The pancreas is a gland with both exocrine and endocrine function. The products of its exocrine component are vital to the food digestion. Its endocrine function is based on secretory action of several types of endocrine cells that cluster together to form islets of Langerhans. Some of them produce insulin and glucagon, hormones that regulate primarily carbohydrate metabolism and are essential for maintaining optimal blood glucose concentrations. Secretory action of the pancreas, especially its endocrine component, is controlled by a complex endocrine, paracrine and neural mechanisms. Thyroid hormones are key regulators of the basal metabolism, growth and development. They are necessary for normal function of almost all organs and organ systems; their importance in the metabolism of carbohydrates has been known for decades. The functions of the endocrine pancreas and thyroid gland, and effects of their hormones are mutually connected and interdependent. In clinical practice the coexistence of thyroid dysfunction and the development of insulin resistance, which is a good prognostic factor for type 2 diabetes occurrence, is relatively frequent. A diet rich in simple sugars, along with reduced physical activity is a feature of modern lifestyle in developed countries of the world. Continuous intake of carbohydrates represents a form of stress in which pancreas intensively produces insulin, which in the long term can lead to pathophysiological processes at the level of intracellular organelles, and eventually to loss of β-cells, i.e. to type 2 diabetes. The aim of this work was to gain an insight into the detailed morpho-functional characteristics of the rat pancreas under the influence of sucrose rich diet, in terms of systemic hypothyroidism induced by methimazole. The obtained results show that: - Moderate systemic hypothyroidism was established after three-week methimazole treatment, regardless of the diet. Levels of thyroid hormones in the circulation were reduced, and the animals fell behind in growth. - In hypothyroid animals, regardless of the diet, total energy intake was reduced due to lower basal metabolism rate and reduced energy requirements. In sucrose fed euthyroid animals energy input was significantly above control values, primarily at the expense of carbohydrates, but negative impact on glucose homeostasis was not evident. - Reduced absolute mass of the pancreas in all experimental animals resulted from the proportional reduction of exocrine and endocrine components of the organ, and in both groups of hypothyroid animals occurred in parallel with a smaller body mass gain. Pancreas relative mass reduction in the sucrose fed euthyroid animals was in part the consequence of a slight increase in body mass, and partially as we assume the result of the increased cell degranulation/exocytosis. - The results of morphological analysis showed that exocrine pancreas of the euthyroid animals with sucrose diet was more active in synthesis and secretion than of control animals. The mechanic effect of the gastric and intestinal contents had a key regulatory role in these processes. - Exocrine pancreas of normally fed hypothyroid animals was less active, due to a general reduction of metabolic processes and lower food intake. In acinar cells the zymophagy is initiated as a protection mechanism from digestive enzyme's activation and autodigestion. - Acinar cells in sucrose fed hypothyroid animals were exposed to a greater load than the cells of normally fed animals. This challenge has been successfully overcome, with slight morpho-functional adaptations. In individual cells rER stress could lead to possibly irreversible damage. - The applied treatment did not induce changes in the number and distribution of any cell type in the islets of Langerhans. - In normally fed hypothyroid animals there is a delay in the insulin synthesis/secretion, manifested by accumulation of smaller granules in β-cells, which was somewhat compensated by synthetic activity of insulin and glucagon co-expressing cells. - Most of the β-cells in sucrose consuming animals regardless of thyroid status were functional insulin-producing cells. In euthyroid animals they were active regarding synthesis and secretion, and no hypertrophy or hyperplasia was detected. - In the sucrose fed euthyroid group of animals extra-insular acinar β-cells were detected. At that moment they were not functional in the synthesis and secretion of insulin and could be considered the back-up cells. Most likely these cells originated by acinar cell transdifferentiation. - Sucrose intake in hypothyroid rats distinguishes β-cells fine structure away from those treated only with methimazole and approaches them to the control, which is especially manifested by granule's ultrastructural and stereological features. - The methimazole negative effect on the synthesis and secretion of insulin, with increased requirements for this hormone due to the intake of sucrose, activate the mechanisms that prolong the half-life of insulin. This led to a slightly increased insulin circulation level and created conditions for the development of insulin resistance. Pankreas je žlezda sa egzokrinom i endokrinom funkcijom. Proizvodi njegove egzokrine komponente od vitalnog su značaja za proces varenja hrane. Endokrine ćelije pankreasa grupisane u Langerhansova ostrvca proizvode insulin i glukagon, hormone koji regulišu metabolizam pre svega ugljenih hidrata i neophodni su za održavanje optimalne koncentracije glukoze u krvi. Sekretna aktivnost pankreasa, naročito njegove endokrine komponente, pod kontrolom je kompleksnih endokrinih, parakrinih i neuralnih mehanizama. Hormoni tireoidne žlezde ključni su regulatori bazalnog metabolizma, rasta i razvića. Potrebni su za normalno funkcionisanje gotovo svih organa i organskih sistema, a njihov značaj u metabolizmu ugljenih hidrata poznat je već decenijama. Funkcije endokrinog pankreasa i tireoidne žlezde, kao i efekti koje ostvaruju njihovi hormoni, uzajamno su povezani i međusobno zavisni. U kliničkoj praksi relativno je česta koegzistencija disfunkcije tireoidne žlezde i razvoj insulinske rezistencije, koja je predvorje nastanka dijabetesa tipa 2. Ishrana bogata prostim šećerima, uz smanjen nivo fizičke aktivnosti karakteristika je savremenog načina života, naročito u industrijski razvijenijim zemljama sveta. Pri kontinuiranom unosu ugljenih hidrata pankreas radi pod povećanim opterećenjem, intenzivno proizvodeći insulin, što dugoročno gledano može dovesti do patofizioloških procesa na nivou unutarćelijskih organela i eventualno do gubitka β- ćelija, odnosno do dijabetesa tipa 2. Osnovni cilj ove teze bio je da se detaljnom analizom stekne uvid u morfofunkcionalne karakteristike pankreasa pacova pod uticajem ishrane obogaćene saharozom, u uslovima sistemskog hipotireoidizma indukovanog metimazolom. U tronedeljnom eksperimentu korišćeni su mužjaci albino pacova Wistar soja, držani pod standardnim laboratorijskim uslovima. Životinje su u odnosu na ponuđeni rastvor u vodi za piće podeljene u četiri grupe. Kontrolna grupa životinja pila je čistu česmensku vodu, hipotireoidizam je indukovan 0.02% rastvorom metimazola, dok je pankreas funkcionalno opterećen unosom 10% rastvora saharoze. Pacovi poslednje grupe pili su kombinovani rastvor metimazola i saharoze, već pomenutih koncentracija. Pankreas je na uobičajen način pripremljen za morfološku i stereološku analizu na nivou svetlosne i elektronske mikroskopije. Pored rutinskih metoda bojenja hematoksilinom i eozinom, toluidin plavim i AZAN-om, korišćene su metode imunohistohemije za detekciju insulina, glukagona, somatostatina, pankreasnog polipeptida, PDX1, α-SMA i Ki67 proteina, kao i specifično bojenje propidijum jodidom. Dobijeni rezultati pokazali su sledeće: - Tronedeljni tretman metimazolom doveo je do uspostavljanja umerenog sistemskog hipotireoidizma, nezavisno od režima ishrane. Nivoi tireoidnih hormona u cirkulaciji bili su smanjeni, a životinje su zaostajale u rastu. - Kod hipotireoidnih životinja, bez obzira na način ishrane, ukupan energetski unos bio je smanjen usled sniženja stope bazalnog metabolizma i smanjenja energetskih potreba organizma. Energetski unos eutireoidnih životinja kojima je ponuđen rastvor saharoze bio je znatno iznad kontrolnih vrednosti i to prevashodno na račun ugljenih hidrata, ali se to nije negativno odrazilo na homeostazu glukoze. - Manja apsolutna masa pankreasa životinja svih eksperimentalnih grupa posledica je proporcionalnog smanjivanja egzokrine i endokrine komponente pankreasa, koje se kod obe grupe hipotireoidnih životinja dešavalo paralelno sa manjim prirastom životinja. Smanjenje relativne mase pankreasa eutireoidnih životinja prehranjivanih saharozom delom je bilo posledica blagog povećanja telesne mase, a moguće delom i promena na nivou ćelijske degranulacije/egzocitoze. - Rezultati morfološke analize pokazali su da je sintetska i sekretna aktivnost egzokrinog pankreasa eutireoidnih životinja koje su unosile rastvor saharoze bila povišena u odnosu na životinje iz kontrolne grupe. Mehanički efekat zapremine želudačnog i crevnog sadržaja imao je ključnu regulatornu ulogu u ovim procesima. - Egzokrini pankreas hipotireoidnih normalno hranjenih životinja bio je u stanju niže aktivnosti, zbog opšteg sniženja metaboličkih procesa i manjeg unosa hrane. U acinusnim ćelijama aktivirani su mehanizmi zimofagije kao zaštite od unutraćelijske aktivacije digestivnih enzima i autodigestije. - Acinusne ćelije egzokrinog pankreasa hipotireoidnih životinja koje su unosile rastvor saharoze bile su izložene većem izazovu nego ćelije normalno hranjenih životinja, kojem su uglavnom uspešno izlaze u susret, uz blage morfo-funkcionalne adaptacije. Pojedinačne ćelije trpele su stres endoplazminog retikuluma i, moguće, podlegle ireverzibilnim oštećenjima. - Primenjeni tretman nije doveo do promene zastupljenosti i distribucije pojedinih tipova endokrinih ćelija u Langerhansovim