
Zlatni standard za procjenu IR je hiperinzulinemijska eug-
likemijska spona (engl. clamp): inzulin se daje po ustalje-
IntroductionInsulin resistance (IR) is defned as less than normal re-
sponse to insulin, which leads to hyperinsulinemia or
euglycemic conditions to be maintained (1). Compensa-
tory hyperinsulinemia due to enhanced -cell secretion
is thereore an obligate accompanying eature in IR. The
main characteristics o IR are disinhibited gluconeogen-
esis, impaired uptake o glucose by muscle and disinhib-
ited lipolysis in adipose tissue.
Clinical markers o IR are visceral obesity, acanthosis nigri-
cans (2), acne, hirsutism (3) and hepatic steatosis (1).
The golden standard or evaluation o IR is hyperinsu-
linemic euglycemic clamp: insulin is inused at a con-
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Biochemia Medica god. 16, br. 1, 2006. Biochemia Medica Vol. 16, No. 1, 2006
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Mlinar B. i sur. Inzulinska rezistencija, pretilost i metaboliki sindrom
Mlinar B. et al. Insulin Resistance, Obesity and Metabolic Syndrome
noj stopi inuzijom, a glukoza se odrava na bazalnim
razinama inuzijom glukoze. Stopa inuzije glukoze daje
mjeru preuzimanja glukoze u svim tkivima (4). Alternativ-
ne mjere za IR su koncentracije inzulina u plazmi natate
(2) i procjena modela homeostaze (engl. homeostasis mo-del assessment, HOMA) izvedena iz koncentracija inzulina
i glukoze u plazmi natate (5).
Etiologija IR ukljuuje genetske imbenike koji rezultira-
ju sindromnim oblicima IR, te imbenike okoline: unos
hrane, nedostatna tjelesna aktivnost, starenje, puenje ili
uzimanje lijekova tiazidnih diuretika, beta adrenerginih
antagonista, glukokortokoida, koji mogu uzrokovati IR ili
doprinijeti njegovu nastanku (2). Najvaniji imbenik je pre-
tilost koja je obino sloenog poligenetskog i okolinskog
podrijetla (2, 6). Abdominalno masno tkivo je izvor slobod-
nih masnih kiselina (engl. free fat ty acids, FFA) i razliitih
hormona (adipokina) koji su upleteni u razvoj IR. Nasuprot
tome, ogranien unos kalorija, smanjenje teine i tjelesna
aktivnost poboljavaju inzulinsku osjetljivost (2, 3, 7).
U radu se objanjavaju mehanizmi IR koji ukljuuju: pore-
meeno luenje adipokina i povean dotok FFA iz sredi-
njeg masnog tkiva, te druge poremeaje inzulinskih pred-
receptora, receptora i postreceptora.
Mehanizmi inzulinske rezistencije
Faktor tumorske nekroze i slobodne masne kiseline
Udruenost IR s povienim aktorom tumorske nekroze
(engl. tumor necrosis factor, TNF-), interleukinom
6 (IL-6), makroazima i monocitnim kemoatraktantnimproteinom-1 (engl. monocyte chemoattractant protein-
1, MCP-1), inhibitorom-1 aktivatora plazminogena (engl.
plasminogen activator inhibitor-1, PAI-1), adipsinom te sni-
enim adiponektinom utvrena je u mnogim studijama
(8). IR je popratno obiljeje u mnogih pretilih bolesnika.
Masno tkivo otputa velike koliine TNF-, koji je barem
djelomice odgovoran za razvoj IR kod pretilosti (9). S dru-
ge strane, poznato je da se s gubitkom na teini poveava
inzulinska osjetljivost; smatra se kako tome dijelom pos-
reduje smanjeno luenje adipoznog TNF- (10). TNF- je
glavni autokrini/parakrini imbenik koji pokree luenje
slobodnih masnih kiselina (FFA) iz masnog tkiva u krvotok(9). Meutim, ostaje nejasno koji imbenici doista pokre-
u otputanje adipokina iz masnog tkiva.
TNF- posreduje potiskivanje mnogih gena odgovornih
za preuzimanje i pohranu glukoze i FFA. Za adipocite
3T3-L1 je pokazano kako se regulacija navie i nanie ge-
na ovisnih o TNF- odvija obveznim aktiviranjem aktora
nuklearne transkripcije B (11). Djelovanjem TNF- dolazi
do pojaane lipolize uz otputanje FFA i citokina.
TNF- i FFA remete inzulinsko signaliziranje u tkivima
koja odgovaraju na inzulin, poglavito u miiima. Prema
hipotezi o opskrbi lipidima (Randleova hipoteza), otpu-
tene FFA djeluju kao prevladavajui supstrat u intermedi-
stant rate and glucose is held at basal levels by glucose
inusion. The rate o the latter is a measure o all tissues
glucose uptake (4). Alternative measures o IR are asting
plasma insulin concentrations (2) and homeostasis model
assessment (HOMA) derived rom asting plasma insulinand glucose concentrations (5).
The etiology o IR includes genetic actors resulting in
syndromic orms o IR, and environmental actors: ood
intake, poor physical activity, aging, smoking or admin-
istration o drugs thiazide diuretics, beta adrenergic
antagonists and glucocorticoids, which can cause or
contribute to IR (2). The most important actor is obesity,
which is usually o combined polygenetic and environ-
mental origin (2, 6). Abdominal adipose tissue is a source
o ree atty acids (FFA) and various hormones (adipo-
kines) implicated in the development o IR. Conversely,
restricted calorie intake, weight reduction and physical
activity improve insulin sensitivity (2, 3, 7).
The present paper explains the mechanisms o IR which
include disregulated secretion o adipokines and in-
creased e ux o FFA rom central adipose tissue, and
other insulin prereceptor, receptor and postreceptor im-
pairments.
The Mechanisms o Insulin Resistance
Tumor necrosis actor and ree atty acids
Numerous studies have ound associations between
increased tumor necrosis actor (TNF-), interleukin 6
(IL-6), macrophages and monocyte chemoattractant pro-tein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1),
adipsin, and decreased adiponectin with IR (8).
In the majority o obese patients IR is an accompanying
eature. Adipose tissue releases great amounts o TNF-,
which is at least partly responsible or the development
o IR in obesity (9). On the other hand, weight loss is well
known to increase insulin sensitivity, which is thought to be
mediated in part by decreased adipose TNF- release (10).
TNF- is the main autocrine/paracrine actor triggering the
secretion o FFA rom adipose tissue into the circulation (9).
However, it remains unclear which actors actually trigger
the release o adipokines rom adipose tissue.TNF- mediates repression o many genes responsible
or glucose and FFA uptake and storage. For 3T3-L1 adi-
pocytes it has been shown that TNF- dependent gene
up- and down-regulation occurs by obligatory activation
o nuclear transcription actor B (11). Upon TNF- action,
enhanced lipolysis occurs with the release o FFA and cy-
tokines.
TNF- and FFA impair insulin signaling in insulin respon-
sive tissues, especially muscle. The released FFA, accord-
ing to the lipid supply hypothesis (Randle hypothesis), act
as a predominant substrate in intermediary metabolism.
Increased NADH/NAD+ and acetyl-CoA/CoA ratios could
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Mlinar B. i sur. Inzulinska rezistencija, pretilost i metaboliki sindrom
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Biochemia Medica god. 16, br. 1, 2006. Biochemia Medica Vol. 16, No. 1, 2006
10
jarnom metabolizmu. Povieni omjeri NADH/NAD+ i ace-
til-CoA/CoA mogli bi biti razlogom smanjenog preuzima-
nja glukoze, to znai poremeene inzulinske osjetljivosti
(12, 13). Visceralno masno tkivo lui FFA izravno u portalni
krvotok, ime snano utjee na jetru, a ne na potkonomasno tkivo otputajui svoje proizvode u periernu cirku-
laciju (1).
U jetri velike koliine FFA osiguravaju obilan supstrat za
sintezu triglicerida i VLDL, te za glukoneogenezu. TNF-
potiskuje gene za preuzimanje glukoze i beta oksidaciju
(14). Dolazi do de novo sinteze kolesterola, potom do regu-
lacije navie odgovarajuih gena pomou TNF- (8).
FFA takoer pokreu sintezu fbrinogena i PAI-1 u jetri
(15). FFA koje iz visceralnog masnog tkiva otjeu u portal-
nu cirkulaciju i u jetru smanjuju jetreni klirens inzulina, i-
me doprinose hiperinzulinemiji (13). Suviak triglicerida
se nakuplja u jetri (1). U miiima pak visoke koncentracije
FFA pogoduju beta oksidaciji, ime se smanjuje preuzima-
nje i oksidacija glukoze (16). No, beta oksidacija je nedos-
tatna za djelotvorno uklanjanje FFA iz krvotoka, osobito
ako nema tjelesne aktivnosti (17). Sinteza glikogena u mi-
iima je suspregnuta. Mii ima glavnu ulogu u uklanja-
nju glukoze (8090%), pa njezino smanjeno preuzimanje
u velikoj mjeri doprinosi hiperglikemiji (9, 18). Suvine FFA
pohranjuju se kao kapljice triglicerida u miiima (1, 7, 17).
U masnom tkivu FFA suzbijaju aktivnost lipoprotein lipa-
ze, koju inae potie inzulin, te tako onemoguavaju klire-
ns FFA iz krvotoka (19). Sve u svemu, lipidi otputeni iz adi-
pocita kao FFA prenose se kao trigliceridi pomou VLDL i
premjetaju u nemasna tkiva (20).
Pokazano je kako TNF- nanie regulira gene za adipo-
nektin, transporter glukoze 4 (engl. glucose transporter
4, GLUT4), supstrat-1 inzulinskog receptora (engl. insulin
receptor substrate-1, IRS-1), CCAAT/pojaajni vezni protein (engl. CCAAT/enhancer binding protein , C/EBP-), pe-
roksizomni prolierator-aktivirani receptor (engl. peroxi-
some prolierator-activated receptor, PPAR-) i perilipin u
adipocitima (11, 14). TNF- navie regulira mnoge gene iz-
raene u masnom tkivu, koji su odgovorni za upalu, imuni
odgovor i energetsku ravnoteu (vaskularna stanina pria-
njajua molekula-1 (VCAM-1), PAI-1, IL-6, IL-1, angiotenzi-
nogen, rezistin, leptin) (14).
Leptin
Leptin je hormon to ga u najveoj mjeri lui masno tkivo,
a oznaava dostatnu koliinu energije. Leptin smanjuje
unos hrane i poveava potronju energije (21). Ovi uinci
nastupaju djelovanjem leptina na hipotalamus i izravno
na ciljna tkiva (mii, gonade, -stanice, jetru) (22).
U normalnim uvjetima odravanja teine koncentracije
leptina pozitivno koreliraju s ukupnom tjelesnom mas-
nom masom. Kod kratkotrajnog uskraivanja hrane se-
rumske razine leptina se sniavaju, dok se obrnuto doga-
a kod kratkotrajnog prekomjernog hranjenja (23).
be the reason or the decreased glucose uptake, which
means impaired insulin sensitivity (12, 13). Visceral adi-
pose tissue secretes FFA directly to the portal blood ow
thereby exerting potent eects on the liver rather than
subcutaneous adipose tissue releasing its products toperipheral circulation (1).
In the liver, high amounts o FFA provide an abundant
substrate or triglyceride and VLDL-synthesis, and gluco-
neogenesis. TNF- represses genes or glucose uptake
and beta oxidation (14). De novo cholesterol synthesis oc-
curs ollowed by TNF- up-regulation o the correspond-
ing genes (8).
FFA also trigger fbrinogen and PAI-1 synthesis in the liver
(15). FFA draining rom visceral adipose tissue to portal
circulation and to the liver decrease hepatic insulin clear-
ance, thereby contributing to hyperinsulinemia (13). Ex-
cess triglycerides are accumulating in the liver (1).
In the muscle, high FFA concentrations avor beta oxida-
tion, which diminishes glucose uptake and oxydation
(16). However, beta oxidation is inadequate to clear FFA
e ciently rom the circulation, even more in the lack o
physical activity (17). Glycogen synthesis in the muscle is
inhibited. Muscle is in orce as the main glucose disposer
(80%90%) and diminished uptake contributes largely to
hyperglycemia (9, 18). Excess FFA are stored as triglycer-
ide droplets in the muscle (1, 7, 17).
In adipose tissue, FFA inhibit lipoprotein lipase activ-
ity which is otherwise stimulated by insulin, and thereby
render clearance o FFA rom circulation impossible (19).
Overall, lipids released rom adipocytes as FFA are trans-
ported as triglycerides by VLDL and shited to non-adi-
pose tissues (20).
TNF- has been shown to down-regulate the genes or
adiponectin, glucose transporter 4 (GLUT4), insulin recep-
tor substrate-1 (IRS-1), CCAAT/enhancer binding protein (C/EBP-), peroxisome prolierator-activated receptor (PPAR-) and perilipin in adipocytes (11, 14). TNF- up-
regulates many genes expressed in adipose tissue, which
are responsible or inammation, immune response
and energy balance (vascular cell adhesion molecule-1
(VCAM-1), plasminogen activator inhibitor-1 (PAI-1), IL-6,
IL-1, angiotensinogen, resistin, leptin) (14).
Leptin
Leptin is a hormone secreted predominantly by adipose
tissue and is a signal o energy su ciency. It decreases
ood intake and increases energy expenditure (21).
These eects are mediated by leptin action on the hypo-
thalamus and directly on target tissues (muscle, gonads,-cells, liver) (22). In normal conditions o weight main-
tenance leptin concentrations positively correlate with
total body at mass. In short term ood deprivation serum
leptin levels decrease and the opposite is true or short
term overeeding (23).
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Mlinar B. i sur. Inzulinska rezistencija, pretilost i metaboliki sindrom
Mlinar B. et al. Insulin Resistance, Obesity and Metabolic Syndrome
Leptin predstavlja bitan imbenik ertiliteta, jer se je poka-
zalo kako su sniene koncentracije leptina nakon uskrai-
vanja hrane odgovorne za suzbijanje hipotalamo-hipofz-
no-gonadne osi (24).
Klinika stanja sa smanjenom masnom masom (lipodis-trofje) obiljeena su snienim koncentracijama leptina u
plazmi i IR. Davanjem leptina znaajno se poboljava in-
zulinska osjetljivost u ovim stanjima (25), to pokazuje da
je normalna koliina masnog tkiva presudna za normalnu
inzulinsku osjetljivost, a to se barem djelomice ispunjava
kroz luenje leptina i njegovim uincima.
Vaan uinak leptina je simpatika stimulacija putem neu-
rona koji odgovaraju na leptin u hipotalamusu (8). To bi
moglo djelomice objasniti razvoj hipertenzije kod visce-
ralne pretilosti te u nepretilim stanjima. U skladu s tim, mi-
ina simpatika aktivnost kod nepretilih normotenzivnih
mukaraca dobro korelira s koncentracijama leptina veza-
nog za bjelanevine (26).
Adiponektin
Adiponektin pokazuje snanu obrnutu korelaciju s IR
u lipodistrofji i pretilosti, te s upalnim stanjima (27, 28).
Adiponektin lue iskljuivo adipociti (27). Adiponektin po-
boljava inzulinsku osjetljivost kroz razliite mehanizme.
U jetri izaziva oksidaciju masnih kiselina, smanjuje sinte-
zu lipida, smanjuje preuzimanje FFA i suzbija glukoneoge-
nezu regulirajui enzime nanie (8, 23, 29). U miiu adi-
ponektin pogoduje oksidaciji glukoze i FFA. Ove uinke
dijelom omoguuje aktiviranje AMP-kinaze (28). Tako adi-
ponektin sniava razine FFA i glukoze u plazmi (8, 23). Ka-
tabolizam FFA se potie izravno ili kroz poticanje nuklear-
nih receptora PPAR- (30).
Adiponektin smanjuje izraenost prianjajuih molekula
na stijenci krvnih ila, suzbija kemotaksu makroaga i nji-
hovu pretvorbu u pjenaste stanice, prolieraciju glatko-
miinih stanica i upalne dogaaje u aterogenezi to ih
promiu IL-6, PAI-1 itd. (8). Adiponektin takoer suzbija lu-
enje TNF- (31).
Razine adiponektina poveavaju se s gubitkom teine (32)
i lijeenjem tiazolidinedionima (engl. thiazolidinediones,
TZD) (33), koji su agonisti PPAR-. Sinteza adiponektina je
poremeena u stanjima suvika kalorija, to bi moglo bitipovezano s rezistencijom ili nedostatkom leptina (23). In-
zulin i inzulinu slian aktor rasta (engl. insulin-like growth
actor-1, IGF-1) potiu sintezu adiponektina (23).
Slino tome, IL-10 isto tako ima antidijabetogeni uinak:
kod pretilosti bez metabolikog sindroma razine IL-10 u
plazmi su poviene, ali je IL-10 snien u metabolikom sin-
dromu (34).
Rezistin
Visceralno masno tkivo lui rezistin u daleko veoj mjeri
nego potkono masno tkivo (8). Kod pretilosti u glodava-
ca su serumske razine rezistina poviene, a neki su pokusi
Leptin represents an essential ertility actor as decreased
leptin concentrations ollowing ood deprivation have
been shown to be responsible or the suppression o the
hypothalamic-pituitary-gonadal axis (24).
Clinical states with diminished adipose mass (lipodys-trophies) are characterized by reduced plasma leptin
concentrations and IR. Leptin administration signifcantly
improves insulin sensitivity in these conditions (25), indi-
cating that normal amount o adipose tissue is critical or
normal insulin sensitivity, and this is at least partly ulflled
via leptin secretion and its eects.
An important leptin eect is sympathetic stimulation
achieved by eliciting leptin-responsive neurons in the
hypothalamus (8). This could in part explain the develop-
ment o hypertension in visceral obesity and non-obese
states. In accordance with this, muscle sympathetic activ-
ity in non-obese normotensive men correlates well with
protein-bound leptin concentrations (26).
Adiponectin
Adiponectin shows strong inverse correlation to IR in
lipodystrophy and obesity, and to inammatory states
(27, 28). It is secreted exclusively by adipocytes (27). Adi-
ponectin improves insulin sensitivity by various mecha-
nisms: in the liver, it induces atty acid oxidation, decreas-
es lipid synthesis, decreases uptake o FFA and represses
gluconeogenesis by enzyme down-regulation (8, 23, 29).
In muscle, adiponectin avors glucose and FFA oxidation.
These eects are partly due to the activation o AMP-
kinase (27). Thereby, adiponectin decreases plasma FFA
and glucose levels (8, 23). FFA catabolism is stimulated
either directly or through stimulation o PPAR- nuclear
receptors (30).
Adiponectin decreases the expression o adhesion mol-
ecules on blood vessel wall, inhibits chemotaxis o mac-
rophages and their conversion to oam cells, proliera-
tion o smooth muscle cells and inammatory events in
atherogenesis, which are promoted by IL-6, PAI-1 etc. (8).
Adiponectin also suppresses secretion o TNF- (31).
Adiponectin levels increase with weight loss (32) and
treatment with thiazolidinediones (TZD) (33), which are
PPAR- agonists. The synthesis o adiponectin is impairedin the states o calorie excess, which might be associ-
ated with leptin resistance or defciency (23). Insulin and
insulin-like growth actor (IGF-1) stimulate adiponectin
synthesis (23).
Similarly, IL-10 also exerts an antidiabetogenic eect: in
obesity without the metabolic syndrome IL-10 plasma
levels are increased, but in the metabolic syndrome IL-10
is decreased (34).
Resistin
Resistin is secreted to a much greater extent by visceral
than by subcutaneous adipose tissue (8). In rodent obe-
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Biochemia Medica god. 16, br. 1, 2006. Biochemia Medica Vol. 16, No. 1, 2006
12
potvrdili da rezistin uzrokuje IR (35). Meutim, druga pak
ispitivanja nisu potvrdila takve rezultate (8, 36).
Ljudski rezistin pokazuje tek 64%-tnu homolognost s re-
zistinom glodavaca (37) i izraenost rezistina u ljudskim
adipocitima nije jednako udruena s IR ili pretilou (23).S druge strane, tiazolidinedioni (TZD) moda svoje uinke
djelomice ostvaruju kroza smanjeno djelovanje rezistina,
jer se njegovo luenje smanjuje tijekom lijeenja TZDima
(23). Sve u svemu, ulogu rezistina u ljudi tek treba podrob-
nije razjasniti.
Ostali adipokini
Makroazi i monocitni kemoatraktantni protein-1 (MCP-1)
su izravno uzrono povezani s IR: MCP-1 remeti ulazak glu-
koze i inzulinske signale u stanicama (38). Adipociti lue
MCP-1; on privlai makroage u masno tkivo i promie nji-
hovo otputanje IL-1 i TNF- (8). On isto tako suzbija rast
i dierencijaciju adipocita. MCP-1 promie aterosklerozu
privlaei makroage i pogodujui njihovom nakupljanju
u staninim stijenkama (39).
PAI-1 je vie izraen u visceralnom u usporedbi s potko-
nim masnim tkivom (40). On je snano udruen s visceral-
nom pretilou, IR i metabolikim sindromom. Pretpostav-
lja se da PAI-1 doprinosi pretilosti i IR, te da ima uzronu
ulogu u daljnjem razvoju kardiovaskularne bolesti zbog
svog protrombotskog djelovanja (8). Razine PAI-1 u plaz-
mi sniavaju se s gubitkom teine (8) i lijeenjem tvarima
za inzulinsku senzibilizaciju (41).
Studije s IL-6 ukazuju na njegovu uzronu ulogu u IR, jer
plazmatske koncentracije i izraenost u masnom tkivu te
polimorfzam IL-6 dobro koreliraju s pretilou i IR. Poka-
zano je kako IL-6 remeti inzulinsko signaliziranje (42), suz-
bija adipogenezu i luenje adiponektina (8). Isto tako, IL-6
izaziva IR u jetri i adipocitima (43).
U sredinjem ivanom sustavu IL-6 ima suprotne uinke
to ukazuje na to da on pogoduje potronji energije. Da-
vanje IL-6 transgeninim glodavcima kojima je uklonjen
gen za IL-6 ponitio je razvoj pretilosti (44).
Glukokortikoidi
Glukokortikoidi su dobro poznati antagonisti inzulina. Oni
se suprotstavljaju uincima inzulina i time mogu izazvatiIR. Oni djeluju na objema razinama IR: pojaavaju jetrenu
glukoneogenezu i otputanje glukoze iz jetre, te remete
preuzimanje glukoze u periernim tkivima. Prethodno
spomenute visoke razine FFA predstavljaju mehanizam
za ovaj potonji uinak, a najmanje su tri mogua puta koji-
ma moe nastupiti lipoliza:
1. glukokortikoidi poveavaju pretvorbu noradrenalina
u adrenalin (enil-etanolamin N-metiltranseraza u ske-
letnim miiima), koji djeluje na hormonski osjetljivu
lipazu u masnom tkivu i provodi lipolizu (45);
2. oni posreduju lipolizu kroz reguliranje navie PPAR-
(46);
sity, serum resistin levels are increased and some experi-
ments have confrmed resistin as causing IR (35). However,
some other studies ailed to confrm these results (8, 36).
Human resistin shows only 64% homology with rodent re-
sistin (37) and expression o resistin in human adipocytesis not uniormly associated with IR or obesity (23). On the
other hand, TZD may exert their eects partly through a
diminished action o resistin as its secretion is decreased
during TZD therapy (23). Taken together, the role o resis-
tin in humans remains to be urther elucidated.
Other adipokines
Macrophages and monocyte chemoattractant protein-1
(MCP-1) are directly causally associated with IR: MCP-1 im-
pairs glucose entrance and insulin signaling in cells (38).
MCP-1 is secreted by adipocytes; it attracts macrophages
to adipose tissue and promotes their IL-1 and TNF-
release (8). It also inhibits adipocyte growth and dier-
entiation. MCP-1 promotes atherosclerosis by attracting
macrophages and avoring their accumulation in vessel
walls (39).
PAI-1 has higher expression in visceral compared to sub-
cutaneous adipose tissue (40). It is strongly associated
with visceral obesity, IR and metabolic syndrome. PAI-1 is
hypothesized to contribute to obesity and IR, and has a
causal role in urther development o cardiovascular dis-
ease or its prothrombotic activity (8). PAI-1 plasma levels
decrease ater weight loss (8) and therapy with insulin
sensitizing substances (41).
Studies with IL-6 have suggested its causal role in IR, as
plasma concentrations and adipose tissue expression, and
polymorphisms o IL-6 correlate well with obesity and IR.
IL-6 was shown to interere with insulin signaling (42), and
to inhibit adipogenesis and secretion o adiponectin (8).
IL-6 also induces IR in the liver and adipocytes (43).
In the central nervous system IL-6 has opposite eects
suggesting that it avors energy expenditure. Admin-
istration o IL-6 to IL-6 gene knockout rodents reversed
obesity (44).
Glucocorticoids
Glucocorticoids are well known insulin antagonists. Theyoppose the eects o insulin and thereby could induce
IR. They act on both levels o IR: they enhance liver glu-
coneogenesis and glucose release, and impair glucose
uptake by peripheral tissues. The mechanism or the lat-
ter are previously mentioned high levels o FFA, and there
are at least three possible ways how lipolysis can occur:
1. glucocorticoids increase norepinephrine conversion
to epinephrine (phenyl-ethanolamine N-methyltrans-
erase in skeletal muscle), which acts on hormone sen-
sitive lipase in adipose tissue and perorms lipolysis
(45);
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Mlinar B. et al. Insulin Resistance, Obesity and Metabolic Syndrome
3. oni suzbijaju lipoprotein lipazu i time onemoguavaju
preuzimanje FFA u masnom tkivu (47).
U skeletnim miiima je pokazana poremeena transloka-
cija GLUT4 kao posljedica djelovanja glukokortikoida (48).
Pokazano je kako glukokortikoidi suzbijaju vazodilataciju(izazvanu inzulinom putem duinom oksida), pa su tada
ciljna tkiva dobivala manje glukoze (49). Ove uinke gluko-
kortikoida jo pojaavaju FFA poveanim vezanjem gluko-
kortikoida za njihove receptore (50).
Molekularni mehanizmi poremeenog inzu-
linskog signaliziranja
Normalno inzulinsko signaliziranje
Inzulinski receptor je heterotetramerni receptor koji je
izraen na jetrenim, adipoznim i skeletno miinim stani-
cama. Vezanje inzulina pokree oligomerizaciju i autoos-orilaciju receptora na tirozinskim ostacima, te tirozinsku
osorilaciju IRS-1, -2, -3, -4, IRS5/DOK4, IRS6/DOK5. Ova
osorilacija ini osnovu za daljnje udruivanje s nizvod-
nim signalnim bjelanevinama koje se razilaze u tri razlii-
te putanje: putanju osoinozitid-3-kinazu (engl.phosphoi-
nositide-3-kinase, PI3K), putanju CAP/Cbl/TC10 i putanju
ovisnu o mitogenom aktiviranoj protein kinazi (engl. mito-
gen-activated protein kinase, MAP-kinase) (Slika 1.) (51, 52).
PI3K uzajamno djeluje s osoriliranim Tyr na molekule IRS
te se nakon stvaranja osatidilinozitol-3,4,5-triosata (en-
gl. phosphatidylinositol-3,4,5-triphosphat, PIP3) aktiviraju
razliite protein kinaze (53). Posljedino tome dolazi dodeaktiviranja glikogen sintaze kinaze 3 (engl. glycogen
synthase kinase 3, GSK-3), to na koncu rezultira sintezom
glikogena; gen sintaze masnih kiselina reguliran je navie,
dok je gen osoenolpiruvat karboksikinaze (engl. phos-
phoenolpyruvate carboxykinase, PEPCK) reguliran nanie.
Bitan uinak puta PI3K je translociranje glavnog prijenos-
nika glukoze GLUT4 u plazmatsku membranu (51, 52). Sin-
teza bjelanevina nastupa aktiviranjem ciljnog enzima za
rapamicin koji je svojstven sisavcima (engl. mammalian
target o rapamycin, mTOR) (54).
Kako bi se preuzimanje glukoze odvijalo u potpunosti, pri-
lagodbena bjelanevina CAP upoljava proto-onkogenCbl u osorilirani inzulinski receptor, to u konanici dovo-
di do pojaane translokacije GLUT4 (51).
Trei put dovodi do aktiviranja MAP-kinaze te stanine
prolieracije i dierencijacije putem regulacije genske tran-
skripcije (52, 55).
Nedostatci u inzulinskom signaliziranju
Manji broj sluajeva inzulinske rezistencije obiljeen je
po jednom genetskom ili steenom znaajkom. Protuin-
zulinska autoantitijela naena su kod eerne bolesti tipa
1. (56). S druge strane, u genu inzulinskih receptora utvr-
eno je vie od 60 mutacija. Meu njima je IR tip A udru-
en sa stanjem heterozigotne mutacije, koje ini osnovu
2. they mediate lipolysis via up-regulation o PPAR-
(46); and
3. they inhibit lipoprotein lipase and thus disable the
uptake o FFA by adipose tissue (47).
In skeletal muscle impaired translocation o GLUT4 wasshown as a consequence o glucocorticoid action (48).
Glucocorticoids were shown to inhibit vasodilatation
(induced by insulin via nitrogen oxide) and less glucose
was then delivered to target tissues (49). These eects o
glucocorticoids are even potentiated by FFA increasing
glucocorticoids binding to their receptors (50).
Molecular Mechanisms o Impaired Insulin
Signaling
Normal insulin signaling
Insulin receptor is a heterotetramer receptor, which isexpressed on the liver, adipose and skeletal muscle cells.
Binding o insulin triggers oligomerization and receptor
autophosphorylation on tyrosine residues and tyrosine
phosphorylation o IRS-1, -2, -3, -4, IRS5/DOK4, IRS6/DOK5.
This phosphorylation provides the base or ollowing as-
sociation with downstream signal proteins which diverge
into three dierent pathways: phosphoinositide-3-kinase
(PI3K) pathway, CAP/Cbl/TC10 pathway and mitogen-ac-
tivated protein kinase (MAP-kinase) dependent pathway
(Fig. 1) (51, 52). PI3K interacts with phosphorylated Tyr on
IRS molecules and upon ormation o phosphatidylino-
sitol-3,4,5-triphosphate (PIP3) various protein kinasesare activated (53). As a consequence, glycogen synthase
kinase 3 (GSK-3) is inactivated, which at the fnal stage re-
sults in glycogen synthesis; the atty acid synthase gene
is up-regulated and phosphoenolpyruvate carboxykinase
(PEPCK) gene is down-regulated. An essential eect o
PI3K pathway is translocation o the main glucose trans-
porter GLUT4 to the plasma membrane (51, 52). Protein
synthesis is activated via enzyme mammalian target o
rapamycin (mTOR) activation (54). For glucose uptake to
maniest ully, the adapter protein CAP recruits proto-on-
cogene Cbl to the phosphorylated insulin receptor, which
fnally results in reinorced GLUT4 translocation (51). Thethird pathway leads to MAP-kinase activation and cellular
prolieration and dierentiation via gene transcription
regulation (52, 55).
Deects in insulin signaling
A minority o insulin resistant cases are characterized by a
single genetic or acquired trait. Anti-insulin autoantibod-
ies have been ound in diabetes mellitus DM type 1 (DM1)
(56). On the other hand, more than 60 mutations have
been identifed in the insulin receptor gene. Among them
type A IR is associated with heterozygous mutation state
which underlies decreased Tyr phosphorylation o the -
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14
za smanjenu osorilaciju Tyr u -podjedinici nakon veza-
nja inzulina (57). Pretpostavlja se da mutacije gena inzu-
linskih receptora kod Rabson-Mendenhallova sindroma
i Donohueva sindroma remete vezanje inzulina za recep-
tor (57). IR moda nastaje zbog nenormalne proizvodnje
protutijela za protuinzulinske receptore (IR tip B) (58). Za
mutacije PPAR- koje nisu udruene s lipodistrofjom tako-
er se izvjetava da uzrokuju IR (59).
Neki autori izvjetavaju o poveanoj razgradnji inzulin-
skih receptora (60). Uz to, pretpostavlja se kako bi oso-
rilacija serina/treonina raznim protein kinazama C (engl.
protein kinase C, PKC) mogla biti dodatnim imbenikom
FIGURE 1. Insulin signal transduction (51-55). Ater insulin receptor
Tyr autophosphorylation, insulin receptor substrates 1 to 4 (IRS-1 to4) Tyr phorphorylation takes place and subsequently three dierent
pathways transduce the signal: PI3K-dependent pathway mediating
metabolic responses including glucose/lipid/protein metabolism and
insulin-stimulated glucose uptake; CAP/Cbl pathway which is additio-
nally required or glucose transporter-4 (GLUT4) translocation; and
mitogen-activated protein kinase (MAPK) pathway resulting in cell
prolieration and dierentiation. Solid line: stimulation; dashed line:
inhibition. IRS, insulin receptor substrate; PI3K, phosphoinositide-3-ki-
nase; PDK-1, phosphoinositide-dependent kinase 1; PKB, protein kina-
se B; aPKC, atypical proteinkinases C; mTOR, mammalian target o rapa-
mycin; p70S6K, p70 ribosomal S6 kinase; PEPCK, phosphoenolpyruvate
carboxykinase; GSK3, glycogen synthase kinase 3.
subunit ater insulin binding (57). In Rabson-Mendenhall
syndrome and leprechaunism (Donohue syndrome) insu-
lin receptor gene mutations are presumed to impair insu-
lin binding to the receptor (57). IR may be due to abnor-
mal production o anti-insulin-receptor antibodies (type
B IR) (58). PPAR- mutations which are not associated with
lipodystrophy are also reported to cause IR (59).
Some studies report an increased degradation o insulin
receptor (60). Besides, it is hypothesized that serine/threo-
nine phosphorylation by various protein kinases C (PKCs)
could be an additional actor to regulate insulin receptor
activity (61). Decreased Tyr phosphorylation state o IRS-1
SLIKA 1. Pretvorba inzulinskih signala (51-55). Nakon Tyr autoosori-
lacije inzulinskih receptora dolazi do Tyr osorilacije supstrata za inzu-linke receptore 1 to 4 (IRS-1 do -4), a potom se signal pretvara trima
razliitim putovima: putom ovisnim o PI3K koji posreduje metabolike
odgovore ukljuujui metabolizam glukoze/lipida/bjelanevi na inzuli-
nom poticano preuzimanje glukoze, putom CAP/Cbl koje je dodatno
potreban za translokaciju prijenosnika glukoze 4 (GLUT4) i putom mi-
togenom aktivirane protein kinaze (MAPK) koji rezultira staninom
prolieracijom i dierencijacijom. Puna crta: poticanje; isprekidana cr-
ta: suzbijanje. IRS, supstrat za inzulinske receptore; PI3K, osoinozitid-
3-kinaza; PDK-1, kinaza 1 ovisna o osoinozitidu; PKB, protein kinaze
B; aPKC, atipine protein kinaze C; mTOR, cilj za rapamicin u sisavaca;
p70S6K, p70 ribosomna S6 kinaza; PEPCK, osoenolpiruvat karboksiki-
naza; GSK3, glikogen sintaza kinaza 3.
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regulacije aktivnosti inzulinskih receptora (61). Stanje sma-
njene Tyr osorilacije IRS-1, koje je zapaeno kod hiperin-
zulineminih ob/ob mieva, moglo bi biti posljedica sma-
njenje aktivnosti inzulinskih receptora (62).
Novija ispitivanja su uglavnom usredotoena na povea-nu Ser/Thr osorilaciju IRS-1, koja bi mogla biti posljedi-
ca povienih koncentracija TNF- i dalje se pogorava hi-
perinzulinemijom koju uzrokuje IR. Smatra se da su PKC,
PI3K-daljnje kinaze i MAP-kinaze odgovorne za Ser/Thr
osorilaciju, nakon ega slijedi pojaana proteazomna raz-
gradnja IRS-1. Naime, smanjen sadraj IRS-1 bjelanevine
opisan je u ljudi, ivotinja i uzgojenim stanicama s IR (51).
Valja naglasiti kako je stanovito bazalno stanje Ser/Thr os-
orilacije IRS-1 neophodno za uspjenu Tyr osorilaciju i
inzulinsko signaliziranje. Zato preostaje rasvijetliti koji je
stupanj osorilacije IRS-1 i na kojim Ser/Thr mjestima pot-
reban da bi pokazao svoje raznovrsne uinke.
Uz to to posreduje razgradnju IRS-1, hiperinzulinemija
moe utjecati na koncentraciju bjelanevina u IRS-2 i izaz-
vati neke promjene nie na putu inzulinske signalizacije (51).
TNF-, IL-6 i inzulin induciraju drugu vanu skupinu im-
benika IR supresore citokinskog signaliziranja (engl. sup-
pressors o cytokine signalling-1-3, SOCS-1-3), koji imaju naj-
manje tri razliita mehanizma djelovanja: oni se natjeu s
IRS-1 za udruivanje s inzulinskom receptorom, suzbijaju
Janus kinazu upletenu u inzulinsko signaliziranje i povea-
vaju proteazomnu razgradnju IRS-1 (63). Za hiperglikemi-
ju je pokazano kako teko smanjuje aktivnost protein ki-
naze B (engl.protein kinase B, PKB), iako su bile aktivirane
neke druge proksimalne sastavnice inzulinske signalizaci-
je (inzulinski receptor, IRS-1, IRS-2, PI3K).
Pokazano je kako slobodne masne kiseline u visokim plaz-
matskim koncentracijama kroz pretvorbu u diacilglicerol
i acil-CoA smanjuju aktivnosti IRS-1, -2, te aktivnosti PI3K
i razliitih izoorma PKB i PKC u miiu takora (51). Kod
transgeninih mieva FFA su poveale aktivnost bjelane-
vine Munc18c, negativnog regulatora translokacije GLUT4
u plazmatsku membranu (64). Ipak, nezasiene FFA su ko-
risne utoliko to omoguavaju normalnu inzulinsku osjet-
ljivost u nekim ciljnim tkivima (51).
Pokazano je kako glicirane bjelanevine, koje nastaju kao
posljedica hiperglikemije, unutar stanice smanjuju aktiv-
nost PI3K, PKB i GSK-3, te tako moda doprinose IR. Slino
tome, glukozamin (UDP-N-acetil glukozamin), koji nastaje
iz glukoze i predstdavlja glavni supstrat za staninu gliko-
zilaciju, pojaava glikozilaciju IRS-1 smanjujui tako njego-
vu aktivnost, te glikozilaciju glikogen sintaze, smanjujui
tako njezinu sposobnost odgovora na inzulin (51).
Pretilost
Stanje uhranjenosti se najbolje opisuje pomou indeksa
tjelesne mase (engl. body mass index, BMI). BMI se izrau-
nava tako da se teina osobe u kilogramima podijeli kvad-
ratom visine u metrima. Uz neke iznimke BMI dobro kore-
that was ound in hyperinsulinemic ob/ob mice could be
a consequence o decreased insulin receptor activity (62).
Recent studies ocus mainly on increased Ser/Thr phos-
phorylation o IRS-1, which could be a consequence o
increased TNF- concentrations and urther exacerbatedby hyperinsulinemia which is secondary to IR. PKCs,
PI3K-downstream kinases and MAP-kinases are thought
to be responsible or Ser/Thr phosphorylation, which is
ollowed by enhanced proteasomal degradation o IRS-1.
Namely, decreased IRS-1 protein content has been re-
ported in humans, animals and cultured cells with IR (51).
It is to emphasize that certain basal Ser/Thr phosphory-
lation state o IRS-1 is necessary or successul Tyr phos-
phorylation and insulin signaling. Thereore, it remains
to be elucidated to which degree and on which Ser/Thr
sites IRS-1 must be phosphorylated to display its diverse
eects.
Besides mediating IRS-1 degradation, hyperinsulinemia
might aect protein concentration o IRS-2 and provoke
some downstream changes in insulin signaling (51).
TNF-, IL-6 and insulin induce another important group
o IR actors suppressors o cytokine signaling (SOCS-1
and -3), which have at least three dierent mechanisms o
action: they compete with IRS-1 or association with insu-
lin receptor, they inhibit Janus kinase, involved in insulin
signaling, and they augment proteasomal IRS-1 degrada-
tion (63).
Hyperglycemia was shown to severely decrease protein
kinase B (PKB) activity, although some other proximal
components o insulin signaling (insulin receptor, IRS-1,
IRS-2, PI3K) were activated.
FFA in high plasma concentrations were shown, by trans-
ormation to diacylglycerol and acyl-CoA, to diminish the
activities o IRS-1, -2 and activities o PI3K and various iso-
orms o PKB and PKC in rat muscle (51). In transgenic mice,
FFA increased the activity o Munc18c protein, a negative
regulator o GLUT-4 translocation to plasma membrane
(64). Nevertheless, unsaturated FFA have beneft to allow
normal insulin sensitivity in some target tissues (51).
Glycated proteins, emerging as a consequence o hyper-
glycemia were shown intracellularly to diminish the PI3K,
PKB, and GSK-3 activity, thus possibly contributing to IR.
Similarly, glucosamine (UDP-N-acetyl glucosamine), pro-
duced rom glucose and being the main substrate or cel-
lular glycosylation, enhances IRS-1 glycosylation thereby
decreasing its activity, and glycogen-synthase glycosyl-
ation, which reduces its insulin responsiveness (51).
Obesity
The state o nutrition is best described by body mass in-
dex (BMI). BMI is calculated by dividing a person's weight
in kilograms by the square o his height in meters. BMI
is, with some exceptions, in good correlation with the
amount o total body at. According to BMI, the ollowing
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lira s koliinom ukupne tjelesne masti. Prema BMI utvre-
ne su slijedee kategorije prekomjerne tjelesne mase ili
uhranjenosti (65):
BMI 25-30 kg/m2 prekomjerna teina
BMI 30-40 kg/m
2
pretilostBMI 40-50 kg/m2 bolesna pretilost
BMI >50 kg/m2 krajnja pretilost
Inzulinska i leptinska rezistencija kod pretilosti
Visceralna pretilost predisponira razvoj hipertenzije, e-
erne bolesti tipa 2, kardiovaskularne bolesti i odreenih
vrsta raka (66). Povean rizik za zdravlje postoji ve i u sku-
pini prekomjerne teine. Uz ukupnu tjelesnu masu masti,
za mogue metabolike komplikacije bitna je i raspodjela
masti. Visceralno i potkono masno tkivo razlikuju se pre-
ma njihovim endokrinim aktivnostima. Specifni recep-
tori kao to su receptori tipa 1 angiotenzina II. (AT1), 1
-,
2- i
3-adrenergini receptori, receptori glukokortikoida
i androgena zastupljeni su u veoj mjeri u visceralnom
masnom tkivu, gdje promiu lipolizu (8, 67, 68). S druge
strane, antilipolitini inzulinski receptori,-2A adrenergi-
ni receptori i estrogenski receptori prevladavaju u potko-
nom masnom tkivu (67, 68). Uz to, visceralno masno tkivo
lui svoje proizvode u portalnu cirkulaciju i tako dovodi
osloboene FFA izravno u jetru gdje one onda pogoduju
glukoneogenezi, sintezi VLDL, smanjuju preuzimanje glu-
koze i uzrokuju sveopu IR.
Visceralno masno tkivo je obiljeeno relativno visokim lu-
enjem IL-1 i PAI-1, dok je luenje leptina i adiponektina
vee u potkonom masnom tkivu (8). To je odgovorno za
odnos izmeu visceralne pretilosti i upalnih/trombotskih
dogaaja, te objanjava uinkovitost TZD u poboljanju
inzulinske osjetljivosti kroz preraspodjelu lipida u potko-
no masno tkivo (69).
Kod pretilih osoba su koncentracije leptina u plazmi povi-
ene pa egzogeno davanje leptina nema uinka na tjeles-
nu teinu (8). Ova se pojava objanjava leptinskom rezis-
tencijom ili desenzibilizacijom (23). Uz to, kod pretilosti su
koncentracije topljivog leptinskog receptora niske, a time
i koncentracije rakcije vezanog leptina. Ovo obiljeje je
neovisno udrueno s abdominalnom pretilou i IR. Smat-
ra se kako topljivi leptinski receptori imaju vanu uloguu prijenosu u i kroz krvno-modanu barijeru, pa bi zasie-
nost ovoga prijenosa ili poremeaj u pretvaranju signala
leptinskog receptora mogli biti uzrokom leptinske rezis-
tencije. Koncentracije leptina u cerebrospinalnoj tekuini
pretilih bolesnika tek su blago poviene (23).
Patofziologija pretilosti
Svaka osoba ima genetski odreenu teinsku strukturu
kojom se tjelesna teina strogo regulira energetskim ho-
meostatskim mehanizmom (Slika 2.) (6, 66, 71). Adipociti
lue leptin, a -stanice lue inzulin, oboje razmjerno sad-
raju tjelesne masti. Ova dva hormona ulaze u mozak; ve-
categories o excessive body mass or nutrition are postu-
lated (65):
BMI 25-30 kg/m2 overweight
BMI 30-40 kg/m2 obesity
BMI 40-50 kg/m
2
morbid obesityBMI >50 kg/m2 extreme obesity
Insulin and leptin resistance in obesity
Visceral obesity predisposes to the development o hy-
pertension, diabetes mellitus type 2 (DM2), cardiovascu-
lar disease, and certain types o cancer (66). An increased
risk or health exists already in the overweight group. Be-
sides total body at mass, distribution o at is essential or
eventual metabolic complications. Visceral and subcuta-
neous adipose tissues dier in their endocrine activities.
Specifc receptors such as angiotensin II receptors type-1
(AT1), 1
-, 2
-, 3
-adrenergic receptors, glucocorticoid and
androgen receptors are represented to a larger degree
in visceral adipose tissue where they promote lipolysis
(8, 67, 68). On the other hand, antilipolytic insulin recep-
tors, -2A adrenergic receptors, and estrogen receptors
are predominantly expressed in subcutaneous adipose
tissue (67, 68). Additionally, visceral adipose secretes its
products to the portal circulation, which brings the re-
leased FFA directly to the liver where they promote glu-
coneogenesis, VLDL synthesis, decrease glucose uptake
and cause overall IR.
Visceral adipose tissue is characterized by a relatively
higher secretion o IL-1 and PAI-1, whereas leptin and
adiponectin secretion is greater in subcutaneous adipose
tissue (8). This accounts or the relationship between vis-
ceral obesity and inammatory/thrombotic events, and
explains the eectivity o TZD to improve insulin sensitiv-
ity by redistribution o lipids to subcutaneous adipose
tissue (69).
In obese individuals there are increased plasma leptin
concentrations and exogenous administration o leptin
has no eect on body weight (8). The phenomenon has
been explained as leptin resistance or desensitization
(23). Besides, soluble leptin receptor concentrations are
low in obesity and hence the raction o bound leptin
concentrations. This eature is independently associatedwith abdominal obesity and IR. Soluble leptin receptors
are thought to be important or transport to or over the
blood brain barrier and it is the saturation o this trans-
port or impairment o leptin receptor signal transduction
that may be the cause o leptin resistance. Leptin concen-
trations in the cerebrospinal uid o obese patients are
only modestly increased (23).
The pathophysiology o obesity
Each individual has a genetically determined weight set-
point and hence body weight is tightly regulated by an
energy homeostatic mechanism (Figure 2) (6, 66, 71). Adi-
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u se na svoje sredinje receptore na neuronima hipotala-
musa i djeluju tako da smanjuju tjelesnu teinu. Neuroni
hipotalamusa izraavaju peptide i njihove receptore, koji
se mogu svrstati kao oreksigeni: neuropeptid Y, agouti-
povezan protein (engl. agouti-related protein, AgRP), hor-mon za koncentriranje melanina (engl. melanin-concentra-
ting hormone, MCH), oreksini A i B; ili anoreksigeni: mela-
nokortini (tj. hormon koji potie melanocite; engl. melano-
cyte-stimulating hormone,-MSH) i transkript povezan s
kokainom i ametaminom (engl. cocaine and amphetami-
ne related transcript, CART). U stanju preobilja leptina ili
inzulina prevladavaju anoreksigeni putovi: porast potro-
nje energije, porast termogeneze, smanjen unos hrane.
Smanjene serumske koncentracije leptina i inzulina dovo-
pocytes secrete leptin and -cells secrete insulin, both in
proportion to the body-at content. The two hormones
enter the brain. They bind to their central receptors on
the hypothalamic neurons exerting eects to reduce
body weight. Hypothalamic neurons express peptidesand their receptors that could be categorized as orexi-
genic: neuropeptide Y, agouti-related protein (AgRP),
melanin-concentrating hormone (MCH), orexins A and B;
or anorexigenic: melanocortins (i.e. melanocyte-stimu-
lating hormone, -MSH) and cocaine and amphetamine
related transcript (CART). In leptin or insulin abundance
the anorexigenic pathways prevail: increase o energy
expenditure, increase o thermogenesis, diminished ood
intake. Decreased leptin and insulin serum concentrations
FIGURE 2. Energy homeostasis. NeuropeptideY (NPY)/agouti relatedprotein (AgRP) neurons and proopiomelanocortin (POMC)/cocaine
and amphetamine related transcript (CART) neurons in the arcuate
nucleus in the hypothalamus receive signals rom the periphery. They
relay orexigenic and anorexigenic signals to the downstream neurons,
which provide balance between the ood intake and energy expendi-
ture (6,66,71).
Solid line: stimulation; dashed line: inhibition. PYY, peptide YY3-36; Y1R
and Y2R, subtypes o neuropeptide Y receptor; a-MSH, a-melanocyte
stimulating hormone derived by cleavage o POMC; Mc4R, melanocor-
tin 4 receptor; GHSR, growth hormone secretagogue receptor (recep-
tor or ghrelin); InsR, insulin receptor; MCH, melanin concentrating hor-
mone; TRH, thyrotropin-releasing hormone; CRH, corticotropin-releas-ing hormone.
SLIKA 2. Energetska homeostaza. Neuroni neuropeptida Y (NPY)/pro-teina povezanog s agouti (AgRP) te neuroni proopiomelanokortina
(POMC)/transkripta povezanog s kokainom i ametaminom (CART) u
lunoj jezgri hipotalamusa primaju signale iz perierije. Oni prenose
oreksigene i anoreksigene signale do nizvodnih neurona koji osigu-
ravaju ravnoteu izmeu unosa i potronje energije (6, 66, 71).
Puna crta: poticanje; isprekidana crta: suzbijanje. PYY, peptid YY3-36;
Y1R i Y2R, podtipovi receptora neuropeptida Y; a-MSH, hormon za
poticanje a-melanocita, izveden cijepanjem POMC; Mc4R, receptor
melanokortina 4; GHSR, sekretagogni receptor hormona rasta (recep-
tor za grelin); InsR, inzulinski receptor; MCH, hormon za koncentriran-
je melanina; TRH, hormon za otputanje tirotropina; CRH, hormon za
otputanje kortikotropina.
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18
de do aktiviranja oreksigenih putova, to dovodi do niske
stope metabolizma i pojaanog apetita (6).
Leptin i inzulin posreduju dugoronu regulaciju tjelesne
mase. Oni su isto tako djelatni u kratkoronim signalima
kojima se pojedini obrok zapoinje ili zavrava. Uz to,unos hrane praen je nekim drugim kratkodjelujuim hor-
monima/imbenicima: grelin, motilin, neuromedin U, neu-
rotenzin (70), kolecistokinin, peptid YY3-36
(engl. peptide
YY3-36
, PYY) (71) i glukagonu slian peptid-1 (72), od kojih
se svi lue u probavnom sustavu, te vagalnim aerentnim
signaliziranjem (72). Grelin se lui u bazi eluca i pojaa-
va osjeaj gladi te potie pranjenje eluca (70), dok PYY
signalizira sitost i suzbija crijevnu pokretljivost (71). Grelin
potie neuropeptid Y i ArRP neurone, dok PYY suzbija te
iste neurone kod ivotinja (71). Nedavno je otkriven pep-
tid izveden iz istoga prohormona kao grelin. Nazvali su
ga obestatin, a on se suprotstavlja uincima grelina (73).
Izgleda kako je leptinsko-melanokortinski put anoreksi-
genog signaliziranja osobito ouvan meu vrstama i mu-
tacije gena koji kodiraju sastavnice ovoga puta, odnosno
leptin, leptinski receptor, pro-opiomelanokortin (engl.
pro-opiomelanocortin, POMC), prohormon-konvertazu 1
(engl. prohormone-convertase 1, PC1) i receptor melano-
kortina 4 (engl. melanocortin 4 receptor, Mc4R), uzrokuju
rijetke oblike bolesne monogene pretilosti te dovode do
nekih prirodno nastalih modela pretilosti kod mieva i ta-
kora (ob, db, Ay i mg) (6). Suprotno tome, uklanjanje gena
(knockout) za oreksigene putove kod mieva ne dovodi
do stvaranja krtih enotipova, ukazujui na iznimno sna-
ne uzajamne uinke sastavnica u sustavu anabolizma i po-
rasta teine (71).
Dananja visoka incidencija pretilosti mogla bi se objasni-
ti hipotezom o tedljivom genotipu: kroz dua vremen-
ska razdoblja birali su se aleli koji pogoduju porastu tei-
ne i pohrani masti kako bi se osigurali dostatni nutrijenti
za vrijeme nedostatka hrane. U dananje vrijeme dostup-
nosti hrane i smanjenje tjelesne aktivnosti takvi genotipo-
vi uzrokuju pretilost (74).
Sposobnost tijela da precizno odrava tjelesnu teinu od-
raava se u neuspjehu intervencija kojima je cilj smanje-
nje tjelesne teine. Dijete ogranienih kalorija dovode do
kompenzacijskog porasta razina grelina, ime se potie
uzimanje hrane (71). Smanjenje tjelesne teine rezultira
padom razina leptina, to opet potie porast teine (71).
Kirurko uklanjanje masnog tkiva dovodi do obnavljanja
masti na novim lokacijama, dok poticanje termogeneze
adrenerginim 3-agonistima izaziva kompenzacijski od-
govor sredinjega ivanog sustava (6). Tek se je krajnjom
intervencijom u mieva s opsenom prekomjernom ek-
spresijom nevezujueg proteina-3 (UCP-3), koji je signal-
na bjelanevina u termogenezi, uspjelo prevladati sredi-
nje prilagodbene mehanizme i mievi su ostali mravi
(75). Kod ljudi je uspjean operacijski zahvat eluanog
premotenja, koji dovodi do snienja plazmatske koncen-
lead to the activation o orexigenic pathways resulting in
low metabolic rate and enhanced appetite (6).
Leptin and insulin mediate long-term body mass regula-
tion. They are also active in short-term signals that eect
single meal to be initiated and terminated. In addition,there are some other short-acting hormones/actors
which accompany ood intake: ghrelin, motilin, neuro-
medin U, neurotensin (70), cholecystokinin, peptide YY3-36
(PYY) (72) and glucagon-like peptide-1 (72), all secreted
by the gastrointestinal tract, and vagal aerent signaling
(71). Ghrelin is secreted by the stomach undus and in-
creases the sense o hunger and stimulates gastric emp-
tying (70), whereas PYY signals satiety and inhibits gut
motility (71). Ghrelin stimulates neuropeptide Y and AgRP
neurons, while PYY exerts inhibition o the same neurons
in animals (71). Recently, a peptide derived rom the same
prohormone as ghrelin, was discovered. It has been named
obestatin and it opposes the eects o ghrelin (73).
Particularly the leptin-melanocortin anorexigenic signal-
ing pathway appears to be very conserved among spe-
cies, and mutations in genes encoding or components o
this pathway: leptin, leptin receptor, pro-opiomelanocor-
tin (POMC), prohormone-convertase 1 (PC1), and mela-
nocortin 4 receptor (Mc4R), cause rare orms o morbid
monogenic obesity and lead to some naturally occurring
murine models o obesity (ob, db, Ay and mg) (6). On the
contrary, knockouts in genes or orexigenic pathways in
mice ail to produce lean phenotypes, demonstrating
the extremely powerul mutual eects o anabolism and
weight gain system components (71).
Todays high incidence o obesity could be explained by
the thrity genotype hypothesis: over periods o time
the alleles were selected which avored weight gain and
at storage in order to provide enough nutrients or times
o ood deprivation. In todays times o ood availability
and decreased physical activity such genotypes cause
obesity (74).
The potential o the body to precisely maintain body
weight is reected in the ailure o interventions aimed at
body weight reduction. Calorie-restricted diet results in
compensatory increase in ghrelin levels thereby stimulat-
ing eating (71). Reduction o body weight results in the all
o leptin levels, which again stimulates weight gain (71).
Surgical removal o adipose tissue results in restoration
o at at new locations, and stimulation o thermogenesis
by adrenergic 3-agonists elicits a compensatory central
nerve system response (6). Only extreme intervention in
mice with gross overexpression o uncoupling protein-3
(UCP-3), which is a signal protein in thermogenesis, was
successul to override central adaptive mechanisms,
and mice remained lean (75). In humans, gastric bypass
surgery is successul as it results in ghrelin plasma con-
centration decrease and PYY increase, which suppresses
hunger and maintains reduced body weight (71).
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tracije grelina i porasta PYY koji zatomljuje glad i odrava
smanjenu tjelesnu teinu (71).
Razvoj mravog ivotinjskog modela suzbijanjem razvoja
masnog tkiva rezultirao je hiperaginim mievima s te-
kim dijabetesom otpornim na inzulin (76). Pretpostavljenimehanizam koji je uzrokovao IR bio je nedostatak leptina
i adiponektina zbog odsutnosti masnog tkiva. Naime, da-
vanje ovih hormona zajedno preokrenulo je stanje IR (77).
Tako se ini da su ova dva hormona potrebna za normal-
nu inzulinsku osjetljivost.
Uz monogene oblike pretilosti postoji barem 20 rijetkih
sindroma s oitom genetskom osnovom koji izgledaju slo-
enijima, jer se povezuju s veim brojem disunkcija (men-
talna retardacija, viestruki znaci poremeaja hipotalamu-
sa) (66).
Obina pretilost u ljudi smatra se oligogenim stanjem i
njezinu izraenost mijenjaju mnogobrojni modifcirajui
geni i imbenici okoline: unos hrane, tjelesna aktivnost i
puenje (6). Procjenjuje se kako genetska osnova sudjelu-
je s 4080% u patofziologiji pretilosti (66). Identifcirana
su najmanje 204 navodna genska lokusa udruena s preti-
lou, a oni koji su potvreni u vie studija prikazani su u
tablici 1. (78).
Metaboliki sindrom
Grupiranje hipertenzije, hiperglikemije i gihta prvobitno
je prepoznato jo dvadesetih godina 20. stoljea (1). Rea-
ven je 1988. godine identifcirao sindrom X koji potjee iz
IR. Godine 2004. je III. panel o lijeenju odraslih Nacional-nog obrazovnog programa o kolesterolu (engl. National
Cholesterol Education Programs Adult Treatment Panel III,
ATPIII) defnirao metaboliki sindrom pod alternativnim
Development o lean animal model by suppression o ad-
ipose tissue development resulted in hyperphagic mice
with severe insulin resistant diabetes (76). The hypoth-
esized mechanism causing IR was leptin and adiponectin
defciency due to the absence o adipose tissue. Namely,the administration o these hormones together reversed
IR (77). Thus, these two hormones appear to be required
or normal insulin sensitivity.
Besides monogenic orms o obesity there are at least
20 rare syndromes with obvious genetic basis, which
appears to be more complex as it predisposes more dys-
unctions (mental retardation, multiple signs o hypotha-
lamic disorder) (66).
The common human obesity is thought to be an oligo-
genic state and its expression is modulated by multiple
modifer genes and by environmental actors: ood intake,
physical activity, and smoking (6). The genetic basis in the
pathophysiology o obesity is estimated to be 40%-80%
(66). At least 204 putative gene loci associated with obesity
have been identifed, and those which have been con-
frmed by multiple studies are presented in Table 1 (78).
Metabolic Syndrome
The frst recognition o clustering o hypertension, hyper-
glycemia and gout came already in the twenties o 20 th
century (1). In 1988, Reaven identifed syndrome X origi-
nating rom IR. In 2004, the National Cholesterol Educa-
tion Programs Adult Treatment Panel III (ATPIII) defnedthe metabolic syndrome with alternative names: IR syn-
drome, Reaven syndrome, characterized by the ollowing
components (G52):
Gene name* Protein name Gene name* Protein name
ADIPOQ Adiponectin LEPR Leptin receptor
ADRA2A Adrenergic receptor -2A NR3C1 Nuclear receptor subamily 3, group C
ADRA2B Adrenergic receptor -2B PPARG PPAR-
ADRB1 Adrenergic receptor -1 UCP1 Uncoupling protein 1
ADRB2 Adrenergic receptor -2 UCP2 Uncoupling protein 2
ADRB3 Adrenergic receptor -3 UCP3 Uncoupling protein 3
DRD2 Dopamine receptor D2 TNF TNF-
LEP Leptin LIPE Hormone sensitive lipase
* according to HUGO Nomenclature Committee
TABLE 1.The list o genes associated with obesity confrmed by5 or more studies
TABLICA 1. Popis gena udruenih s pretilou potvrenih u 5 ilivie studija
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imenima: sindrom IR i Reavenov sindrom, obiljeen slije-
deim sastavnicama (G52):
abdominalna pretilost
aterogena dislipidemija
hipertenzijaIR
proupalno stanje
protrombotsko stanje
Ova klinika obiljeja su snani imbenici rizika za eer-
nu bolest tipa 2 i kardiovaskularnu bolest s moguim do-
datnim komplikacijama ukljuujui kolesterolne une
kamence, apneju u snu, sindrom policistinog jajnika kod
ena, masnu jetru i neke vrste raka (7).
Pretpostavljene su tri mogue etiologije za metaboliki
sindrom: utvreno je kako je pretilost odgovorna za pre-
komjerno otputanje slobodnih masnih kiselina, citokina
i drugih proupalnih proizvoda koji su upleteni u razvoj
IR, hipertenzije i dislipidemije. IR kao drugi mogui uzrok
metabolikog sindroma postavlja pitanje je li mogue raz-
dvojiti pretilost i IR. Zapravo, IR u razliitim stupnjevima
postoji u svim kategorijama indeksa tjelesne mase, ukazu-
jui na njen neovisan nasljedni doprinos, barem do neke
mjere. Neke populacije (iz june Azije) s blago prekomjer-
nom tjelesnom teinom pokazuju IR i to se smatra primar-
nom IR. S tog stajalita se IR moe svrstati kao zaseban
etioloki imbenik za metaboliki sindrom. Hiperinzuline-
mija kao posljedica IR moe poveati luenje VLDL iz jetre
i uzrokovati hipertenziju. Miina IR moe uzrokovati hi-
perglikemiju koja se pojaava glukoneogenezom kod jet-
re rezistentne na inzulin (7). Smatra se da trea etiologija
ukljuuje neovisne imbenike: imune, vaskularne, jetrene
itd., na koje utjee specifna genetska osnova pojedine
osobe, kao i imbenici okoline (7).
Klinike pojavnosti i kriteriji za dijagnosticiranje me-
tabolikog sindroma
Razine glukoze i FFA u plazmi
Hiperinzulinemija se razvija kao posljedica IR. U ovom sta-
nju su koncentracije FFA u plazmi tek umjereno poviene,
dok koncentracija glukoze moe biti normalna ili povie-
na. Ova potonja ukazuje na poremeenu toleranciju glu-koze, koja se dokazuje vrijednostima oralnoga testa tole-
rancije glukoze (OGTT) viim od normalnih, ali jo uvijek
ne toliko povienim da bi oznaavale eernu bolest (79).
Drugo mogue obiljeje metabolikog sindroma je pore-
meena glukoza natate (7). Kad se koncentracije inzulin u
plazmi snize kao rezultat razgradnje -stanica, razine FFA
se znatno povisuju uz popratnu hiperglikemiju i stanje me-
tabolikog sindroma prerasta u eernu bolest (79).
Aterogena dislipidemija
Hipertrigliceridemija nastaje kao posljedica poveane sin-
teze VLDL u jetri. HDL u plazmi je snien, uz veu zastup-
abdominal obesity
atherogenic dyslipidemia
hypertension
IR
proinammatory stateprothrombotic state
These clinical eatures are strong risk actors or DM2 and
cardiovascular disease with additional possible complica-
tions including cholesterol gallstones, sleep apnea, poly-
cystic ovary syndrome in women, atty liver and some
types o cancer (7).
Three possible etiologies or the metabolic syndrome
have been postulated: obesity was ound to be respon-
sible or excess release o FFA, cytokines and other proin-
ammatory products which are implicated in the devel-
opment o IR, hypertension and dyslipidemia.
IR as the second possible cause o metabolic syndrome
rises a question o whether it is possible to dissociate be-
tween obesity and IR. Indeed, IR exists to various degrees
in all particular classes o body mass index, suggesting
an independent inheritable contribution o it to at least
some extent. Some populations (South Asians) with mild
overweight display IR and this is said to be primary IR.
From this point o view IR can be classifed as a separate
etiological actor or metabolic syndrome. Hyperinsu-
linemia as a consequence o IR is capable to increase
VLDL secretion rom the liver and to cause hypertension.
IR o muscle can cause hyperglycemia, exaggerated by
gluconeogenesis in insulin-resistant liver (7).
The third etiology is thought to include independent ac-
tors: immune, vascular, hepatic, etc., which are inuenced
by specifc genetic background o an individual, and by
environmental actors (7).
Clinical maniestations and criteria or the diagnosis
o metabolic syndrome
Glucose and FFA plasma level
As a consequence o IR, hyperinsulinemia develops. In
this condition plasma FFA concentrations are only mod-
erately elevated, but glucose concentration can be nor-
mal or increased, the latter denoting impaired glucosetolerance which is demonstrated by oral glucose toler-
ance test (OGTT) values above normal, yet not elevated
enough to defne DM (79). Another possible eature in
the metabolic syndrome is impaired asting glucose (7).
When plasma insulin concentrations decline, as a result
o -cell degeneration, FFA levels increase considerably
with accompanying hyperglycemia and the condition o
metabolic syndrome grows to DM2 (79).
Atherogenic dyslipidemia
As a consequence o increased liver VLDL synthesis hy-
pertriglyceridemia occurs. Plasma HDL is decreased with
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ljenost malog gustog HDL. Slino tome, sastav LDL se po-
mie prema prevlasti malog gustog LDL. Ovaj potonji se
smatra aterogenijim od obinog LDL. Isto tako dolazi do
promjena u apolipoproteinima (1).
HipertenzijaKod zdravih osoba inzulin potie simpatiki ivani sustav
i djeluje na krvne ile uzrokujui vazodilataciju. Inzulin is-
to tako potie ponovnu apsorpciju natrija u bubregu. U
stanju inzulinske rezistencije vazodilatacija se moe izgu-
biti, ali se uinak na bubrege i simpatika stimulacija od-
ravaju i ak poveavaju. To oboje doprinosi hipertenziji,
koji dodatno pogoravaju FFA koje pogoduju vazokon-
strikciji. Pa ipak, ini se kako dogaaji povezani izravno
s IR imaju tek umjerenu ulogu u razvoju hipertenzije (1).
Uz to, leptin bi mogao u stanovitoj mjeri doprinositi hiper-
tenziji, jer plazmatske koncentracije leptina vezanog uz
bjelanevine kod normotenzivnih mukaraca korelirajusa simpatikom ivanom aktivnou (26).
Ostala klinika obiljeja
Proupalno stanje je obiljeeno porastom C-reaktivnog
proteina u plazmi, a protrombotsko stanje povienjem
PAI-1 i fbrinogena (7).
Dodatne pojavnosti metabolikog sindroma su: masna
jetra i steatohepatitis zbog poveane jetrene proizvodnje
VLDL u stanju IR, hiperuricemija, povieni homocistein i
vaskularne nenormalnosti s mikroalbuminurijom (1). Oso-
bito je zanimljiva hiperuricemija, koja je najvjerojatnije
posljedica hiperinzulinemije: bubreg koji odrava normal-
nu osjetljivost za inzulin prilagoava se na visoke koncen-tracije inzulina smanjenim luenjem mokrane kiseline,
ime se poveava njegova razina u plazmi (79).
Drugi vaan kliniki biljeg IR je crnkasta akantoza (2) ko-
ja se oituje kao hiperpigmentirane kone promjene zas-
novane na epidermnoj hiperplaziji. Smatra se kako je ovo
obiljeje povezano s hiperinzulineminim stanjem, jer se
je pokazalo da inzulin ubrzava rast epidermnih stanica u
kulturi (80).
Dijagnostiki kriteriji to su ih prihvatili ATPIII i Internatio-
nal Diabetes Federation (engl. International Diabetes Fede-
ration, IDF) prikazani su u tablici 2. Prema dogovoru pri
ATPIII, dijagnoza metabolikog sindroma moe se posta-viti u bolesnika koji imaju najmanje 3 od 5 slijedeih obi-
ljeja: abdominalnu pretilost, poviene trigliceride, snien
HDL-kolesterol, povien krvni tlak ili povienu glukozu u
plazmi natate (7). Kriteriji koje je postavio IDF uglavnom
su sukladni onima iz ATPIII (81). Manje razlike odnose se
na sredinju pretilost kao glavno obiljeje i ispunjavanje
dviju od etiri druga pojavnosti. Granina koncentracija
glukoze nia je u kriterijima IDF, priem se preporua nap-
raviti OGTT kad je vrijednost via.
a greater proportion o small dense HDL. Similarly, the
composition o LDL is shited towards predominance o
small dense LDL. The latter is thought to be more athero-
genic than ordinary LDL. Changes o apolipoproteins also
occur (1).
Hypertension
In healthy subjects insulin stimulates sympathetic ner-
vous system and acts on blood vessels causing vasodila-
tation. Insulin also stimulates sodium reabsorption in the
kidney. In insulin resistant state the vasodilatation can be
lost but the renal eect and sympathetic stimulation are
maintained and even increased. Both contribute to hy-
pertension, which is urther exacerbated by FFA avoring
vasoconstriction. Nevertheless, it appears that the events
linked directly to IR play only a moderate role in the de-
velopment o hypertension (1). Additionally, leptin might
have some contribution to hypertension as protein-bound leptin plasma concentrations in normotensive
men correlate with sympathetic nerve activity (26).
Other clinical eatures
Proinammatory state is characterized by a rise in plasma
C-reactive protein, and prothrombotic state by elevation
o PAI-1 and fbrinogen (7). Additional maniestations o
the metabolic syndrome are atty liver and steatohepa-
titis because o increased liver VLDL production in the
state o IR, hyperuricemia, increased homocystein, and
vascular abnormalities with microalbuminuria (1). Par-
ticularly interesting is hyperuricemia which is most likelya consequence o hyperinsulinemia: the kidney which
maintains normal sensitivity to insulin, adapts to high
insulin concentrations by decreased uric acid secretion,
thereby elevating its plasma level (79).
Another important clinical marker o IR is acanthosis
nigricans (2), which maniests as hyperpigmented skin
changes based on epidermal hyperplasia. The eature is
thought to be related to the hyperinsulinemic state, as
insulin was shown to accelerate epidermal cell growth in
culture (80).
Diagnostic criteria accepted by ATPIII and International
Diabetes Federation (IDF) are presented in Table 2. Ac-
cording to ATPIII agreement, patients having at least 3 o
5 characteristics can be diagnosed as having the meta-
bolic syndrome: abdominal obesity, elevated triglycer-
ides, decreased HDL-cholesterol, increased blood pres-
sure or increased asting plasma glucose (7). IDF declares
criteria airly consistent with ATPIII (82). Slight dierences
include central obesity as the major eature and ulflled
two o our other maniestations. The borderline glucose
concentration is lower in IDP criteria, with a strong rec-
ommendation or OGTT when exceeded.
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Biochemia Medica god. 16, br. 1, 2006. Biochemia Medica Vol. 16, No. 1, 2006
22
ZakljuakGlavni osnovni uzrok IR je visceralna pretilost, jer je visce-
ralno masno tkivo sklonije lipolizi od potkonog masnog
tkiva. Smatra se kako su najvaniji mehanizmi za razvoj IR
poveano luenje FFA, sniene koncentracije adiponekti-
na, leptina, IL-6 i drugih adipokina. Uz to to je IR prisut-
na zajedno s pretilou i drugim obiljejima poznatim kao
metaboliki sindrom, smatra se da ima vanu ulogu i u
razvoju sindroma policistinih jajnika kod ena (82) te daje glavno obiljeje kod lipodistrofja (83). Ove potonje su
obiljeene selektivnim gubitkom masnog tkiva, to ukazu-
je na to da je odreena koliina masnog tkiva neophodna
za normalnu inzulinsku osjetljivost, vjerojatno tako to osi-
gurava mjesto za pohranu triglicerida, te to lui dovoljno
adiponektina i leptina (77).
Meutim, tek valja u potpunosti razjasniti etiologiju boles-
ti udruenih s IR. Postoje prigovori defniranju pretilosti
i s njom povezanih kardiovaskularnih rizinih imbenika
kao metaboliki sindrom zbog nesigurnosti njihova za-
jednikog podrijetla (84). S druge pak strane, pojavljuju
se nova vana saznanja o novootkrivenom inzulin-mime-
tinom adipokinu podrijetlom iz masnog tkiva. Nazvan je
visatin, jer je u znatno veim koncentracijama otkriven u
visceralnom nego u potkonom masnom tkivu. Za visa-
tin je pokazano kako sniava koncentraciju glukoze u plaz-
mi i djeluje neovisno od inzulina, vjerojatno veui se za
razliita vezna mjesta istoga receptora (85).
Bolje razumijevanje mehanizama koji dovode do IR i ud-
ruenih bolesti te otkrivanje dodatnih terapijskih ciljeva
kao to je visatin biti e korisno u lijeenju najozbiljnijih
komplikacija IR eerne bolesti tipa 2 i kardiovaskularne
bolesti.
ConclusionThe main underlying cause o IR is visceral obesity, as vis-
ceral adipose tissue is more prone to lipolysis than subcu-
taneous adipose tissue. The most important mechanisms
or the development o IR are thought to be increased se-
cretion o FFA, and decreased adiponectin, leptin, IL-6 and
other adipokine concentrations. Besides the coexistence
o IR with obesity and other eatures known as metabolic
syndrome, IR is thought to play an important role in thedevelopment o polycystic ovary syndrome in women
(82) and is the main eature o lipodystrophies (83). The
latter are characterized by selective loss o adipose tissue,
which indicates that a certain amount o adipose tissue
is necessary or normal insulin sensitivity, presumably by
providing the place or triglyceride storage and by secret-
ing su cient adiponectin and leptin (77).
However, the etiology o IR-associated disorders remains
to be ully elucidated. There are some objections to de-
fning obesity and related cardiovascular risk actors as
the metabolic syndrome or the uncertainty about their
common origin (84). On the other hand, some important
knowledge is arising such as about a newly discovered
insulin-mimetic adipokine derived rom adipose tissue.
It has been named visatin or being detected in a much
higher concentration in visceral than in subcutaneous
adipose tissue. It has been shown to lower plasma glu-
cose concentration and to act independently o insulin,
presumably by binding to a dierent binding site o the
same receptor (85).
Better understanding o the mechanisms leading to IR
and associated diseases, and discovery o additional
therapy targets such as visatin would prove benefcial in
the management o the most serious complications o IR,
DM2 and cardiovascular disease.
ATPIII IDF
Clinical eature Defning level Defning level
Central obesity
waist circumerence
men >102 cm men (European)94 cm (or specifc values or other
ethnic groups)
women >88 cm women (European) 80 cm
Plus any 2 o the ollowing:
Triglycerides 1.7 mmol/L 1.7 mmol/L or specifc treatment
HDL-cholesterolmen 1.03 mmol/L men 1.03 mmol/L or specifc treatment
women 1.29 mmol/L women 1.29 mmol/L
Blood pressure130/85
mm Hg
130/85 mm Hg or treatment o pre-
viously diagnosed hypertension
Fasting plasma glucose 6.1 mmol/L 5.6 mmol/L or previously diagno-sed DM2
TABLE 2. Diagnostic criteria or metabolic syndrome accordingto ATPIII (7) and IDF (81)
TABLICA 2. Dijagnostiki kriteriji za metaboliki sindrom premaATPIII (7) i IDF (81)
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23
Mlinar B. i sur. Inzulinska rezistencija, pretilost i metaboliki sindrom
Mlinar B. et al. Insulin Resistance, Obesity and Metabolic Syndrome
Adresa za dopisivanje:
Pro. dr. Janja Marc
Katedra za klinino biokemijo
Fakulteta za armacijo
Univerza v Ljubljani
Akereva 71000 Ljubljana
Slovenija
e-pota:[email protected]
tel: +386-1-4769-500
aks: +386-1-4258-031
Corresponding author:
Pro. Janja Marc, PhD
Department o Clinical Biochemistry
Faculty o Pharmacy
University o Ljubljana
Akereva 71000 Ljubljana
Slovenia
e-mail: [email protected] -lj.si
phone: +386-1-4769-500
ax: +386-1-4258-031
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