o:1312 Uloga galektina-3 u patofiziologiji ß ćelija pankreasa ǂThe ǂrole of galectin-3 in pancreatic ß cells pathophysiology : doctoral dissertation sr Šećerna bolest predstavlja sve značajniji zdravstveni problem u svetu. U patogenezi tipa 1 šećerne bolesti centralno mesto zauzima autoimunsko zapaljenje pankreasnih ostrvaca koje vodi apsolutnom nedostatku insulina. Centralno mesto u patogenezi tipa 2 šećerne bolesti, zauzima razvoj gojaznosti sa pojavom rezistencije perifernih tkiva na insulin i posledičnim povećanjem stvaranja insulina. Povećani zahtevi za produkciju insulina stimulišu, ali i opterećuju β ćelije, što postepeno vodi njihovom oštećenju koje je praćeno smanjenim stvaranjem insulina, pojavom hiperglikemije i razvojem tipa 2 šećerne bolesti. Dosadašnja istraživanja u kojima su korišćeni galektin-3 deficijentni miševi, pokazala su prozapaljensku ulogu galektina-3 u razvoju tipa 1 šećerne bolesti, dok su rezultati ispitivanja uloge ovog molekula u patogenezi tipa 2 šećerne bolesti kontradiktorni. Do sada nema podataka o efektu selektivno pojačane ekspresije galektina-3 u β ćelijama na patogenezu šećerne bolesti. Cilj: Ispitati efekat pojačane ekspresije galektina-3 u β ćelijama na patogenezu šećerne bolesti. Materijal i metode: Eksperimentalnim životinjama, C57Bl/6 miševima divljeg soja i miševima sa transgeno pojačanom ekspresijom galektina-3 u β ćelijama, tip 1 šećerne bolesti je indukovan primenom streptozotocina u pet malih doza od 40mg/kg, dok je tip 2 šećerne bolesti indukovan korišćenjem hrane bogate mastima (engl. high fat diet, HFD, 60% kalorija porekla iz masnih kiselina) tokom 16 nedelja. U in vitro eksperimentima korišćena su izolovana pankreasna ostrvca koja su tretirana metaboličkim noksama nakon čega je analizirano preživljavanje β ćelija kao i oskidativni potencijal tretiranih β ćelija. U eksperimenatlnom modelu tipa 1 šećerne bolesti, aplikovan je interleukin 33 u 4 doze od 12-18 dana modela. Rezultati: U eksperimentalnom modelu tipa 1 šećerne bolesti transgeno pojačana ekspresija galektina-3 u β ćelijama deluje protektivno, na indukciju bolesti upotrebom niskih uzastopnih doza streptozotocina. Tretiranje transgenih miševa interleukinom 33 dodatno ublažava razvoj hiperglikemija. U eksperimentalnom modelu tipa 2 šećerne bolesti trasngeno pojačana ekspresija galektina-3 u β ćelijama deluje prozapaljenski pospešujući oštećenje β ćelija nakon ishrane bogate mastima. In vitro rezultati ukazuju na prooksidantni efekat pojačane ekspresije galektina-3 u β ćelijama, dok rezultati nakon stimulacije metaboličkim i inflamatornim noksama pokazuju značajan prozapaljenski efekat pojačane ekspresije galektina-3 u β ćelijama. Zaključak: Rezultati pokazuju da efekat pojačane ekspresije galektina-3 u β ćelijama može biti dvojak, od protektivnog do prozapaljenskog, u zavisnosti od nokse koja deluje na β ćelije i mehanizma kojim noksa dovodo do oštećenja β ćelije. Transgeno pojačana ekspresija galektina-3 u β ćelijama i primena interleukina 33 nakon pojave hiperglikemije imaju terapijski efekat i sprečavaju razvoj šećerne bolesti. Introduction: Diabetes is a serious and emerging health problem around the world. The central place in type 1 diabetes pathogenesis belongs to autoimmune inflammation of the pancreatic islets, which leads to an absolute lack of insulin. In type 2 diabetespathogenesis, central role belongs to development of obesity, metainflammation and appearance of peripheral tissue resistance to insulin with the consequent increase in insulin production. β cells, burdened with increased demands, cannot withstand the new condition for a long time, which gradually leads to their damage, accompanied by reduced insulin production, hyperglycemia and type 2 diabetes onset. Previous studies which used galectin-3 deficient mice shown its proinflammatory role in the development of type 1 diabetes, while the results of examining the role of this molecule in the pathogenesis of type 2 diabetes are contradictory. There are no data in the literature about the effect of selectively enhanced galectin-3 expression in β cells on the pathogenesis of diabetes. Aim: The aim of the research project was to delineate the role of galectin-3, expressed on β cells, in the pathogenesis of diabetes. Material and methods: Type 1 diabetes was induced by multiple low doses of streptozotocin (40 mg/kg) in C57Bl/6 wild type mice and mice with transgenically enhanced galectin-3 expression in β cells. Type 2 diabetes was induced by use of high-fat diet (HFD, 60% calories from fat) for 16 weeks. In in vitro experiments, isolated islets were treated with metabolically harmful factors, after which the survival of β cells was investigated, as well as the oxidative potential of the treated β cells. In experimental model of type 1 diabetes, additional experimental groups were treated with interleukin 33 in 4 doses from 12 to 18 days. Results: In experimental model of type 1 diabetes, enhanced galectin-3 expression in β cells has a protective effect on disease induction. Interleukin 33 treatment further reduces the development of hyperglycemia in transgenic mice group. In experimental model of type 2 diabetes, transgenically enhanced galectin-3 in β cells has pro-inflammatory effect, accelerating β cell damage after 16 weeks of high fat diet. In vitro results indicated that transgenically enhanced galectin-3 expression in β cells has a prooxidant effect, while results after stimulation with metabolically and immune harmful factors showed a significant pro-inflammatory effect of enhanced galectin-3 in β cells. Conclusion: It seems that the effect of transgenically increased expression of galectin-3 in β cells can be twofold, from protective to pro-inflammatory. The end effect depends on the type of harmful factor acting on the β cells, as well as the pathways that leads to damage to the β cells. The therapeutic effect of interleukin 33, after the development of hyperglycemia, is significantly pronounced in mice with transgenically enhanced galectin-3 expression in β cells. ID=32289545 ; D-3395 91552101 7896 91552100 32289545 2021-02-18T11:26:33.053Z 45 no 46 mentor Ivica, 1985-, 64895753 Petrović 2020 63 mentor Nemanja, 1981-, 19685223 Jovičić 2020 63 predsednik komisije Nebojša M., 1958-, 12505447 Lalić 2020 63 član komisije Miodrag L., 1941-, 13590887 Lukić 2020 63 član komisije Snežana, 1960-, 12071527 Živančević Simonović 2020 63 član komisije Aleksandar, 1967-, 13561191 Đukić 2020 63 član komisije Nada, 1957-, 7584359 Pejnović 2020 159 listova 2685586 http://phaidrabg.bg.ac.rs/o:1312 no yes 6 2021-02-18T11:26:33.320Z 70 pojačana ekspresija galektina-3, oksidativni stres, ishrana bogatamastima, streptozotocin, apoptoza β ćelija, interleukin 33, terapija šećerne bolesti enhanced expression of galectin-3, diabetes, oxidative stress, high fat diet,streptozotocin, β-cell apoptosis, interleukin 33, diabetes therapy 616.37:616.379-008.64-085(043.3) 1738 2020