Premda je rudarstvo Drniša bilo uistinu značajno ne samo za drniške zemljopisne prostore, već i za države u okviru kojih se odvijalo, do sada nije napisana bilo kakva monografija ili opsežniji ...pregledni rad o toj djelatnosti. To je ključni motiv za pisanje ovoga rada. U njemu se opisuju počeci, tok i uvjeti i vrijeme okončanja rudarske aktivnosti, najprije mrkog uglja, a potom boksita. Druge su mineralne sirovine, osim povremenog vađenja i obrade ukrasnog kamena, bile, a i danas su posve nezanimljive za eksploataciju.
Ovaj se rad pojavljuje mnogo godina nakon konačnog gašenja rudarske djelatnosti na prostoru koji gravitira Drnišu. Zato je moguće jedino ukazivati na njegovo nesporno značenje u većem dijelu 19. i nešto duže od polovine 20. stoljeća. Temeljni je zaključak da rudarstvo nije dalo doprinose razvitku drniškog prostora kakvo je moglo i trebalo dati.
There is an increasing amount of evidence that indicates presence of brown
adipose tissue (BAT) in adult humans, and its potential role in prevention of
obesity, insulin resistance and metabolic ...syndrom, in general. That is why
number of studies on elucidation of the metabolic importance of this tissue,
along with its thermogenic stimulation in order to treat these disorders,
increases. As an important anabolic hormone, insulin is considered as a major
modulator of BAT structure and function. The aim of this study was to
elucidate the molecular basis of insulin-induced structural remodeling of BAT
through the identification of mechanisms that regulate insulin-stimulated
proliferation and differentiation and through the identification of
mechanisms involved in cell damage and death. Wistar strain rats were treated
intraperitoneally with physiological (0.4 IU/kg BW) or supraphysiological (4
IU/kg BW ) dose of insulin for one (acute treatment) or three days (chronic
treatment), respectively. Two groups of rats served as physiological
controls, and were treated with saline (acute and chronic control). Three
hours after the last injection the animals were sacrificed and the
interscapular portion of BAT was removed, its weight was measured and it was
processed for electron and light microscopic examinations. Methods of
histochemical staining, immunohistochemical labeling, confocal and
transmission electron microscopy, tissue electron-dispersive X-ray
microanalysis (EDX) and stereological and morphometric analyses were
performed. The results showed the existence of structural and functional
remodeling of BAT, based on adipocyte hypertrophy and hyperplasia which are
followed by increasing of thermogenic capacity (expression of uncoupling
protein 1 (UCP1), cellular proportion of mitochondria, mitochondrial
biogenesis). On the other hand, it is obvious that, especially after chronic
and high-dose treatments, insulin cytotoxic and inhibitory effects on
individual cells or cell clusters occur: incidence of cell death increases,
as well as red blood cell extravasation and their removal by brown adipocytes
and macrophages (which is evidently toxic for the adipocyte, since expression
of antioxidative defense enzymes, lipid peroxidation, protein nitrosilation
and lipofuscin formation were increased). Also, during chronically high
hyperinsulinemia, expression of peroxisome proliferator-activated receptor -
γ coactivator - 1α (PGC-1α), regulator of thermogenesis decreases, indicating
that prolonged exposure to high doses of insulin can inhibit thermogenic
response of BAT, as evidenced by the increased frequency of mitochondrial
damage in brown adipocytes. Increased expression of proinflammatory cytokines
(tumornecrosis factor - α (TNF-α), interleukin 6), nuclear factor – kB
(NF-kB) and macrophage inflammatory protein - 3β (MIP-3β) in individual
mature, multilocular adipocytes, preadipocytes and unilocular adipocytes,
demonstrates their potential role in local decrease of insulin sensitivity.
Regarding hyperplasia of cells, it was noticed spaciotemporal association
between processes of adipogenesis and angiogenesis, which means that there is
a connection between these processes, demonstrating the need for the coupled
differentiation of adipocytes and endothelial cells, for the purpose of
efficient structural and functional remodeling of the tissue. In summary, it
can be concluded that hyperinsulinemia has a significant impact on BAT – we
confirmed the anabolic effect of insulin, and the importance of its role in
BAT stimulation, but also demonstrated the toxicity of high dose and chronic
exposure to insulin on BAT cells, all of which contribute to understanding
the molecular mechanisms underlying structural remodeling of the tissue. In
addition, it was shown that the high plasticity of BAT is reflected in the
existence of functional clusters of cells, which take place in all the
important processes in the tissue (adipo/angiogenesis, cell death,
erythrophagocytosis), indicating the proper arrangement of tissue
organization and structural remodeling as a prerequisite for the proper
functioning of the tissue under physiological conditions and during altered
tissue homeostasis, as shown on the model of hyperinsulinemia.
U svetlu sve većeg broja dokaza koji ukazuju na prisustvo metabolički
aktivnog mrkog masnog tkiva (BAT – brown adipose tissue, engl.) kod odraslih
ljudi, kao i na njegovu potencijalnu ulogu u sprečavanju razvoja gojaznosti,
insulinske rezistence i metaboličkog sindroma uopšte, sve je više studija o
rasvetljavanju metaboličkog značaja ovog tkiva, kao i njegovoj termogenoj
stimulaciji u svrhu terapije navedenih poremećaja. Insulin se, kao važan
anabolički hormon, smatra značajnim modulatorom strukturne organizacije i
funkcije BAT. Cilj ovog istraživanja bio je rasvetljavanje molekulskih osnova
insulinomindukovanog strukturnog remodeliranja BAT putem identifikacije
mehanizama koji regulišu insulinom-stimulisanu proliferaciju i
diferencijaciju ćelija, kao i identifikacije mehanizama koji učestvuju u
oštećenjima ćelija i njihovom umiranju. Pacovi soja Wistar su jednom dnevno
tretirani fiziološkom (0.4 IU/kg telesne mase) i suprafiziološkom (4 IU/kg
telesne mase) dozom insulina, jedan (akutan tretman) ili tri (hroničan
tretman) dana. Kao fiziološka kontrola, dve grupe pacova su u istom trajanju
tretirane fiziološkim rastvorom (akutna i hronična kontrola). Tri sata nakon
poslednje doze, životinje su žrtvovane, a interskapularni depo BAT je
izolovan, izmeren i pripremljen za tehnike svetlosne i elektronske
mikroskopije. Analiza tkiva izvršena je korišćenjem metoda histohemijskog i
imunohistohemijskog bojenja, metoda konfokalne i transmisione elektronske
mikroskopije i elektron-disperzivne analize X-zracima (EDX) hemijskog sastava
tkiva kao i metoda stereološke i morfometrijske analize. Rezultati su
pokazali postojanje strukturnog i funkcijskog remodeliranja BAT, gde
dominiraju procesi hipertrofije i hiperplazije ćelija, praćene povećanjem
termogenog kapaciteta mrkih adipocita (raste ekspresija dekuplujućeg proteina
1 (UCP1 – uncoupling protein 1, engl.), udeo mitohondrija, procesi
mitohondriogeneze). S druge strane, primetno je da se, naročito pri hroničnim
i tretmanima visokom dozom insulina, javljaju citotoksični i inhibitorni
efekti na pojedine ćelije ili klastere ćelija: raste učestalost ćelijske
smrti, ekstravazacija eritrocita i njihovo uklanjanje od strane mrkih
adipocita i makrofaga, (evidentno toksično po adipocite sudeći po rastu:
ekspresije enzima antioksidativne odbrane; lipidne peroksidacije i
nitrozilacije proteina, učestalosti lipofuscinogeneze). Takođe se pri
hronično visokoj hiperinsulinemiji smanjuje ekspresija regulatora termogeneze
(PGC-1α - peroxisome proliferator-activated receptor – γ coactivator - 1α,
engl.) ukazujući da produženo izlaganje visokim dozama insulina, može da
inhibira termogeni odgovor tkiva, o čemu svedoči i povećana učestalost
mitohondrijalnih oštećenja. Povećana ekspresija proinflamatornih citokina
(TNF-α - tumor-necrosis factor – α, engl., interleukina 6), nukleusnog
faktora – kB (NF-kB) i makrofagnog inflamatornog proteina - 3β (MIP-3β) u
pojedinačnim zrelim, multilokulusnim adipocitima, preadipocitima i
unilokulusnim adipocitima ukazuje na njihovu potencijalnu ulogu u lokalnom
smanjenju insulinske senzitivnosti. U vezi sa hiperplazijom ćelija, primećeno
je da su adipogeneza i angiogeneza u BAT vremenski i prostorno povezane, tj.
da postoji udruženost navedenih procesa, koja ukazuje na potrebu udruženog
nastanka adipocita i endotelskih ćelija, u svrhu efikasnog
strukturno-funkcijskog remodeliranja tkiva. Sumarno, može se zaključiti da
hiperinsulinemija ima značajan efekat na BAT – potvrđeno je anaboličko
dejstvo insulina i važnost njegove uloge u stimulaciji BAT, ali je i pokazana
toksičnost visoke doze i hroničnog izlaganja na ćelije BAT; što je sve
doprinelo rasvetljavanju molekulskih mehanizama u osnovi strukturnog
remodeliranja ovog tkiva. Takođe, pokazano je da se visoka plastičnost BAT
ogleda u postojanju funkcionalnih klastera ćelija, u kojima se odvijaju svi
važni tkivni procesi (adipo/angiogeneza, ćelijska smrt, eritrofagocitoza),
što ukazuje na pravilnu uređenost tkivne organizacije i strukturnog
remodeliranja, kao preduslova za pravilno funkcionisanje tkiva, kako u
fiziološkim, tako i u uslovima izmenjene tkivne homeostaze, što je pokazano
na modelu hiperinsulinemije.
