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Local metabolism of glucocorticoids in female Prague hereditary hypertriglyceridemic rats
Klusoňová, Petra ; Pácha, Jiří (advisor) ; Kopecký, Jan (referee) ; Haluzík, Martin (referee)
11-hydroxysteroid dehydrogenase (11HSD1) is an oxidoreductase which catalyzes conversion of inactive 11-oxo steroid derivatives into active 11-hydroxy forms. 11HSD1 elevates intracellular level of active glucocorticoid (GC) hormones: cortisol in human tissues and corticosterone in rodents, therefore local level of active GCs can be set independently from systemic secretion driven by hypothalamo-pituitary-adrenal axis (HPA axis). Chronic systemic excess of GCs results in development of Cushing's syndrome which is characterised by central obesity and other metabolic disturbances. Despite normal serum levels of GCs, the patients with idiopathic obesity also develop metabolic syndrome. It was suggested that GCs could be elevated locally in target tissues due to enhanced 11HSD1 activity. This hypothesis was confirmed in transgenic rodent models. Prague hereditary hypertriglyceridemic (HHTg) rats represent a non-obese model of metabolic syndrome without genetic manipulations or specific mutations. The strain was bred by cross-mating of Wistar rat individuals with elevated serum levels of triglycerides (TGs). The strain exhibit hypertriglyceridemia and hypertension. When kept on high carbohydrate diet HHTg rats exhibit alterations in glucose homeostasis. Since there are no data that would describe...
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The importance of biosynthetic and catabolic pathway of cholesterol in inflammatory and tumor diseases
Leníček, Martin ; Vítek, Libor (advisor) ; Haluzík, Martin (referee) ; Mareček, Zdeněk (referee)
This thesis focuses on the importance of intermediate products of biosynthetic and catabolic pathway of cholesterol. The aim of the first part of the thesis is mainly to investigate, whether statins (HMG- CoA reductase inhibitors) possess antitumor properties and to compare the differences in antitumor potential of individual statins. The other part of the thesis aims at the utilization of 7α-hydroxycholest-4-en-3-one (C4), a promising marker of cholesterol 7α-monooxygenase (CYP7A1) activity and bile acid malabsorption. We demonstrated antitumor effect of statins on an experimental model of pancreatic cancer. Individual statins, however, differed significantly in their efficacy, depending on their physico-chemical properties. Our data suggests, that the most likely (but not the only) mechanism of antitumor effect of statins is decreased prenylation of signaling proteins, especially Ras protooncogene. We set up a reliable method for measurement of C4, which facilitated our research in CYP7A1 regulation. We demonstrated, that promoter polymorphism -203A>C might affect CYP7A1 activity, that diurnal variability of CYP7A1 activity might be triggered by insulin, and that insulin resistance in patients with non-alcoholic fatty liver disease impedes the feedback regulation of CYP7A1, which may lead to disease...
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Signalling of protein kinase B and expression of cyclooxygenase in early phases of diabetic nephropathy
Ždychová, Jana ; Komers, Radko (advisor) ; Haluzík, Martin (referee) ; Matoušovic, Karel (referee) ; Škrha, Jan (referee)
Introduction: Renal hypertrophy, extracellular matrix accumulation, aItered apoptosis as well as changes in regional hemodynamics have been implicated in the pathophysiology of nephropathy in diabetes mellitus (DM). On the molecular level the detailed mechanisms for development of diabetic nephropathy (DN) have becn intensively studied. Insulin induces a variety of biologicaI effects in a number of cell types via phosphatidylinositol-3 kinase (PI3K)/Akt kinase signaling pathway. Considering multiple function of Akt that incIude potentiaIly hannful pro-growth effects mediated by mTOR and cyclooxygenas-2 (COX-2), as well as protective effects mediated by endotheliaI nitric oxide synthase (eNOS), it is possible that aIterations in activities of Akt may play role in the pathophysiology ofDN. Renal corticaI activity and expression of Akt, its down-strearn effectors mTOR, eNOS, and "C<JIX-:Z. as well as PTEN, an endogenous Akt inhibitor, were investigated in streptozotocin (STZ): diabetic rats as a model of Type 1 DM with different levels of glycenůc control, and in Zucker ~d.iabetic fatty rats, a model ofDM2, and in nondiabetic rats as controls. Methods: Akt activity was measured by kinase assay. Protein expressions were measured by .immunoblotting and immunohistochemistry in renal cortex of 4- and 12- week old...
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Novel approaches to diagnosis and treatment of selected endocrine disorders
Ježková, Jana ; Marek, Josef (advisor) ; Haluzík, Martin (referee) ; Vladyka, Vilibald (referee)
Je známou zkušeností, že hyperkortizolismus urychluje aterosklerotické děje. Ty je možné sledovat ultrazvukovým vyšetřováním karotid a nověji též vyšetřováním cévní mikrocirkulace laser-Dopplerovskou metodou. Pro urychlení aterosklerotických změn u nemocných s Cushingovým syndromem jsou nesporně důležité známé faktory: hypertenze, obezita a hyperlipidemie. К nim se počítá zvýšená inzulínová rezistence, ale nemocní s floridním hyperkortizolismem mají normální hladiny glykemie a imunoreaktivního inzulínu. К aterogenezi u floridního hyperkortizolismu může přispívat zvýšená tvorba volných kyslíkových radikálů vznikajících při oxidaci lipidů a zvýšené hladiny pozitivního proteinu akutní fáze-orosomukoidu. Imunosupresivní charakter se projevuje snížením hladin autoprotilátek a snížením hladiny intercelulární adhezivní molekuly-1 (ICAM-1). К urychlení aterogeních dějů dochází i u nemocných, kteří jsou již dlouhou dobu po úspěšné normalizaci hyperkortizolemie. I když čerstvě operovaní a normalizovaní nemocní ztrácí do jednoho roku svou Cushingovskou obezitu, dochází později u operovaných nemocných opět к nadváze. Ta je spojena s poruchami lipidového spektra a u čtvrtiny nemocných i s hypertenzí. Nemocné po operaci pro Cushingův syndrom je nutné pravidelně sledovat, i když jsou dlouhodobě normalizováni. Je třeba u...
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The influence of pharmacology and reduction diet on metabolism of adipose tissue in obese patients with diabetes type 2
Anderlová, Kateřina ; Haluzík, Martin (advisor) ; Vítek, Libor (referee) ; Stárka, Luboslav (referee)
Insulin resistance, obesity, type 2 diabetes mellitus and their complications are linked together under definition called Metabolic or Reaven Syndrome. The presence of Metabolic Syndrome increases the risk of atherosclerosis and consequently cardiovascular morbidity and mortality. Metabolic Syndrome belongs among civilization diseases and due to changes in our life styles becomes major health and social-economic issue. The insulin resistance is considered primary pathology that may induce other components of Metabolic Syndrome. Research conducted within last decade brought significant results and showed how important is the adipose tissue in the development of insulin resistance especially in the context of discovery of endocrine function of adipose tissue. The existence of nuclear receptors PPAR (peroxisome proliferator activated receptor) could explain the interaction between particular tissues and hormonal factors which may induce insulin resistance. When the PPAR receptors are bound by lipophilic ligands they directly affect transcriptional processes in cell nucleus and induce expression of genes involved in metabolism of lipids and carbohydrates, in the regulation of inflammation, in tumor growth regulation, in immune response, in cell differentiation and etc. In current medical practice...
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Coincidental finding of hyperglycemia in children and adolescents
Feigerlová, Eva ; Lebl, Jan (advisor) ; Houšťková, Hana (referee) ; Haluzík, Martin (referee) ; Stárka, Luboslav (referee)
Donedávna se v souvislosti s diabetem v pediatrické populaci uvažovalo téměř výhradně O diabetu mellitu I. typu (Tl DM) s jeho typickou klinickou symptomatologií zahrnující polyurii, polydipsii, váhový úbytek a případně projevy ketoacidÓzy. Nyní na diabetes mellitus dětského věku a adolescence pohlížíme jako na heterogenní onemocnění zahrnující skupinu poruch s rozdílnou patogenezí, průběhem a odpovědí na léčbu (ADA 2005). V některých případech je klinická symptomatologie velmi sporá a může se omezit jen na náhodné zjištění mírné hyperglykémie v rámci vyšetřování pro různé klinické stavy. Náhodnou hyperglykémií se rozumí zvýšená glykémie nad referenční mez u jinak zdravého, klinicky asymptomatického jedince, stanovená z náhodného žilního odběru nalačno za bazálních podmínek (např. v rámci preventivní prohlídky) či během zátěžové situace (např. v průběhu akutně probíhající onemocnění, v souvislosti s chirurgickým zákrokem či úrazem). Dle definice (ADA 2005, WHO 1999) se za fyziologické považují hodnoty plazmatické glykémie nalačno nižší než 5,6 mmol/I za předpokladu dodržení podmínek preanalytické přípravy. Normální hodnota glykémie měřená 2 hodiny po standartní zátěži v průběhu OGTI (orálního glukózového tolerančního testu) je nižší než 7,8 mmolll. I přes existenci jasných kritérií nepovažuj í některé...
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The influence of deep hypothermia on the endocrine function of adipose tissue
Drápalová, Jana ; Haluzík, Martin (advisor) ; Flachs, Pavel (referee)
Introduction and aims: Deep hypothermia is a medical method used in a variety of car- diological operations. Adipose tissue is one of the main endocrine organs and therefore its en- docrine function significantly influences the state of a patient. The aim of this study was to explore the influence of deep hypothermia on the expression of selected proteins in adipose tissue, which has yet to be described in scientific literature. Material and methods: Samples of subcutaneous and visceral fat were taken from 10 pa- tients, who underwent planned surgery for pulmonary hypertension. The samples were taken at the beginning and the end of hypothermia, and at the end of the operation, respctively. Real-time PCR method was used to determine relative gene expression of selected adipocy- tokines (BCL-2, GLUT1, GPX1, HIF1- , IL-6, IRS1, MCP1, MIF, MT3, TNF-) from total fat and isolated adipocytes. Results: Gene expression of GLUT1 (total subcutaneous fat), HIF1- (total subcutaneous and visceral fat) and IL-6 a MCP-1 (in all tissues) at the end of the operation was significantly higher compared to the gene expression at the beginning and end of hypothermia. Gene ex- pression of TNF- in total subcutaneous fat increased significantly at the end of the operation compared to the beginning of hypothermia. Gene...
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Labeling of pancreatic islets with superparamagnetic iron oxide nanoparticles for magnetic resonance imaging
Berková, Zuzana ; Saudek, František (advisor) ; Mandys, Václav (referee) ; Haluzík, Martin (referee)
Type I diabetes mellitus is primarily an autoimmune disease resulting from selective destruction of insulin producing pancreatic beta cells. Transplantation of purified pancreatic islets is an alternative method for standard insulin therapy of these patients. Though the islet transplantation represents a promising approach for a selected group of patients, there is still a number of problems to be solved and one of them, perhaps the most important, is the lack of a reliable method of transplanted islets monitoring. (...) The results of this experimental study lead to the improvement of the labeling protocol in experimental transplantation and to its translation into clinical research. While different methods such as PET and SPECT will be soon available for shorttime in vivo followup of transplanted pancreatic islet, magnetic resonance imaging represents so far the only available technique able to provide a direct, longterm and reliable visualization of the transplanted islets with sufficient spatial resolution. At present, is this method ready for clinical application.
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Options of continual glycemia monitoring in critically ill patients and treatment of hyperglycemia with the use of insulin algorithms
Bláha, Jan ; Haluzík, Martin (advisor) ; Matějovič, Martin (referee) ; Vaněk, Tomáš (referee)
Glycaemia control is nowadays one of the most discussed topics in intensive care. The landmark Leuven study, which has brought hyperglycaemia in intensive care to the centre of interest, demonstrated that tight glycaemia control (TGC) targeted to maintain euglycaemia between 4.4 to 6.1 mmol/l reduced mortality and frequency of organ complications associated with critical illness. Although this study was published eight years ago, there is still no general agreement about approach to tight glycaemia control in critically ill patients. Doubts have been raised about both the universality of intensive glycaemia control, and especially its safety in terms of potential damage to patients by episodes of hypoglycaemia. Our studies did not focus on questions of importance or risk of TGC, but we concentrated on key point of hole TGC concept - on glycaemia control in critically ill patients itself. The aims of our studies were the research of subcutaneous adipose tissue as an alternative-site for continuous glucose measurements in ICU patients, and comparison and development of insulin algorithms for hyperglycaemia treatment and normoglycaemia management. We demonstrated good correlation between arterial and interstitial subcutaneous glucose concentrations in critically ill patients undergoing deep hypothermia. We...
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