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

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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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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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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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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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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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13



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.


8/17


15



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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16

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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17



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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19



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



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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20

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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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



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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