Molecular Mechanisms of Insulin Resistance, Obesity and Metabolic Syndrome

Mo le ku lar ni me ha niz mi in zu lin ske re zis ten ci je, pre ti los ti i me ta bo lič kog sin dro ma Abstract Insulin resistance is a state of impaired responsiveness to insulin action. The most common underlying cause is central obesity although primary insulin resistance in normal-weight individuals is also possible. Excess abdominal adipose tissue has been shown to release increased amounts of tumor necro-sis factor α and free fatty acids, which directly aff ect insulin signaling, diminish glucose uptake in the muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in the liver. Other factors 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 of polygenic origin with infl u-ence of "obesogenic" environment, i.e. increased food intake and the lack of physical activity. Today's high prevalence of obesity could be explained by evolutionary pressure for selection of genes promoting fat storage to survive in starvation. Insulin resistance frequently coexists with central obesity, hypertension and dyslipidemia, which have collectively been denoted as metabolic syndrome. These manifestations represent strong risk factors for diabetes mellitus type 2 and cardiovascular disease. Pregledni članak Rewiev Pristiglo: 2. si ječ nja 2006.


Introduction
Insulin resistance (IR) is defi ned as less than normal response to insulin, which leads to hyperinsulinemia for euglycemic conditions to be maintained (1).Compensatory hyperinsulinemia due to enhanced β-cell secretion is therefore an obligate accompanying feature in IR.The main characteristics of IR are disinhibited gluconeogenesis, impaired uptake of glucose by muscle and disinhibited lipolysis in adipose tissue.Clinical markers of IR are visceral obesity, acanthosis nigricans (2), acne, hirsutism (3) and hepatic steatosis (1).The golden standard for evaluation of IR is hyperinsulinemic euglycemic clamp: insulin is infused at a con-noj sto pi in fu zi jom, a glu ko za se od r ža va na ba zal nim ra zi na ma in fu zi jom glu ko ze.Sto pa in fu zi je glu ko ze da je mje ru preu zi ma nja glu ko ze u svim tki vi ma (4).Al ter na tivne mje re za IR su kon cen tra ci je in zu li na u plaz mi na taš te (2) i proc je na mo de la ho meos ta ze (en gl.homeos ta sis model as ses sme nt, HOMA) iz ve de na iz kon cen tra ci ja in zu li na i glu ko ze u plaz mi na taš te (5).Etio lo gi ja IR uk lju ču je ge net ske čim be ni ke ko ji re zul ti raju sin drom nim ob li ci ma IR, te čim be ni ke oko li ne: unos hra ne, ne dos tat na tje les na ak tiv no st, sta re nje, pu še nje ili uzi ma nje li je ko va -tia zid nih diu re ti ka, be ta ad re ner gič nih an ta go nis ta, glu ko kor to koi da, ko ji mo gu uz ro ko va ti IR ili dop ri ni je ti nje go vu nas tan ku (2).Naj važ ni ji čim be nik je preti lo st ko ja je obič no slo že nog po li ge net skog i oko lin skog pod ri jet la (2,6).Ab do mi nal no mas no tki vo je iz vor slo bodnih mas nih ki se li na (en gl.free fat ty aci ds, FFA) i raz li či tih hor mo na (adi po ki na) ko ji su up le te ni u raz voj IR.Na sup rot to me, og ra ni čen unos ka lo ri ja, sma nje nje te ži ne i tje les na ak tiv no st po bolj ša va ju in zu lin sku os jet lji vo st (2,3,7).U ra du se ob jaš nja va ju me ha niz mi IR ko ji uk lju ču ju: po reme će no lu če nje adi po ki na i po ve ćan do tok FFA iz sre dišnjeg mas nog tki va, te dru ge po re me ća je in zu lin skih predre cepto ra, re cep to ra i pos tre cep to ra.

Me ha niz mi in zu lin ske re zis ten ci je
Fak tor tu mor ske nek ro ze α i slo bod ne mas ne ki se li ne Ud ru že no st IR s po vi še nim fak to rom tu mor ske nek ro ze α (en gl.tumor nec ro sis fac tor α, TNF-α), in ter leu ki nom 6 (IL-6), mak ro fa zi ma i mo no cit nim ke moat rak tan tnim pro tei no m-1 (en gl.mono cyte che moat trac ta nt pro tei n-1, MCP-1), in hi bi to ro m-1 ak ti va to ra plaz mi no ge na (en gl.plas mi no gen ac ti va tor in hi bi to r-1, PAI-1), adip si nom te sniže nim adi po nek ti nom ut vr đe na je u mno gim stu di ja ma (8).IR je pop rat no obi ljež je u mno gih pre ti lih bo les ni ka.Mas no tki vo ot puš ta ve li ke ko li či ne TNF-α, ko ji je ba rem dje lo mi ce od go vo ran za raz voj IR kod pre ti los ti (9).S druge stra ne, poz na to je da se s gu bit kom na te ži ni po ve ća va in zu lin ska os jet lji vo st; smat ra se ka ko to me di je lom posre du je sma nje no lu če nje adi poz nog TNF-α (10).TNF-α je glav ni au tok ri ni/parakrini čim be nik ko ji pok re će lu če nje slo bod nih mas nih ki se li na (FFA) iz mas nog tki va u kr vo tok (9).Me đu tim, os ta je ne jas no ko ji čim be ni ci dois ta pok reću ot puš tanje adi po ki na iz mas nog tki va.TNF-α pos re du je po tis ki va nje mno gih ge na od go vor nih za preu zi ma nje i poh ra nu glu ko ze i FFA.Za adi po ci te 3T3-L1 je po ka za no ka ko se re gu la ci ja na vi še i na ni že gena ovis nih o TNF-α od vi ja ob vez nim ak ti vi ra njem fak to ra nuk lear ne tran skrip ci je κB (11).Dje lo va njem TNF-α do la zi do po ja ča ne li po li ze uz ot puš ta nje FFA i ci to ki na.TNF-α i FFA re me te in zu lin sko sig na li zi ra nje u tki vi ma ko ja od go va ra ju na in zu lin, pog la vi to u mi ši ći ma.Pre ma hi po te zi o opskr bi li pi di ma (Ran dleo va hi po te za), ot pušte ne FFA dje lu ju kao prev la da va ju ći sup strat u in ter me di-stant rate and glucose is held at basal levels by glucose infusion.The rate of the latter is a measure of all tissues' glucose uptake (4).Alternative measures of IR are fasting plasma insulin concentrations (2) and homeostasis model assessment (HOMA) derived from fasting plasma insulin and glucose concentrations (5).The etiology of IR includes genetic factors resulting in syndromic forms of IR, and environmental factors: food intake, poor physical activity, aging, smoking or administration of drugs -thiazide diuretics, beta adrenergic antagonists and glucocorticoids, which can cause or contribute to IR (2).The most important factor is obesity, which is usually of combined polygenetic and environmental origin (2,6).Abdominal adipose tissue is a source of free fatty acids (FFA) and various hormones (adipokines) implicated in the development of IR.Conversely, restricted calorie intake, weight reduction and physical activity improve insulin sensitivity (2,3,7).The present paper explains the mechanisms of IR which include disregulated secretion of adipokines and increased effl ux of FFA from central adipose tissue, and other insulin prereceptor, receptor and postreceptor impairments.

The Mechanisms of Insulin Resistance
Tumor necrosis factor α and free fatty acids Numerous studies have found associations between increased tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), macrophages and monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), adipsin, and decreased adiponectin with IR (8).In the majority of obese patients IR is an accompanying feature.Adipose tissue releases great amounts of TNF-α, which is at least partly responsible for the development of 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-α release (10).TNF-α is the main autocrine/paracrine factor triggering the secretion of FFA from adipose tissue into the circulation (9).However, it remains unclear which factors actually trigger the release of adipokines from adipose tissue.TNF-α mediates repression of many genes responsible for glucose and FFA uptake and storage.For 3T3-L1 adipocytes it has been shown that TNF-α dependent gene up-and down-regulation occurs by obligatory activation of nuclear transcription factor κB (11).Upon TNF-α action, enhanced lipolysis occurs with the release of FFA and cytokines.TNF-α and FFA impair insulin signaling in insulin responsive tissues, especially muscle.The released FFA, according to the lipid supply hypothesis (Randle hypothesis), act as a predominant substrate in intermediary metabolism.Increased NADH/NAD+ and acetyl-CoA/CoA ratios could  (12,13).Vis ce ral no mas no tki vo lu či FFA iz rav no u por tal ni kr vo tok, či me snaž no ut je če na jet ru, a ne na pot kož no mas no tki vo ot puš ta ju ći svo je proiz vo de u pe ri fer nu cir kula ci ju (1).U jet ri ve li ke ko li či ne FFA osi gu ra va ju obi lan sup strat za sin te zu trig li ce ri da i VLDL, te za glu koneo ge ne zu.TNF-α po tis ku je ge ne za preu zi ma nje glu ko ze i be ta ok si da ci ju (14).Do la zi do de no vo sin te ze ko les te ro la, po tom do re gula ci je na vi še od go va ra ju ćih ge na po mo ću TNF-α (8).FFA ta ko đer pok re ću sin te zu fi b ri no ge na i PAI-1 u jet ri (15).FFA ko je iz vis ce ral nog mas nog tki va ot je ču u por talnu cir ku la ci ju i u jet ru sma nju ju jet re ni kli re ns in zu li na, čime dop ri no se hi pe rin zu li ne mi ji (13).Su vi šak trig li ce ri da se na kup lja u jet ri (1).U mi ši ći ma pak vi so ke kon cen tra ci je FFA po go du ju be ta ok si da ci ji, či me se sma nju je preu zi manje i ok si da ci ja glu ko ze (16).No, be ta ok si da ci ja je ne dostat na za dje lot vor no uk la nja nje FFA iz kr vo to ka, oso bi to ako ne ma tje les ne ak tiv nos ti (17).Sin te za gli ko ge na u miši ći ma je sus preg nu ta.Mišić ima glav nu ulo gu u uk la njanju glu koze (80-90%), pa nje zi no sma nje no preu zi ma nje u ve li koj mje ri dop ri no si hi per gli ke mi ji (9,18).Su viš ne FFA poh ra nju ju se kao kap lji ce trig li ce ri da u mi ši ći ma (1,7,17).U mas nom tki vu FFA suz bi ja ju ak tiv no st li pop ro tein li paze, ko ju ina če po ti če in zu lin, te ta ko one mo gu ća va ju kli rens FFA iz kr vo to ka (19).Sve u sve mu, li pi di ot puš te ni iz adipo ci ta kao FFA pre no se se kao trig li ce ri di po mo ću VLDL i prem ješ ta ju u ne mas na tki va (20).Po ka za no je ka ko TNF-α na ni že re gu li ra ge ne za adi ponek tin, tran spor ter glu ko ze 4 (en gl.glu co se tran spor ter 4, GLU T4), sup stra t-1 in zu lin skog re cep to ra (en gl. in su lin re cep tor sub stra te-1, I R S-1), CCAAT/po ja čaj ni vez ni pro tein α (en gl.CCAAT/enhancer bin di ng pro tein α, C/EBP-α), perok si zom ni pro li fe ra to r-ak ti vi ra ni re cep tor γ (en gl.pe roxiso me pro li fe ra to r-ac ti va ted re cep tor γ, PPA R-γ) i pe ri li pin u adi po ci ti ma (11,14).TNF-α na vi še re gu li ra mno ge ge ne izra že ne u mas nom tki vu, ko ji su od go vor ni za upa lu, imu ni od go vor i ener get sku rav no te žu (vas ku lar na sta nič na prianja ju ća mo le ku la-1 (VCA M-1), PAI-1, IL-6, IL-1β, an gio ten zino gen, re zis tin, lep tin) (14).

Lep tin
Lep tin je hor mon što ga u naj ve ćoj mje ri lu či mas no tki vo, a oz na ča va dos tat nu ko li či nu ener gi je.Lep tin sma nju je unos hra ne i po ve ća va pot roš nju ener gi je (21).Ovi učin ci nas tu pa ju dje lo va njem lep ti na na hi po ta la mus i iz rav no na cilj na tki va (mi šić, go na de, β-sta ni ce, jet ru) (22).U nor mal nim uv je ti ma od r ža va nja te ži ne kon cen tra ci je lep ti na po zi tiv no ko re li ra ju s ukup nom tje les nom masnom ma som.Kod krat kot raj nog us kra ći va nja hra ne serum ske ra zi ne lep ti na se sni ža va ju, dok se ob r nu to do gađa kod krat kot raj nog pre kom jer nog hra nje nja (23).
be the reason for the decreased glucose uptake, which means impaired insulin sensitivity (12,13).Visceral adipose tissue secretes FFA directly to the portal blood fl ow thereby exerting potent eff ects on the liver rather than subcutaneous adipose tissue releasing its products to peripheral circulation (1).
In the liver, high amounts of FFA provide an abundant substrate for triglyceride and VLDL-synthesis, and gluconeogenesis.TNF-α represses genes for glucose uptake and beta oxidation (14).De novo cholesterol synthesis occurs followed by TNF-α up-regulation of the corresponding genes (8).FFA also trigger fi brinogen and PAI-1 synthesis in the liver (15).FFA draining from visceral adipose tissue to portal circulation and to the liver decrease hepatic insulin clearance, thereby contributing to hyperinsulinemia (13).Excess triglycerides are accumulating in the liver (1).
In the muscle, high FFA concentrations favor beta oxidation, which diminishes glucose uptake and oxydation (16).However, beta oxidation is inadequate to clear FFA effi ciently from the circulation, even more in the lack of physical activity (17).Glycogen synthesis in the muscle is inhibited.Muscle is in force as the main glucose disposer (80%-90%) and diminished uptake contributes largely to hyperglycemia (9,18).Excess FFA are stored as triglyceride droplets in the muscle (1,7,17).

Leptin
Leptin is a hormone secreted predominantly by adipose tissue and is a signal of energy suffi ciency.It decreases food intake and increases energy expenditure (21).These eff ects are mediated by leptin action on the hypothalamus and directly on target tissues (muscle, gonads, β-cells, liver) (22).In normal conditions of weight maintenance leptin concentrations positively correlate with total body fat mass.In short term food deprivation serum leptin levels decrease and the opposite is true for short term overfeeding (23).Lep tin pred stav lja bi tan čim be nik fer ti li te ta, jer se je po kaza lo ka ko su sni že ne kon cen tra ci je lep ti na na kon us kra ćiva nja hra ne od go vor ne za suz bi ja nje hi po ta la mo-hi po fi zno-go nad ne osi (24).Kli nič ka sta nja sa sma nje nom mas nom ma som (li po distro fi je) obi lje že na su sni že nim kon cen tra ci ja ma lep ti na u plaz mi i IR.Da va njem lep ti na zna čaj no se po bolj ša va inzu lin ska os jet lji vo st u ovim sta nji ma (25), što po ka zu je da je nor mal na ko li či na mas nog tki va pre sud na za nor mal nu in zu lin sku os jet lji vo st, a to se ba rem dje lo mi ce is pu nja va kroz lu če nje lep ti na i nje go vim učin ci ma.Va žan uči nak lep ti na je sim pa tič ka sti mu la ci ja pu tem neuro na ko ji od go va ra ju na lep tin u hi po ta la mu su (8).To bi mog lo dje lo mi ce ob jas ni ti raz voj hi per ten zi je kod vis ceral ne pre ti los ti te u nep re ti lim sta nji ma.U skla du s tim, mišić na sim pa tič ka ak tiv no st kod nep re ti lih nor mo ten ziv nih muš ka ra ca dob ro ko re li ra s kon cen tra ci ja ma lep ti na ve zanog za bje lan če vi ne (26).

Adi po nek tin
Adi po nek tin po ka zu je snaž nu ob r nu tu ko re la ci ju s IR u li po dis tro fi ji i pre ti los ti, te s upal nim sta nji ma (27,28).Adi po nek tin lu če is klju či vo adi po ci ti (27).Adi po nek tin pobolj ša va in zu lin sku os jet lji vo st kroz ra zliči te me ha niz me.U jet ri iza zi va ok si da ci ju mas nih ki se li na, sma nju je sin tezu li pi da, sma nju je preu zi ma nje FFA i suz bi ja glu ko neo gene zu re gu li ra ju ći en zi me na ni že (8,23,29).U mi ši ću adipo nek tin po go du je ok si da ci ji glu ko ze i FFA.Ove učin ke di je lom omo gu ću je ak ti vi ra nje A MP-ki na ze (28).Ta ko adipo nek tin sni ža va razine FFA i glu ko ze u plaz mi (8,23).Kata bo li zam FFA se po ti če iz rav no ili kroz po ti ca nje nuk learnih re cep to ra PPA R-γ (30).Adi po nek tin sma nju je iz ra že no st pria nja ju ćih mo le ku la na sti jen ci kr vnih ži la, suz bi ja ke mo tak su mak ro fa ga i njiho vu pret vor bu u pje nas te sta ni ce, pro li fe ra ci ju glat komi šić nih sta ni ca i upal ne do ga đa je u ate ro ge ne zi što ih pro mi ču IL-6, PAI-1 itd.(8).Adi po nek tin ta ko đer suz bi ja luče nje TNF-α (31).Ra zi ne adi po nek ti na po ve ćava ju se s gu bit kom te ži ne (32) i li je če njem tia zo li di ne dio ni ma (en gl.thia zo li di ne dio nes, TZD) (33), ko ji su ago nis ti PPA R-γ.Sin te za adi po nek ti na je po re me će na u sta nji ma su viš ka ka lo ri ja, što bi mog lo bi ti po ve za no s re zis ten ci jom ili ne dos tat kom lep ti na (23).Inzu lin i in zu li nu sli čan fak tor ras ta (en gl. in su li n-li ke growth fac to r-1, I GF-1) po ti ču sin te zu adi po nek ti na (23).Slič no to me, IL-10 is to ta ko ima an ti di ja be to ge ni uči nak: kod pre ti los ti bez me ta bo lič kog sin dro ma ra zi ne IL-10 u plaz mi su po vi še ne, ali je IL-10 sni žen u me ta bo lič kom sindro mu (34).

Re zis tin
Vis ce ral no mas no tki vo lu či re zis tin u da le ko ve ćoj mje ri ne go pot kož no mas no tki vo (8).Kod pre ti los ti u glo da vaca su se rum ske ra zi ne re zis ti na po vi še ne, a ne ki su po ku si Leptin represents an essential fertility factor as decreased leptin concentrations following food deprivation have been shown to be responsible for the suppression of the hypothalamic-pituitary-gonadal axis (24).Clinical states with diminished adipose mass (lipodystrophies) are characterized by reduced plasma leptin concentrations and IR.Leptin administration signifi cantly improves insulin sensitivity in these conditions (25), indicating that normal amount of adipose tissue is critical for normal insulin sensitivity, and this is at least partly fulfi lled via leptin secretion and its eff ects.An important leptin eff ect is sympathetic stimulation achieved by eliciting leptin-responsive neurons in the hypothalamus (8).This could in part explain the development of hypertension in visceral obesity and non-obese states.In accordance with this, muscle sympathetic activity 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 infl ammatory states (27,28).It is secreted exclusively by adipocytes (27).Adiponectin improves insulin sensitivity by various mechanisms: in the liver, it induces fatty acid oxidation, decreases lipid synthesis, decreases uptake of FFA and represses gluconeogenesis by enzyme down-regulation (8,23,29).In muscle, adiponectin favors glucose and FFA oxidation.These eff ects are partly due to the activation of AMPkinase (27).Thereby, adiponectin decreases plasma FFA and glucose levels (8,23).FFA catabolism is stimulated either directly or through stimulation of PPAR-γ nuclear receptors (30).Adiponectin decreases the expression of adhesion molecules on blood vessel wall, inhibits chemotaxis of macrophages and their conversion to foam cells, proliferation of smooth muscle cells and infl ammatory events in atherogenesis, which are promoted by IL-6, PAI-1 etc. (8).
Adiponectin also suppresses secretion of TNF-α (31).Adiponectin levels increase with weight loss (32) and treatment with thiazolidinediones (TZD) (33), which are PPAR-γ agonists.The synthesis of adiponectin is impaired in the states of calorie excess, which might be associated with leptin resistance or defi ciency (23).Insulin and insulin-like growth factor (IGF-1) stimulate adiponectin synthesis (23).
Similarly, IL-10 also exerts an antidiabetogenic eff ect: 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-pot vr di li da re zis tin uz ro ku je IR (35).Me đu tim, dru ga pak is pi ti va nja ni su pot vr di la tak ve re zul ta te (8,36).Ljud ski re zis tin po ka zu je tek 64%-tnu ho mo log no st s rezis ti nom glo da va ca (37) i iz ra že no st re zis ti na u ljud skim adi po ci ti ma ni je jed na ko ud ru že na s IR ili pre ti loš ću (23).S dru ge stra ne, tia zo li di ne dio ni (TZD) mož da svo je učin ke dje lo mi ce os tva ru ju kro za sma nje no dje lo va nje re zis ti na, jer se nje go vo lu če nje sma nju je ti je kom li je če nja TZDi ma (23).Sve u sve mu, ulo gu re zis ti na u lju di tek tre ba pod robni je raz jas ni ti.

Os ta li adi po ki ni
Mak ro fa zi i mo no cit ni ke moat rak tan tni pro tei n-1 (MCP-1) su iz rav no uz roč no po ve zani s IR: MCP-1 re me ti ula zak gluko ze i in zu lin ske sig na le u sta ni ca ma (38).Adi po ci ti lu če MCP-1; on priv la či mak ro fa ge u mas no tki vo i pro mi če njiho vo ot puš tanje IL-1 i TNF-α (8).On is to ta ko suz bi ja ra st i di fe ren ci ja ci ju adi po ci ta.MCP-1 pro mi če ate ros kle ro zu priv la če ći mak ro fa ge i po go du ju ći nji ho vom na kup lja nju u sta nič nim sti jen ka ma (39).PAI-1 je vi še iz ra žen u vis ce ral nom u us po red bi s pot kožnim mas nim tki vom (40).On je snaž no ud ru žen s vis ce ralnom pre ti loš ću, IR i me ta bo lič kim sin dro mom.Pret pos tavlja se da PAI-1 dop ri no si pre ti los ti i IR, te da ima uz roč nu ulo gu u dalj njem raz vo ju kar dio vas ku lar ne bo les ti zbog svog prot rom bot skog dje lo va nja (8).Ra zi ne PAI-1 u plazmi sni ža va ju se s gu bit kom te ži ne (8) i li je če njem tva ri ma za in zu lin sku sen zi bi li za ci ju (41).Stu di je s IL-6 uka zu ju na nje go vu uz roč nu ulo gu u IR, jer plaz mat ske kon cen tra ci je i iz ra že no st u mas nom tki vu te po li mor fi zam IL-6 dob ro ko re li ra ju s pre ti loš ću i IR.Po kaza no je ka ko IL-6 re me ti in zu lin sko sig na li zi ra nje (42), suzbi ja adi po ge ne zu i lu če nje adi po nek ti na (8).Is to ta ko, IL-6 iza zi va IR u jet ri i adi po ci ti ma (43).U sre diš njem živ ča nom sus ta vu IL-6 ima sup rot ne učin ke -što uka zu je na to da on po go du je pot roš nji ener gi je.Dava nje IL-6 tran sge nič nim glo dav ci ma ko ji ma je uk lo njen gen za IL-6 po niš tio je raz voj pre ti los ti (44).

Glu ko kor ti koi di
Glu ko kor ti koi di su dob ro poz na ti an ta go nis ti in zu li na.Oni se sup rot stav lja ju učin ci ma in zu li na i ti me mo gu izaz va ti IR.Oni dje lu ju na ob je ma ra zi na ma IR: po ja ča va ju jet re nu glu ko neo ge ne zu i ot puš ta nje glu ko ze iz jet re, te re me te preu zi ma nje glu ko ze u pe ri fer nim tki vi ma.Pret hod no spo me nu te vi so ke ra zi ne FFA pred stav lja ju me ha ni zam za ovaj po to nji uči nak, a naj ma nje su tri mo gu ća pu ta ko jima mo že nas tu pi ti li po li za: 1. glu ko kor ti koi di po ve ća va ju pret vor bu no rad re na li na u ad re na lin (fe ni l-e ta no la min N-me til tran sfe ra za u skelet nim mi ši ći ma), ko ji dje lu je na hor mon ski os jet lji vu li pa zu u mas nom tki vu i provo di li po li zu (45); 2. oni pos re du ju li po li zu kroz re gu li ra nje na vi še PPA R-γ (46); sity, serum resistin levels are increased and some experiments have confi rmed resistin as causing IR (35).However, some other studies failed to confi rm these results (8,36).
Human resistin shows only 64% homology with rodent resistin (37) and expression of resistin in human adipocytes is not uniformly associated with IR or obesity (23).On the other hand, TZD may exert their eff ects partly through a diminished action of resistin as its secretion is decreased during TZD therapy (23).Taken together, the role of resistin in humans remains to be further elucidated.

Other adipokines
Macrophages and monocyte chemoattractant protein-1 (MCP-1) are directly causally associated with IR: MCP-1 impairs 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-α release (8).It also inhibits adipocyte growth and diff erentiation.MCP-1 promotes atherosclerosis by attracting macrophages and favoring their accumulation in vessel walls (39).PAI-1 has higher expression in visceral compared to subcutaneous 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 further development of cardiovascular disease for its prothrombotic activity (8).PAI-1 plasma levels decrease after 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 of IL-6 correlate well with obesity and IR.IL-6 was shown to interfere with insulin signaling (42), and to inhibit adipogenesis and secretion of adiponectin (8).IL-6 also induces IR in the liver and adipocytes (43).
In the central nervous system IL-6 has opposite eff ects -suggesting that it favors energy expenditure.Administration of IL-6 to IL-6 gene knockout rodents reversed obesity (44).

Glucocorticoids
Glucocorticoids are well known insulin antagonists.They oppose the eff ects of insulin and thereby could induce IR.They act on both levels of IR: they enhance liver gluconeogenesis and glucose release, and impair glucose uptake by peripheral tissues.The mechanism for the latter are previously mentioned high levels of FFA, and there are at least three possible ways how lipolysis can occur: 1. glucocorticoids increase norepinephrine conversion to epinephrine (phenyl-ethanolamine N-methyltransferase in skeletal muscle), which acts on hormone sensitive lipase in adipose tissue and performs lipolysis (45); 3. oni suz bi ja ju li pop ro tein li pa zu i ti me one mo gu ća va ju preu zi ma nje FFA u mas nom tki vu (47).U ske let nim mi ši ći ma je po ka za na po re me će na tran slo kaci ja GLU T4 kao pos lje di ca dje lovanja glu ko kor ti koi da (48).Po ka za no je ka ko glu ko kor ti koi di suz bi ja ju va zo di la ta ci ju (izaz va nu in zu li nom pu tem du šič nom ok si da), pa su ta da cilj na tki va do bi va la ma nje glu ko ze (49).Ove učin ke glu kokor ti koi da još po ja ča va ju FFA po ve ća nim ve za njem glu koko rtikoi da za nji ho ve re cep to re (50).

Mo le ku lar ni me ha niz mi po re me će nog in zulin skog sig na li zi ra nja
Nor mal no in zu lin sko sig na li zi ra nje In zu lin ski re cep tor je he te ro tet ra mer ni re cep tor ko ji je iz ra žen na jet re nim, adi poz nim i ske let no mi šić nim sta nica ma.Ve za nje in zu li na pok re će oli go me ri za ci ju i au to fosfo ri la ci ju re cep to ra na ti ro zin skim os ta ci ma, te ti ro zin sku fos fo ri la ci ju I R S-1, -2, -3, -4, IR S5/DOK4, IR S6/DOK5.Ova fos fo ri la ci ja či ni os no vu za dalj nje ud ru ži va nje s niz vodnim sig nal nim bje lan če vi na ma ko je se ra zi la ze u tri raz li čite pu ta nje: pu ta nju fos foi no zi ti d-3-ki na zu (en gl.phos phoino si ti de-3-ki na se, PI3K), pu ta nju CAP/Cbl/TC10 i pu ta nju ovis nu o mi to ge nom ak ti vi ra noj pro tein ki na zi (en gl.mi toge n-ac ti va ted pro tein ki na se, MA P-ki na se) (Sli ka 1.) (51,52).PI3K uza jam no dje lu je s fos fo ri li ra nim Tyr na mo le ku le IRS te se na kon stva ra nja fos fa ti di li no zi to l-3,4,5-trifosfata (engl.phos pha ti dyli no si to l-3,4,5-triphosphat, PIP 3 ) ak ti vi ra ju raz li či te pro tein ki na ze (53).Pos lje dič no to me do la zi do deak ti vi ra nja gli ko gen sin ta ze ki na ze 3 (en gl.glyco gen syntha se ki na se 3, GSK-3), što na kon cu re zul ti ra sin te zom gli ko ge na; gen sin ta ze mas nih ki se li na re gu li ran je na vi še, dok je gen fos foe nol pi ru vat kar bok si ki na ze (en gl.phosphoe nol pyru va te car boxyki na se, PEPCK) re guli ran na ni že.Bi tan uči nak pu ta PI3K je tran slo ci ra nje glav nog pri je nosni ka glu ko ze GLU T4 u plaz mat sku mem bra nu (51,52).Sinte za bje lan če vi na nas tu pa ak ti vi ra njem cilj nog en zi ma za ra pa mi cin ko ji je svoj stven si sav ci ma (en gl.mam ma lian tar get of ra pa mycin, mTOR) (54).Ka ko bi se preu zi ma nje glu ko ze od vi ja lo u pot pu nos ti, prila god be na bje lan če vi na CAP upoš lja va pro to-on ko gen Cbl u fos fo ri li ra ni in zu lin ski re cep tor, što u ko nač ni ci do vodi do po ja ča ne tran slo ka ci je GLU T4 (51).Tre ći put do vo di do ak ti vi ra nja MA P-ki na ze te sta nič ne pro li fe ra ci je i di fe ren ci ja ci je pu tem re gu la ci je gen ske transkrip ci je (52,55).

Ne dos tat ci u in zu lin skom sig na li zi ra nju
Ma nji broj slu ča je va in zu lin ske re zis ten ci je obi lje žen je po jed nom ge net skom ili ste če nom zna čaj kom.Pro tuinzu lin ska au toan ti ti je la na đe na su kod še ćer ne bo les ti tipa 1. (56).S dru ge stra ne, u ge nu in zu lin skih re cep to ra ut vrđe no je vi še od 60 mu ta ci ja.Me đu nji ma je IR tip A ud ružen sa sta njem he te ro zi got ne mu ta ci je, ko je či ni os no vu 2. they mediate lipolysis via up-regulation of PPAR-γ (46); and 3. they inhibit lipoprotein lipase and thus disable the uptake of FFA by adipose tissue (47).In skeletal muscle impaired translocation of GLUT4 was shown as a consequence of 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 eff ects of glucocorticoids are even potentiated by FFA increasing glucocorticoids binding to their receptors (50).

Molecular Mechanisms of Impaired Insulin Signaling
Normal insulin signaling Insulin receptor is a heterotetramer receptor, which is expressed on the liver, adipose and skeletal muscle cells.Binding of insulin triggers oligomerization and receptor autophosphorylation on tyrosine residues and tyrosine phosphorylation of IRS-1, -2, -3, -4, IRS5/DOK4, IRS6/DOK5.This phosphorylation provides the base for following association with downstream signal proteins which diverge into three diff erent pathways: phosphoinositide-3-kinase (PI3K) pathway, CAP/Cbl/TC10 pathway and mitogen-activated protein kinase (MAP-kinase) dependent pathway (Fig. 1) (51,52).PI3K interacts with phosphorylated Tyr on IRS molecules and upon formation of phosphatidylinositol-3,4,5-triphosphate (PIP 3 ) various protein kinases are activated (53).As a consequence, glycogen synthase kinase 3 (GSK-3) is inactivated, which at the fi nal stage results in glycogen synthesis; the fatty acid synthase gene is up-regulated and phosphoenolpyruvate carboxykinase (PEPCK) gene is down-regulated.An essential eff ect of PI3K pathway is translocation of the main glucose transporter GLUT4 to the plasma membrane (51,52).Protein synthesis is activated via enzyme mammalian target of rapamycin (mTOR) activation (54).For glucose uptake to manifest fully, the adapter protein CAP recruits proto-oncogene Cbl to the phosphorylated insulin receptor, which fi nally results in reinforced GLUT4 translocation (51).The third pathway leads to MAP-kinase activation and cellular proliferation and diff erentiation via gene transcription regulation (52,55).

Defects in insulin signaling
A minority of insulin resistant cases are characterized by a single genetic or acquired trait.Anti-insulin autoantibodies have been found in diabetes mellitus DM type 1 (DM1) (56).On the other hand, more than 60 mutations have been identifi ed in the insulin receptor gene.Among them type A IR is associated with heterozygous mutation state which underlies decreased Tyr phosphorylation of the β-za sma nje nu fos fo ri la ci ju Tyr u β-pod je di ni ci na kon ve zanja in zu li na (57).Pret pos tav lja se da mu ta ci je ge na in zulin skih re cep to ra kod Rab so n-Men den hal lo va sin dro ma i Do no hue va sin dro ma re me te ve za nje in zu li na za re ceptor (57).IR mož da nas ta je zbog ne nor mal ne proiz vod nje pro tu ti je la za pro tuin zu lin ske re cep to re (IR tip B) (58).Za mu ta ci je PPA R-γ ko je ni su ud ru že ne s li po dis tro fi jom ta kođer se iz vješ ta va da uz ro ku ju IR (59).Ne ki au to ri iz vješ ta va ju o po ve ća noj raz grad nji in zu linskih re cep to ra (60).Uz to, pret pos tav lja se ka ko bi fos fori la ci ja se ri na/treonina raz nim pro tein ki na za ma C (en gl.pro tein ki na se C, PKC) mog la bi ti do dat nim čim be ni kom FI GU RE 1.In su lin sig nal tran sduc tion (51)(52)(53)(54)(55). Af ter in su lin re cep tor Tyr au top hos pho ryla tion, in su lin re cep tor sub stra tes 1 to 4 (I R S-1 to 4) Tyr phor pho ryla tion ta kes pla ce and sub sequen tly three diff e re nt pat hways tran sdu ce the sig nal: PI3K-de pen de nt pat hway me dia ti ng me ta bo lic res pon ses in clu di ng glu co se/lipid/protein me ta bo li sm and in su li n-sti mu la ted glu co se up ta ke; CAP/Cbl pat hway whi ch is ad di tional ly requi red for glu co se tran spor te r-4 (GLU T4) tran slo ca tion; and mi to ge n-ac ti va ted pro tein ki na se (MAPK) pat hway re sul ti ng in ce ll pro li fe ra tion and diff e ren tia tion.So lid li ne: sti mu la tion; das hed li ne: in hi bi tion.IRS, in su lin re cep tor sub stra te; PI3K, phos phoi no si ti de-3-kina se; PDK-1, phos phoi no si ti de-de pen de nt ki na se 1; PKB, pro tein ki nase B; aP KC, atypi cal pro tein ki na ses C; mTOR, mam ma lian tar get of ra pamycin; p70S6K, p70 ri bo so mal S6 ki na se; PEPCK, phos phoe nol pyru va te car boxyki na se; GSK3, glyco gen syntha se ki na se 3.
subunit after insulin binding (57).In Rabson-Mendenhall syndrome and leprechaunism (Donohue syndrome) insulin receptor gene mutations are presumed to impair insulin binding to the receptor (57).IR may be due to abnormal production of anti-insulin-receptor antibodies (type B IR) (58).PPAR-γ mutations which are not associated with lipodystrophy are also reported to cause IR (59).Some studies report an increased degradation of insulin receptor (60).Besides, it is hypothesized that serine/threonine phosphorylation by various protein kinases C (PKCs) could be an additional factor to regulate insulin receptor activity (61).Decreased Tyr phosphorylation state of IRS-1 SLI KA 1. Pret vor ba in zu lin skih sig na la (51)(52)(53)(54)(55). Na kon Tyr au to fos fo rila ci je in zu lin skih re cep to ra do la zi do Tyr fos fo ri la ci je sup stra ta za in zulin ke re cep to re 1 to 4 (I R S-1 do -4), a po tom se sig nal pret va ra tri ma raz li či tim pu to vi ma: pu tom ovis nim o PI3K ko ji pos re du je me ta bo li čke od go vo re u ključu ju ći me ta bo li zam glu ko ze/lipida/bjelančevi na in zu linom po ti ca no preu zi ma nje glu ko ze, pu tom CAP/Cbl ko je je do dat no pot re ban za tran slo ka ci ju pri je nos ni ka glu ko ze 4 (GLU T4) i pu tom mito ge nom ak ti vi ra ne pro tein ki na ze (MAPK) ko ji re zul ti ra sta nič nom pro li fe ra ci jom i di fe ren ci ja ci jom.Pu na cr ta: po ti ca nje; is pre ki da na crta: suz bi ja nje.IRS, sup strat za in zu lin ske re cep to re; PI3K, fos foi no zi ti d-3-ki na za; PDK-1, ki na za 1 ovis na o fos foi no zi ti du; PKB, pro tein ki na ze B; aP KC, ati pič ne pro tein ki na ze C; mTOR, cilj za ra pa mi cin u si sa va ca; p70S6K, p70 ri bo som na S6 ki na za; PEPCK, fos foe nol pi ru vat kar bok si kina za; GSK3, gli ko gen sin ta za ki na za 3.

Mli nar B. et al. Insulin Resistance, Obesity and Metabolic Syndrome
re gu la ci je ak tiv nos ti in zu lin skih re cep to ra (61).Sta nje smanje ne Tyr fos fo ri la ci je I R S-1, ko je je za pa že no kod hi pe rinzu li ne mič nih ob/ob mi še va, mog lo bi bi ti pos lje di ca smanje nje ak tiv nos ti in zu lin skih re cep to ra (62).
No vi ja is pi ti va nja su ug lav nom us re do to če na na po ve ćanu Ser/Thr fos fo ri la ci ju I R S-1, ko ja bi mog la bi ti pos lje dica po vi še nih kon cen tra ci ja TNF-α i da lje se po gor ša va hipe rin zu li nemijom ko ju uz ro ku je IR.Smat ra se da su PKC, PI3K-dalj nje ki na ze i MA P-ki na ze od go vor ne za Ser/Thr fos fo ri la ci ju, na kon če ga sli je di po ja ča na pro tea zom na razgrad nja I R S-1.Nai me, sma njen sad r žaj I R S-1 bje lan če vi ne opi san je u lju di, ži vo ti nja i uz go je nim stani ca ma s IR (51).
Va lja nag la si ti ka ko je sta no vi to ba zal no sta nje Ser/Thr fosfo ri la ci je I R S-1 neop hod no za us pješ nu Tyr fos fo ri la ci ju i in zu lin sko sig na li zi ra nje.Za to preos ta je ras vi jet li ti ko ji je stu panj fos fo ri la ci je I R S-1 i na ko jim Ser/Thr mjes ti ma potre ban da bi po ka zao svo je raz nov r sne učin ke.Uz to što pos re du je raz grad nju I R S-1, hi pe rin zu li ne mi ja mo že ut je ca ti na kon cen tra ci ju bje lan če vi na u I R S-2 i izazva ti ne ke prom je ne ni že na pu tu in zu lin ske sig na li za ci je (51).TNF-α, IL-6 i in zu lin in du ci raju dru gu važ nu sku pi nu čimbe ni ka IR -sup re so re ci to kin skog sig na li zi ra nja (en gl.suppres so rs of cyto ki ne sig nal li ng-1-3, SO CS-1-3), ko ji ima ju najma nje tri raz li či ta me ha niz ma dje lo va nja: oni se nat je ču s I R S-1 za ud ru ži va nje s in zu lin skom re cep to rom, suzbija ju Ja nus ki na zu up le te nu u in zu lin sko sig na li zi ra nje i po ve ćava ju pro tea zom nu raz grad nju I R S-1 (63).Za hi per gli ke miju je po ka za no ka ko teš ko sma nju je ak tiv no st pro tein kina ze B (en gl.pro tein ki na se B, PKB), ia ko su bi le ak ti vi ra ne ne ke dru ge prok si mal ne sas tav ni ce in zu lin ske sig na li za cije (in zu lin ski re cep tor, I R S-1, I R S-2, PI3K).Po ka za no je ka ko slo bod ne mas ne ki se li ne u vi so kim plazmat skim kon cen tra ci ja ma kroz pret vor bu u dia cil gli ce rol i aci l-CoA sma nju ju ak tiv nos ti I R S-1, -2, te ak tiv nos ti PI3K i raz li či tih izo for ma PKB i PKC u mi ši ću šta ko ra (51).Kod tran sge nič nih mi še va FFA su po ve ća le ak tiv no st bje lan čevi ne Mun c18c, ne ga tiv nog re gu la to ra tran slo ka ci je GLU T4 u plaz mat sku mem bra nu (64).Ipak, ne za si će ne FFA su koris ne uto li ko što omo gu ća va ju normal nu in zu lin sku os jetlji vo st u ne kim cilj nim tki vi ma (51).
Po ka za no je ka ko gli ci ra ne bje lan če vi ne, ko je nas ta ju kao pos lje di ca hi per gli ke mi je, unu tar sta ni ce sma nju ju ak tivno st PI3K, PKB i GSK-3, te ta ko mož da dop ri no se IR.Slič no to me, glu ko za min (U DP-N-a ce til glu ko za min), ko ji nas ta je iz glu ko ze i pred stdav lja glav ni sup strat za sta nič nu gli kozi la ci ju, po ja ča va gli ko zi la ci ju I R S-1 sma nju ju ći ta ko nje govu ak tiv no st, te gli ko zi la ci ju gli ko gen sin ta ze, sma nju ju ći ta ko nje zi nu spo sob no st od go vo ra na in zu lin (51).

Pre ti lo st
Sta nje uh ra nje nos ti se naj bo lje opi su je po mo ću in dek sa tje les ne ma se (en gl.bo dy ma ss in dex, BMI).BMI se iz ra čuna va ta ko da se te ži na oso be u ki log ra mi ma po di je li kvadra tom vi si ne u met ri ma.Uz ne ke iz nim ke BMI dob ro ko re-that was found in hyperinsulinemic ob/ob mice could be a consequence of decreased insulin receptor activity (62).
Recent studies focus mainly on increased Ser/Thr phosphorylation of IRS-1, which could be a consequence of increased TNF-α concentrations and further exacerbated by hyperinsulinemia which is secondary to IR. PKCs, PI3K-downstream kinases and MAP-kinases are thought to be responsible for Ser/Thr phosphorylation, which is followed by enhanced proteasomal degradation of IRS-1.Namely, decreased IRS-1 protein content has been reported in humans, animals and cultured cells with IR (51).
It is to emphasize that certain basal Ser/Thr phosphorylation state of IRS-1 is necessary for successful Tyr phosphorylation and insulin signaling.Therefore, it remains to be elucidated to which degree and on which Ser/Thr sites IRS-1 must be phosphorylated to display its diverse eff ects.
Besides mediating IRS-1 degradation, hyperinsulinemia might aff ect protein concentration of IRS-2 and provoke some downstream changes in insulin signaling (51).TNF-α, IL-6 and insulin induce another important group of IR factors -suppressors of cytokine signaling (SOCS-1 and -3), which have at least three diff erent mechanisms of action: they compete with IRS-1 for association with insulin receptor, they inhibit Janus kinase, involved in insulin signaling, and they augment proteasomal IRS-1 degradation (63).Hyperglycemia was shown to severely decrease protein kinase B (PKB) activity, although some other proximal components of insulin signaling (insulin receptor, IRS-1, IRS-2, PI3K) were activated.FFA in high plasma concentrations were shown, by transformation to diacylglycerol and acyl-CoA, to diminish the activities of IRS-1, -2 and activities of PI3K and various isoforms of PKB and PKC in rat muscle (51).In transgenic mice, FFA increased the activity of Munc18c protein, a negative regulator of GLUT-4 translocation to plasma membrane (64).Nevertheless, unsaturated FFA have benefi t to allow normal insulin sensitivity in some target tissues (51).Glycated proteins, emerging as a consequence of hyperglycemia were shown intracellularly to diminish the PI3K, PKB, and GSK-3 activity, thus possibly contributing to IR.Similarly, glucosamine (UDP-N-acetyl glucosamine), produced from glucose and being the main substrate for cellular glycosylation, enhances IRS-1 glycosylation thereby decreasing its activity, and glycogen-synthase glycosylation, which reduces its insulin responsiveness (51).

Obesity
The state of nutrition is best described by body mass index (BMI).BMI is calculated by dividing a person's weight in kilograms by the square of his height in meters.BMI is, with some exceptions, in good correlation with the amount of total body fat.According to BMI, the following li ra s ko li či nom ukup ne tje les ne mas ti.Pre ma BMI ut vr đene su sli je de će ka te go ri je pre kom jer ne tje les ne ma se ili uh ra nje nos ti ( 65 Vis ce ral no mas no tki vo je obi lje že no re la tiv no vi so kim luče njem IL-1 i PAI-1, dok je lu če nje lep ti na i adi po nek ti na ve će u pot kož nom mas nom tki vu (8).To je od go vor no za od nos iz me đu vis ce ral ne pre ti los ti i upal nih/trombotskih do ga đa ja, te ob jaš nja va učin ko vi to st TZD u po bolj ša nju in zu lin ske os jet lji vos ti kroz pre ras pod je lu li pi da u pot kožno mas no tki vo (69).Kod pre ti lih oso ba su kon cen tra ci je lep ti na u plaz mi po više ne pa eg zo ge no da va nje lep ti na ne ma učin ka na tje lesnu te ži nu (8).Ova se po ja va ob jaš nja va lep tin skom re zisten ci jom ili de sen zi bi li za ci jom (23).Uz to, kod pre ti los ti su kon cen tra ci je top lji vog lep tin skog re cep to ra nis ke, a ti me i kon cen tra ci je frak ci je ve zanog lep ti na.Ovo obi ljež je je neo vis no ud ru že no s ab do mi nal nom pre ti loš ću i IR.Smatra se ka ko top lji vi lep tin ski re cep to ri ima ju važ nu ulo gu u pri je no su u i kroz kr vno-mož da nu ba ri je ru, pa bi za si ćeno st ovo ga pri je no sa ili po re me ćaj u pret va ra nju sig na la lep tin skog re cep to ra mog li bi ti uz ro kom lep tin ske re zisten ci je.Kon cen tra ci je lep ti na u ce reb ros pi nal noj te ku ći ni pre ti lih bo les ni ka tek su bla go po vi še ne (23).

Insulin and leptin resistance in obesity
Visceral obesity predisposes to the development of hypertension, diabetes mellitus type 2 (DM2), cardiovascular disease, and certain types of cancer ( 66).An increased risk for health exists already in the overweight group.Besides total body fat mass, distribution of fat is essential for eventual metabolic complications.Visceral and subcutaneous adipose tissues diff er in their endocrine activities.Specifi c receptors such as angiotensin II receptors type-1 (AT1), β 1 -, β 2 -, β 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 receptors, α-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 released FFA directly to the liver where they promote gluconeogenesis, VLDL synthesis, decrease glucose uptake and cause overall IR.Visceral adipose tissue is characterized by a relatively higher secretion of IL-1 and PAI-1, whereas leptin and adiponectin secretion is greater in subcutaneous adipose tissue (8).This accounts for the relationship between visceral obesity and infl ammatory/thrombotic events, and explains the eff ectivity of TZD to improve insulin sensitivity by redistribution of lipids to subcutaneous adipose tissue (69).
In obese individuals there are increased plasma leptin concentrations and exogenous administration of leptin has no eff ect 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 fraction of bound leptin concentrations.This feature is independently associated with abdominal obesity and IR.Soluble leptin receptors are thought to be important for transport to or over the blood -brain barrier and it is the saturation of this transport or impairment of leptin receptor signal transduction that may be the cause of leptin resistance.Leptin concentrations in the cerebrospinal fl uid of obese patients are only modestly increased (23).

The pathophysiology of obesity
Each individual has a genetically determined weight setpoint and hence body weight is tightly regulated by an energy homeostatic mechanism (Figure 2) (6,66,71).Adi- de do ak ti vi ra nja orek si genih pu to va, što do vo di do nis ke sto pe me ta bo liz ma i po ja ča nog ape ti ta (6).
Lep tin i in zu lin pos re du ju du go roč nu re gu la ci ju tje les ne ma se.Oni su is to ta ko dje lat ni u krat ko roč nim sig na li ma ko ji ma se po je di ni ob rok za po či nje ili zav r ša va.Uz to, unos hra ne pra ćen je ne kim dru gim krat kod je lu ju ćim hormo ni ma/čimbenicima: gre lin, mo ti lin, neu ro me din U, neuro ten zin (70), ko le cis to ki nin, pep tid YY 3-36 (en gl.pep ti de YY 3-36 , PYY) (71) i glu ka go nu sli čan pep ti d-1 (72), od ko jih se svi lu če u pro bav nom sus ta vu, te va gal nim afe ren tnim sig na li zi ra njem (72).Gre lin se lu či u ba zi že lu ca i po ja čava os je ćaj gla di te po ti če praž nje nje že lu ca (70), dok PYY sig na li zi ra si to st i suz bi ja cri jev nu pok ret lji vo st (71).Gre lin po ti če neu ro pep tid Y i ArRP neu ro ne, dok PYY suz bi ja te iste neu ro ne kod ži vo ti nja (71).Ne dav no je ot kri ven peptid iz ve den iz is to ga pro hor mo na kao gre lin.Naz va li su ga obes ta tin, a on se sup rot stav lja učin ci ma gre li na (73).Iz gle da ka ko je lep tin sko-me la no kor tin ski put ano rek sige nog sig na li zi ra nja oso bi to oču van me đu vr sta ma i muta ci je ge na ko ji ko di ra ju sas tav ni ce ovo ga pu ta, od nos no lep tin, lep tin ski re cep tor, pro-o pio me la no kor tin (en gl.pro-o pio me la no cor tin, POMC), pro hor mo n-kon ver ta zu 1 (en gl.pro hor mo ne-con ver ta se 1, PC1) i re cep tor me la nokor ti na 4 (en gl.me la no cor tin 4 re cep tor, Mc4R), uz ro ku ju ri jet ke ob li ke bo les ne mo no ge ne pre ti los ti te do vo de do ne kih pri rod no nas ta lih mo de la pre ti los ti kod mi še va i štako ra (ob, db, Ay i mg) (6).Sup rot no to me, uk la nja nje ge na (knoc kout) za orek si ge ne pu to ve kod mi ševa ne do vo di do stva ra nja kr tih fe no ti po va, uka zu ju ći na iz nim no snažne uza jam ne učin ke sas tav ni ca u sus ta vu ana bo liz ma i poras ta te ži ne (71).Da naš nja vi so ka in ci den ci ja pre ti los ti mog la bi se ob jas niti hi po te zom o "šted lji vom ge no ti pu": kroz du ža vre menska raz dob lja bi ra li su se ale li ko ji po go du ju po ras tu te žine i poh ra ni mas ti ka ko bi se osi gu ra li dos tat ni nut ri jen ti za vri je me nedos tat ka hra ne.U da naš nje vri je me dos tupnos ti hra ne i sma nje nje tje les ne ak tiv nos ti tak vi ge no ti povi uz ro ku ju pre ti lo st (74).Spo sob no st ti je la da pre ciz no od r ža va tje les nu te ži nu odra ža va se u neus pje hu in ter ven ci ja ko ji ma je cilj sma njenje tje les ne te ži ne.Di je te og ra ni če nih ka lo ri ja do vo de do kom pen za cij skog po ras ta ra zi na gre li na, či me se po ti če uzi ma nje hra ne (71).Sma njenje tje les ne te ži ne re zul ti ra pa dom ra zi na lep ti na, što opet po ti če po ra st te ži ne (71).Ki rur ško uk la nja nje mas nog tki va do vo di do ob nav lja nja mas ti na no vim lo ka ci ja ma, dok po ti ca nje ter mo ge ne ze ad re ner gič nim β 3 -a go nis ti ma iza zi va kom pen za cij ski odgo vor središ nje ga živ ča nog sus ta va (6).Tek se je kraj njom in ter ven ci jom u mi še va s op sež nom pre kom jer nom ekspre si jom ne ve zu ju ćeg pro tei na-3 (U CP-3), ko ji je sig nalna bje lan če vi na u ter mo ge ne zi, us pje lo prev la da ti sre dišnje pri la god be ne me ha niz me i mi še vi su os tali mr ša vi (75).Kod lju di je us pje šan ope ra cij ski zah vat že lu ča nog pre moš te nja, ko ji do vo di do sni že nja plaz mat ske kon cen-lead to the activation of orexigenic pathways resulting in low metabolic rate and enhanced appetite (6).
Leptin and insulin mediate long-term body mass regulation.They are also active in short-term signals that eff ect single meal to be initiated and terminated.In addition, there are some other short-acting hormones/factors which accompany food intake: ghrelin, motilin, neuromedin U, neurotensin (70), cholecystokinin, peptide YY 3-36 (PYY) (72) and glucagon-like peptide-1 ( 72), all secreted by the gastrointestinal tract, and vagal aff erent signaling (71).Ghrelin is secreted by the stomach fundus and increases the sense of hunger and stimulates gastric emptying (70), whereas PYY signals satiety and inhibits gut motility (71).Ghrelin stimulates neuropeptide Y and AgRP neurons, while PYY exerts inhibition of the same neurons in animals (71).Recently, a peptide derived from the same prohormone as ghrelin, was discovered.It has been named obestatin and it opposes the eff ects of ghrelin (73).
Particularly the leptin-melanocortin anorexigenic signaling pathway appears to be very conserved among species, and mutations in genes encoding for components of this pathway: leptin, leptin receptor, pro-opiomelanocortin (POMC), prohormone-convertase 1 (PC1), and melanocortin 4 receptor (Mc4R), cause rare forms of morbid monogenic obesity and lead to some naturally occurring murine models of obesity (ob, db, Ay and mg) (6).On the contrary, knockouts in genes for orexigenic pathways in mice fail to produce lean phenotypes, demonstrating the extremely powerful mutual eff ects of anabolism and weight gain system components (71).Today's high incidence of obesity could be explained by the "thrifty genotype" hypothesis: over periods of time the alleles were selected which favored weight gain and fat storage in order to provide enough nutrients for times of food deprivation.In today's times of food availability and decreased physical activity such genotypes cause obesity (74).
The potential of the body to precisely maintain body weight is refl ected in the failure of interventions aimed at body weight reduction.Calorie-restricted diet results in compensatory increase in ghrelin levels thereby stimulating eating (71).Reduction of body weight results in the fall of leptin levels, which again stimulates weight gain (71).Surgical removal of adipose tissue results in restoration of fat at new locations, and stimulation of thermogenesis by adrenergic β 3 -agonists elicits a compensatory central nerve system response (6).Only extreme intervention in mice with gross overexpression of uncoupling protein-3 (UCP-3), which is a signal protein in thermogenesis, was successful to override central adaptive mechanisms, and mice remained lean (75).In humans, gastric bypass surgery is successful as it results in ghrelin plasma concentration decrease and PYY increase, which suppresses hunger and maintains reduced body weight (71).tra ci je gre li na i po ras ta PYY ko ji za tom lju je glad i od r ža va sma nje nu tje les nu te ži nu (71).Raz voj mr ša vog ži vo tinj skog mo de la suz bi janjem raz vo ja mas nog tki va re zul ti rao je hi per fa gič nim mi še vi ma s teškim di ja be te som ot por nim na in zu lin (76).Pret pos tav lje ni me ha ni zam ko ji je uz ro ko vao IR bio je ne dos ta tak lep ti na i adi po nek ti na zbog od sut nos ti mas nog tki va.Nai me, dava nje ovih hor mo na za jed no preok re nu lo je sta nje IR (77).Ta ko se či ni da su ova dva hor mo na pot reb na za nor malnu in zu lin sku os jet lji vo st.Uz mo no ge ne ob li ke pre ti los ti pos to ji ba rem 20 ri jet kih sin dro ma s oči tom ge net skom os no vom ko ji iz gle da ju slože ni ji ma, jer se po ve zu ju s ve ćim bro jem dis fun kci ja (mental na re tar da ci ja, vi šes tru ki zna ci po re me ća ja hi po ta la musa) (66).
Obič na pre ti lo st u lju di smat ra se oli go ge nim sta njem i nje zi nu iz ra že no st mi je nja ju mno gob roj ni mo di fi ci ra ju ći ge ni i čim be ni ci oko li ne: unos hra ne, tje les na aktiv no st i pu še nje (6).Proc je nju je se ka ko ge net ska os no va sud je luje s 40-80% u pa to fi zio lo gi ji pre ti los ti (66).Iden ti fi ci ra na su naj ma nje 204 na vod na gen ska lo ku sa ud ru že na s pre tiloš ću, a oni ko ji su pot vr đe ni u vi še stu di ja pri ka za ni su u tab li ci 1. (78).

Me ta bo lički sin drom
Gru pi ra nje hi per ten zi je, hi per gli ke mi je i gih ta pr vo bit no je pre poz na to još dva de se tih go di na 20.sto lje ća (1  (76).The hypothesized mechanism causing IR was leptin and adiponectin defi ciency due to the absence of adipose tissue.Namely, the administration of these hormones together reversed IR (77).Thus, these two hormones appear to be required for normal insulin sensitivity.
Besides monogenic forms of obesity there are at least 20 rare syndromes with obvious genetic basis, which appears to be more complex as it predisposes more dysfunctions (mental retardation, multiple signs of hypothalamic disorder) (66).
The common human obesity is thought to be an oligogenic state and its expression is modulated by multiple modifi er genes and by environmental factors: food intake, physical activity, and smoking (6).The genetic basis in the pathophysiology of obesity is estimated to be 40%-80% (66).At least 204 putative gene loci associated with obesity have been identifi ed, and those which have been confi rmed by multiple studies are presented in Table 1 (78).

Metabolic Syndrome
The fi rst recognition of clustering of hypertension, hyperglycemia and gout came already in the twenties of 20  ime ni ma: sin drom IR i Rea ve nov sin drom, obi lje žen sli jede ćim sas tav ni ca ma (G52): ab do mi nal na pre ti lo st ate ro ge na dis li pi de mi ja hi per ten zi ja IR prou pal no sta nje prot rom bot sko sta nje Ova kli nič ka obi ljež ja su snaž ni čim be ni ci ri zi ka za šećernu bolest tipa 2 i kar dio vas ku lar nu bo le st s mo gu ćim dodat nim kom pli ka ci ja ma uk lju ču ju ći ko les te rol ne žuč ne ka men ce, ap ne ju u snu, sin drom po li cis tič nog jaj ni ka kod že na, mas nu jet ru i ne ke vr ste ra ka (7).Pret pos tav lje ne su tri mo gu će etio lo gi je za me ta bo lički sin drom: ut vr đe no je ka ko je pre ti lo st od go vor na za prekom jer no ot puš ta nje slo bod nih mas nih ki se li na, ci to ki na i dru gih prou pal nih proiz vo da ko ji su up le te ni u raz voj IR, hi per ten zi je i dis li pi de mi je.IR kao dru gi mo gu ći uz rok me ta bo lič kog sin dro ma pos tav lja pi ta nje je li mo gu će razdvo ji ti pre ti lo st i IR.Zap ra vo, IR u raz li či tim stup nje vi ma pos to ji u svim ka te go ri ja ma in dek sa tje les ne ma se, uka zuju ći na njen neo vi san nas ljed ni dop ri nos, ba rem do ne ke mje re.Ne ke po pu la ci je (iz juž ne Azi je) s bla go pre kom jernom tje les nom te ži nom po ka zu ju IR i to se smat ra pri marnom IR. S tog sta ja liš ta se IR mo že svr sta ti kao za se ban etio loš ki čim be nik za me ta bo lič ki sin drom.Hi pe rin zu li nemi ja kao pos lje di ca IR mo že po ve ća ti lu če nje VLDL iz jet re i uz ro ko va ti hi per ten zi ju.Mi šić na IR mo že uz ro ko va ti hiper gli ke mi ju ko ja se po ja ča va glu ko neo ge ne zom kod jetre re zis ten tne na in zu lin (7).Smat ra se da tre ća etio lo gi ja uk lju ču je neo vis ne čim be ni ke: imune, vas ku lar ne, jet re ne itd., na ko je ut je če spe ci fi č na ge net ska os no va po je di ne oso be, kao i čim be ni ci oko li ne (7).

Kli nič ke po jav nos ti i kri te ri ji za di jag nos ti ci ra nje meta bo lič kog sin droma
Ra zi ne glu ko ze i FFA u plaz mi Hi pe rin zu li ne mi ja se raz vi ja kao pos lje di ca IR.U ovom stanju su kon cen tra ci je FFA u plaz mi tek um je re no po vi še ne, dok kon cen tra ci ja glu ko ze mo že bi ti nor mal na ili po vi šena.Ova po to nja uka zu je na po re me će nu to le ran ci ju gluko ze, ko ja se do ka zu je vri jed nos ti ma oral no ga tes ta to leran ci je glu ko ze (OGTT) vi šim od nor mal nih, ali još uvi jek ne to li ko po vi še nim da bi oz na ča va le šećernu bolest (79).Dru go mo gu će obi ljež je me ta bo lič kog sin dro ma je po reme će na glu ko za na taš te (7).Kad se kon cen tracije in zu lin u plaz mi sni ze kao re zul tat raz grad nje β-sta ni ca, ra zi ne FFA se znat no po vi su ju uz pop rat nu hi per gli ke mi ju i sta nje meta bo lič kog sin dro ma pre ras ta u šećernu bolest (79).
Ate ro ge na dis li pi de mi ja Hi per trig li ce ri de mi ja nas ta je kao pos lje di ca po ve ća ne sinte ze VLDL u jet ri.HDL u plaz mi je sni žen, uz ve ću zas tup-  (7).Three possible etiologies for the metabolic syndrome have been postulated: obesity was found to be responsible for excess release of FFA, cytokines and other proinfl ammatory products which are implicated in the development of IR, hypertension and dyslipidemia.IR as the second possible cause of metabolic syndrome rises a question of whether it is possible to dissociate between obesity and IR.Indeed, IR exists to various degrees in all particular classes of body mass index, suggesting an independent inheritable contribution of 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 of view IR can be classifi ed as a separate etiological factor for metabolic syndrome.Hyperinsulinemia as a consequence of IR is capable to increase VLDL secretion from the liver and to cause hypertension.IR of muscle can cause hyperglycemia, exaggerated by gluconeogenesis in insulin-resistant liver (7).The third etiology is thought to include independent factors: immune, vascular, hepatic, etc., which are infl uenced by specifi c genetic background of an individual, and by environmental factors (7).

Clinical manifestations and criteria for the diagnosis of metabolic syndrome
Glucose and FFA plasma level As a consequence of IR, hyperinsulinemia develops.In this condition plasma FFA concentrations are only moderately elevated, but glucose concentration can be normal or increased, the latter denoting impaired glucose tolerance which is demonstrated by oral glucose tolerance test (OGTT) values above normal, yet not elevated enough to defi ne DM (79).Another possible feature in the metabolic syndrome is impaired fasting glucose (7).When plasma insulin concentrations decline, as a result of β-cell degeneration, FFA levels increase considerably with accompanying hyperglycemia and the condition of metabolic syndrome grows to DM2 (79).

Atherogenic dyslipidemia
As a consequence of increased liver VLDL synthesis hypertriglyceridemia occurs.Plasma HDL is decreased with Hi per ten zi ja Kod zdra vih oso ba in zu lin po ti če sim pa tič ki živ ča ni sus tav i dje lu je na kr vne ži le uz ro ku ju ći va zo di la ta ci ju.In zu lin isto ta ko po ti če po nov nu ap sor pci ju nat ri ja u bub re gu.U sta nju in zu lin ske re zis ten ci je va zo di la ta ci ja se mo že iz gubi ti, ali se uči nak na bub re ge i sim pa tič ka sti mu la ci ja odr ža va ju i čak po ve ća va ju.To obo je dop ri no si hi per ten zi ji, ko ji do dat no po gor ša va ju FFA ko je po go du ju va zo konstrik ci ji.Pa ipak, či ni se ka ko do ga đa ji po ve za ni iz rav no s IR ima ju tek um je re nu ulo gu u raz vo ju hi per ten zi je (1).Uz to, lep tin bi mo gao u sta no vi toj mje ri dop ri no si ti hi perten zi ji, jer plaz mat ske kon cen tra ci je lep ti na ve za nog uz bje lan če vi ne kod nor mo ten ziv nih muš ka ra ca ko re li ra ju sa sim pa tič kom živ ča nom ak tiv noš ću (26).Os ta la kli nič ka obi ljež ja Prou pal no sta nje je obi lje že no po ras tom C-reak tiv nog pro tei na u plaz mi, a prot rom bot sko sta nje po vi še njem PAI-1 i fi b ri no ge na (7).Do dat ne po jav nos ti me ta bo lič kog sin dro ma su: mas na jet ra i stea to he pa ti tis zbog po ve ća ne jet re ne proiz vod nje VLDL u sta nju IR, hi pe ru ri ce mi ja, po vi še ni ho mo cis tein i vas ku lar ne ne nor mal nos ti s mik roal bu mi nu ri jom (1).Osobi to je za nim lji va hi pe ru ri ce mi ja, ko ja je naj vje ro jat ni je pos lje di ca hi pe rin zu li ne mi je: bub reg ko ji od r ža va nor malnu os jet lji vo st za in zu lin pri la go đa va se na vi so ke kon centra ci je in zu li na sma nje nim lu če njem mok rać ne ki se li ne, či me se po ve ća va nje go va ra zi na u plaz mi (79).Dru gi va žan kli nič ki bi ljeg IR je cr nkas ta akan to za (2) koja se oči tu je kao hi per pig men ti ra ne kož ne prom je ne zasno va ne na epi der mnoj hi per pla zi ji.Smat ra se ka ko je ovo obi ljež je po ve za no s hi pe rin zu li ne mič nim sta njem, jer se je po ka za lo da in zu lin ub r za va ra st epi der mnih sta ni ca u kul tu ri (80).Di jag nos tič ki kri te ri ji što su ih prih va ti li ATPIII i In ter na tional Dia be tes Fe de ra tion (en gl.In ter na tio nal Dia be tes Fe dera tion, IDF) pri ka za ni su u tab li ci 2. Pre ma do go vo ru pri ATPIII, di jag no za me ta bo lič kog sin dro ma mo že se pos tavi ti u bo les ni ka ko ji ima ju naj ma nje 3 od 5 sli je de ćih obiljež ja: ab do mi nal nu pre ti lo st, po vi še ne trig li ce ri de, sni žen HDL-koles te rol, po vi šen kr vni tlak ili po vi še nu glu ko zu u plaz mi na taš te (7).Kri te ri ji ko je je pos ta vio IDF ug lav nom su suk lad ni oni ma iz ATPIII (81).Ma nje raz li ke od no se se na sre diš nju pre ti lo st kao glav no obi ljež je i is pu nja va nje dvi ju od če ti ri dru ga po jav nos ti.Gra nič na kon cen tra ci ja glu ko ze ni ža je u kri te ri ji ma IDF, pri čem se pre po ru ča napra vi ti OGTT kad je vri jed no st vi ša.
a greater proportion of small dense HDL.Similarly, the composition of LDL is shifted towards predominance of small dense LDL.The latter is thought to be more atherogenic than ordinary LDL.Changes of apolipoproteins also occur (1).

Hypertension
In healthy subjects insulin stimulates sympathetic nervous system and acts on blood vessels causing vasodilatation.Insulin also stimulates sodium reabsorption in the kidney.In insulin resistant state the vasodilatation can be lost but the renal eff ect and sympathetic stimulation are maintained and even increased.Both contribute to hypertension, which is further exacerbated by FFA favoring vasoconstriction.Nevertheless, it appears that the events linked directly to IR play only a moderate role in the development of hypertension (1).Additionally, leptin might have some contribution to hypertension as proteinbound leptin plasma concentrations in normotensive men correlate with sympathetic nerve activity (26).

Other clinical features
Proinfl ammatory state is characterized by a rise in plasma C-reactive protein, and prothrombotic state by elevation of PAI-1 and fi brinogen (7).Additional manifestations of the metabolic syndrome are fatty liver and steatohepatitis because of increased liver VLDL production in the state of IR, hyperuricemia, increased homocystein, and vascular abnormalities with microalbuminuria (1).Particularly interesting is hyperuricemia which is most likely a consequence of 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 of IR is acanthosis nigricans (2), which manifests as hyperpigmented skin changes based on epidermal hyperplasia.The feature 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.According to ATPIII agreement, patients having at least 3 of 5 characteristics can be diagnosed as having the metabolic syndrome: abdominal obesity, elevated triglycerides, decreased HDL-cholesterol, increased blood pressure or increased fasting plasma glucose (7).IDF declares criteria fairly consistent with ATPIII (82).Slight diff erences include central obesity as the major feature and fulfi lled two of four other manifestations.The borderline glucose concentration is lower in IDP criteria, with a strong recommendation for OGTT when exceeded.

Zak lju čak
Glav ni os nov ni uz rok IR je vis ce ral na pre ti lo st, jer je vis ceral no mas no tki vo sklo ni je li po li zi od pot kož nog mas nog tki va.Smat ra se ka ko su naj važ ni ji me ha niz mi za raz voj IR po ve ća no lu če nje FFA, sni že ne kon cen tra ci je adi po nek tina, lep ti na, IL-6 i dru gih adi po ki na.Uz to što je IR pri sutna za jed no s pre ti loš ću i dru gim obi ljež ji ma poz na tim kao me ta bo lič ki sin drom, smat ra se da ima važ nu ulo gu i u raz vo ju sin dro ma po li cis tič nih jaj ni ka kod že na (82) te da je glav no obi ljež je kod li po dis tro fi ja (83).Ove po to nje su obi lje že ne se lek tiv nim gu bit kom mas nog tki va, što uka zuje na to da je od re đe na ko li či na mas nog tki va neop hod na za nor mal nu in zu lin sku os jet lji vo st, vje ro jat no ta ko što osigu ra va mjes to za poh ra nu trig li ce ri da, te što lu či do volj no adi po nek ti na i lep ti na (77).Me đu tim, tek va lja u pot pu nos ti raz jas ni ti etio lo gi ju bo lesti ud ru že nih s IR.Pos to je pri go vo ri de fi ni ra nju pre ti los ti i s njom po ve za nih kar dio vas ku lar nih ri zič nih čim be ni ka kao "me ta bo lič ki sin drom" zbog ne si gur nos ti nji ho va zajed nič kog pod ri jet la (84).S dru ge pak stra ne, po jav lju ju se no va važ na saz na nja o no voot kri ve nom in zu li n-mi metič nom adi po ki nu pod ri jet lom iz mas nog tki va.Naz van je vis fa tin, jer je u znat no ve ćim kon cen tra ci ja ma ot kri ven u vis ce ral nom ne go u pot kož nom mas nom tki vu.Za vis fatin je po ka za no ka ko sni ža va kon cen tra ci ju glu ko ze u plazmi i dje lu je neo vis no od in zu li na, vje ro jat no ve žu ći se za raz li či ta vez na mjes ta is to ga re cep to ra (85).Bo lje ra zu mi je va nje me ha ni za ma ko ji do vo de do IR i udru že nih bo les ti te ot kri va nje do dat nih te ra pij skih ci lje va kao što je vis fa tin bi ti će ko ris no u li je če nju na joz bilj ni jih kom pli ka ci ja IR -šećerne bolesti tipa 2 i kar dio vas kular ne bo les ti.

Conclusion
The main underlying cause of IR is visceral obesity, as visceral adipose tissue is more prone to lipolysis than subcutaneous adipose tissue.The most important mechanisms for the development of IR are thought to be increased secretion of FFA, and decreased adiponectin, leptin, IL-6 and other adipokine concentrations.Besides the coexistence of IR with obesity and other features known as metabolic syndrome, IR is thought to play an important role in the development of polycystic ovary syndrome in women (82) and is the main feature of lipodystrophies (83).The latter are characterized by selective loss of adipose tissue, which indicates that a certain amount of adipose tissue is necessary for normal insulin sensitivity, presumably by providing the place for triglyceride storage and by secreting suffi cient adiponectin and leptin (77).However, the etiology of IR-associated disorders remains to be fully elucidated.There are some objections to defi ning obesity and related cardiovascular risk factors as the metabolic "syndrome" for 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 from adipose tissue.It has been named visfatin for being detected in a much higher concentration in visceral than in subcutaneous adipose tissue.It has been shown to lower plasma glucose concentration and to act independently of insulin, presumably by binding to a diff erent binding site of the same receptor (85).
Better understanding of the mechanisms leading to IR and associated diseases, and discovery of additional therapy targets such as visfatin would prove benefi cial in the management of the most serious complications of IR, DM2 and cardiovascular disease.TAB LI CA 2. Di jag nos tič ki kri te ri ji za me ta bo lički sin drom pre ma ATPIII (7) i IDF (81) Po vi še ni om je ri NADH/NAD+ i aceti l-CoA/CoA mog li bi bi ti raz lo gom sma nje nog preu zi manja glu ko ze, što zna či po re me će ne in zu lin ske os jet lji vos ti Mli nar B. et al.Insulin Resistance, Obesity and Metabolic Syndrome Biochemia Medica god.16, br. 1, 2006.Biochemia Medica Vol. 16, No. 1, 2006 jar nom me ta bo liz mu.

In zu lin ska i lep tin ska re zis ten ci ja kod pre ti los ti
(8,67,68)l na pre ti lo st pre dis po ni ra raz voj hi per ten zi je, šećer ne bo les ti tipa 2, kar dio vas ku lar ne bo les ti i od re đe nih vr sta ra ka(66).Po ve ćan ri zik za zdrav lje pos to ji već i u skupi ni pre kom jer ne te ži ne.Uz ukup nu tje les nu ma su mas ti, za mo gu će me ta bo lič ke kom pli ka ci je bit na je i ras pod je la mas ti.Vis ce ral no i pot kož no mas no tki vo raz li ku ju se prema nji ho vim en dok ri nim ak tiv nos ti ma.Spe ci fi č ni re cepto ri kao što su re cep to ri ti pa 1 an gio ten zi na II.(AT1), β 1 -, β 2 -i β 3 -ad re ner gič ni re cep to ri, re cep to ri glu ko kor ti koi da i an dro ge na zas tup lje ni su u ve ćoj mje ri u vis ce ral nom mas nom tki vu, gdje pro mi ču li po li zu(8,67,68).S dru ge stra ne, an ti li po li tič ni inzulin ski re cep to ri, α-2A ad re ner gič- (67,68)ep to ri i es tro gen ski re cep to ri prev la da va ju u pot kožnom mas nom tki vu(67,68).Uz to, vis ce ral no mas no tki vo lu či svo je proiz vo de u por tal nu cir ku la ci ju i ta ko do vo di os lo bo đe ne FFA iz rav no u jet ru gdje one on da po go du ju glu ko neo ge ne zi, sin te zi VLDL, sma nju ju preu zi ma nje gluko ze i uz ro ku ju sveop ću IR.
Obesity and Metabolic Syndrome žu se na svo je sre diš nje re cep to re na neu ro nima hi po ta lamu sa i dje lu ju ta ko da sma nju ju tje les nu te ži nu.Neu ro ni hi po ta la mu sa iz ra ža va ju pep ti de i nji ho ve re cep to re, ko ji se mo gu svr sta ti kao orek si ge ni: neu ro pep tid Y, agou tipo ve zan pro tein (en gl.agou ti-re la ted pro tein, AgRP), hormon za kon cen tri ra nje me la ni na (en gl.me la ni n-con cen trati ng hor mo ne, MCH), orek si ni A i B; ili ano rek si ge ni: me lano kor ti ni (tj.hor mon ko ji po ti če me la no ci te; en gl.me la nocyte-sti mu la ti ng hor mo ne, α-MSH) i tran skri pt po ve zan s ko kai nom i am fe ta mi nom (en gl.co cai ne and am phe ta mine re la ted tran scri pt, CART).U sta nju preo bi lja lep ti na ili in zu li na prev la da va ju ano rek si ge ni pu to vi: po ra st pot rošnje ener gi je, po ra st ter mo ge ne ze, sma njen unos hra ne.Sma nje ne se rum ske kon cen tra ci je lep ti na i in zu li na do vo-pocytes secrete leptin and β-cells secrete insulin, both in proportion to the body-fat content.The two hormones enter the brain.They bind to their central receptors on the hypothalamic neurons exerting eff ects to reduce and Y2R, subtypes of neuropeptide Y receptor; a-MSH, a-melanocyte stimulating hormone derived by cleavage of POMC; Mc4R, melanocortin 4 receptor; GHSR, growth hormone secretagogue receptor (receptor for ghrelin); InsR, insulin receptor; MCH, melanin concentrating hormone; TRH, thyrotropin-releasing hormone; CRH, corticotropin-releasing hormone.poticanje a-melanocita, izveden cijepanjem POMC; Mc4R, receptor melanokortina 4; GHSR, sekretagogni receptor hormona rasta (receptor za grelin); InsR, inzulinski receptor; MCH, hormon za koncentriranje melanina; TRH, hormon za otpuštanje tirotropina; CRH, hormon za otpuštanje kortikotropina.
). Reaven je 1988.go di ne iden ti fi ci rao sin drom X ko ji pot je če iz IR.Go di ne 2004.je III.pa nel o li je če nju od ras lih Nacio nalnog ob ra zov nog prog ra ma o ko les te ro lu (en gl.Natio nal Cho les te rol Edu ca tion Prog ra m's Adu lt Treat me nt Pa nel III, ATPIII) de fi ni rao me ta bo lič ki sin drom pod al ter na tiv nim Development of lean animal model by suppression of adipose tissue development resulted in hyperphagic mice with severe insulin resistant diabetes

TABLE 1 .
The li st of ge nes as so cia ted wi th obe si ty con fi r med by 5 or mo re stu dies

TAB LI CA 1.
Po pis ge na ud ru že nih s pre ti loš ću pot vr đe nih u 5 ili vi še stu di ja (1)sity and Metabolic Syndrome lje no st ma log gus tog HDL.Slič no to me, sas tav LDL se pomi če pre ma prev las ti ma log gus tog LDL.Ovaj po to nji se smat ra ate ro ge ni jim od obič nog LDL.Is to ta ko do la zi do prom je na u apo li pop ro tei ni ma(1).