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Genetics MODY diabetes
Dušátková, Petra ; Cinek, Ondřej (advisor) ; Haluzík, Martin (referee) ; Gašperíková, Daniela (referee)
The most common form of monogenic diabetes is MODY (Maturity-Onset Diabetes of the Young). It ranks among genetic defects of the β cell. It is clinically heterogenous group of disorders characterised with non insulin-dependent diabetes mellitus with autosomal dominant inheritance and age at diagnosis up to 40 years. We specified the diagnosis of MODY in more than 240 Czech families using molecular-genetic approach. The most common subtype of MODY is GCK-MODY which was proved in 376 subjects from 175 families. The risk of macrovascular complications in patiens with GCK-MODY was not detected. Additionally, we tested the ancestral origin of 4 recurrent mutations in the GCK gene causing GCK-MODY using genetic and statistical methods. We showed that three mutations (p.Glu40Lys, p.Leu315His, p.Gly318Arg) spread approximately 82-110 generations ago due to a founder effect. We also dealed with the impact of the rs560887 polymorphism on the phenotype of the patients with GCK-MODY. The genotype GG was associated with higher level of glycated haemoglobin. Analysis of patients suspect for HNF1A- or HNF4A-MODY revealed the probably first evidence of patient with HNF1A-MODY present with macrosomia and recurring ketotic hypoglycaemias in the childhood. The rare MODY genes were investigated in patients fulfilling the...
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Preparation and characterization of GlnB22-insulin, a naturally occurring mutant in diabetic patients
Křížková, Květoslava ; Žáková, Lenka (advisor) ; Haluzík, Martin (referee)
Diabetes mellitus is a widespread disease which can be diagnosed in all age groups from newborns to seniors. Diabetes has multiple causes. The final disorder of blood glucose regulation is caused by a complex of factors and agents, in many cases by genetic defects connected with an unhealthy lifestyle. Moreover, a recently discovered form of diabetes, referred to as the monogenic diabetes, results from a gene mutation whereby only a single gene defect causes the onset of disease. The gene encoding the insulin primary structure belongs to several fundamental genes. Each change in a peptide chain is unique and leads to variation in this disease. Diagnosing patients with this mutation results in more detailed specification of their treatment and often also in the improvement of their living conditions. Mutations of the insulin gene have various symptoms. Some of the changes lead to the neonatal diabetes and patients are fully addicted to insulin since their birth. Other variations will never break out at their carriers. Seriousness of the disease course depends on characteristics of an original amino acid, its function in the insulin biosynthesis, its interaction with the insulin receptor, and on characteristics of a newly inserted amino acid and its influence on natural processes. The pathogenic...
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Reduction Modes to 3rd Medical Department in the Treatment of Obesity and Metabolic Syndrome and their Effect on the Outcome of Bariatric Operations
Jungová, Ivana ; Matoulek, Martin (advisor) ; Haluzík, Martin (referee)
(teze): Úvod: Redukční režimy na 3. interní klinice VFN Praha v léčbě obezity a metabolického syndromu a jejich vliv na úbytek hmotnosti po bariatrické operaci při aplikaci těsně před zákrokem. Metody: Porovnávání shromážděných dat týkajících se redukce hmotnosti v době před a 1 rok po bariatrickém zákroku pro dvě skupiny pacientů. Jedna skupina absolvovala těsně před operativním výkonem redukční pobyt. Druhá skupina byla přijata k operačnímu řešení z ambulantního režimu. Výsledky: Obě skupiny pacientů ve sledované době (1 rok po operaci) svou hmotnost významně redukovaly, vyšší úbytek v kilogramech po roce od zákroku byl zaznamenán u skupiny s redukčním pobytem (23,02 kg), u skupiny bez redukčního pobytu byl průměrný úbytek hmotnosti 21,17 kg. Po porovnání úbytku hmotnosti z průměrné hodnoty životního maxima skupin má významně vyšší redukci skupina s redukčním pobytem (51,9 kg), skupina bez redukčního pobytu redukovala ze svého životního maxima průměrně o 32 kg. Hodnota EWL (Excess Weight Loss) jeden rok po operaci byla vyšší u skupiny bez redukčního pobytu (39,36 %), u skupiny s redukčním pobytem dosáhla hodnoty 33,509 %. Stejně tak hodnotu EBMIL (Excess BMI Loss) měla skupina bez redukčního pobytu vyšší než skupina s redukčním pobytem. Procentuální roční úbytek hmotnosti byl u obou skupin...
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The Effect of Bariatric Operations on the Compensation of Diabetes Mellitus
Horáková, Jitka ; Matoulek, Martin (advisor) ; Haluzík, Martin (referee)
This bachelor thesis deals with the problem of obesity and diabetes mellitus in today's society. The theoretical part brings a closer look at the problem of obesity, the complications resulting from it and the possible ways of therapy. Further it discusses the problem of diabetes mellitus and the influence of obesity on diabetes mellitus type 2 that causes serious health complications. The thesis describes the treatment options of the mentioned diseases, especially focusing on lifestyle changes (dietary regimen, physical activity) and bariatric surgery that significantly contributes to weight reduction and reduction of complications risks. The practical part of the thesis deals with the research in this area, comparing a group of diabetic and non-diabetic patients undergoing the bariatric surgery. Furthermore, it focuses on the impact of the bariatric surgery on the compensation of diabetes mellitus. Keywords: obesity, diabetes mellitus, dietary treatment, bariatric operations
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New regulatory metabolic factors in patients with obesity and type 2 diabetes mellitus
Matějková, Mirka ; Haluzík, Martin (advisor) ; Flachs, Pavel (referee)
Fibroblast growth factors are proteins with diverse biological function in development, tissue repair, and metabolism. The human FGF gene family consists of 22 members. FGF 19 subfamily includes FGF 19, FGF 21, and FGF 23. They act as systemic factors in an endocrine manner. FGF 19 subfamily requires klotho protein as a cofactor for its action. FGF 19 produced by intestine acts mainly in the liver through FGFR4, where it inhibits bile acid and fatty acid synthesis. FGF 21 is produced by the liver and contributes to the regulation of carbohydrate and lipid metabolism through modulation of glucose uptake in adipocytes. Serum FGF 21 levels are increased in patients with obesity and type 2 diabetes mellitus. Serum FGF 19 levels are on the contrary decreased in patients with obesity and type 2 diabetes mellitus and more probably depend on the nutritional status of the organism than on the glucose metabolism and insulin sensitivity. Key words: type 2 diabetes mellitus, FGF 19, FGF 21, obesity, adipose tissue
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The role of adipose tissue in endothelial dysfunction, etherosclerosis and other complications of metabolic syndrome: influence of diet and pharmacotherapy
Doležalová, Radka ; Haluzík, Martin (advisor) ; Šenolt, Ladislav (referee) ; Kábrt, Jan (referee)
The metabolic effects of obesity have made this disease one of the most common risk factors for diabetes, hypertension, and atherosclerosis. Adipose tissue is now recognized as an active secretory and immune organ. Chronic inflammation is a common feature of the obesity, and inflammatory signals may originate within visceral adipose tissue as this fat depot expands in response to chronic positive energy balance. Both adipocytes and macrophages within fat secrete numerous hormones and cytokines that have local effects on WAT physiology but also systemic effects on other organs and may markedly contribute to the development of pathophysiological disorders associated with metabolic syndrome. On the contrary, leanness as well as significant weight reduction in obese patients increases production and circulating levels of metabolically beneficial factors and decreases production of proinflammatory and insulin resistance-inducing factors. Endothelial dysfunction and inflammation are important signs of vascular risk and worsened prognosis in patients with metabolic syndrome and type 2 diabetes. Measures of endothelial function remain invaluable for research into disease mechanism and response to new therapies. An interesting area of ongoing investigation is the role of thiazolidinediones in improving endothelial...
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The role of endothelial progenitor cells in the pathogenesis of anti - neutrophil cytoplasmatic antibody - associated vasculitis
Závada, Jakub ; Tesař, Vladimír (advisor) ; Haluzík, Martin (referee) ; Monhart, Václav (referee)
Summary: Introduction: Circulating endothelial progenitor cells (EPC) may provide an endogenous repair mechanism to counteract ongoing endothelial damage. Antineutrophil cytoplasmic antibody - associated vasculitis (AAV) is an inflammatory disorder of small- to medium-sized vessels with relapsing/remitting progression and endothelial injury is a major feature of AAV. EPC thus may play and an important role in the pathogenesis of AAV, or serve as a useful marker for monitoring and/or prediction of outcomes in patients with AAV. Hypotheses: EPC number in patients with AAV could be altered. The decreased capacity for endothelial regeneration paralleled by low EPC numbers could increase the risk of relapse in patients with AAV. Patients and methods: We have measured EPC in healthy volunteers, patients with AAV, chronic kidney failure (CKD) and atherosclerosis by a colony-forming assay. We have investigated the relation between the numbers of EPC, clinical and laboratory characteristics of the patients, and long-term outcomes of patients with AAV. Results: Patients with AAV had a significantly lower number of EPC than healthy subjects, but not than patients with CKD or atherosclerosis. The cumulative relapse-free survival increased stepwise across three increasing baseline levels of endothelial progenitor cells....
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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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