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Bipolar Disorder and Diabetes Mellitus
Růžičková, Martina ; Höschl, Cyril (advisor) ; Haluzík, Martin (referee) ; Papežová, Hana (referee)
Despite lots of research, the genetic and pathophysiological basis of bipolar disorder (BD) remains unclear. One of the possible reasons is that BD spectrum comprises a heterogeneous group of different subtypes of the illness sharing certain pathophysiological or genetic mechanisms. Patients with co-morbid diabetes mellitus (DM) may represent such a subgroup of BD with a distinct pathophysiology and possibly different clinical characteristics of BD. This thesis is aimed at investigating the possible link between BD and DM. Bipolar patients have about 3 times higher risk of DM (type 2 in particular). The first part of my thesis outlines the possible links between DM and BD, including medication, alterations in the hypothalamo-pituitary axis and signal transduction, and genetics. In the second part, I examined the possible differences in clinical characteristics between patients with (N=26) and without (N=196) co-morbid DM. Next, I examined the variables showing differences between groups, using logistic regression. Patients were recruited via The Maritime Bipolar Registry. The prevalence of DM was 11.7%. Diabetic patients were significantly older than non-diabetic patients (P < 0.001), had higher rates of rapid cycling (P = 0.02), more chronic course of BD (P = 0.006), more disability (P < 0.001), lower...
Effects of acute starvation and of type 2 diabetes mellitus upon insulin resistance and substrate utilization in obese subjects
Duška, František ; Anděl, Michal (advisor) ; Haluzík, Martin (referee) ; Mourek, Jindřich (referee) ; Stárka, Luboslav (referee)
Very-low calorie diet or even total short-term fasting is widely used in clinical practice in order to improve metabolic compensation of patients with type 2 diabetes mellitus. Although benefits of weight reduction are well proven in T2DM, much less is known about effects of acute starvation, during which the interruption of the afflux of energy substrates is not followed by a major change of body composition. We hypothesize the improvement of insulin effects on glucose metabolism in T2DM as these patients may lack the key metabolic responses which impair insulin sensitivity in lean, non-diabetic subjects. Moreover, we assume according to "thrifty genotype hypothesis" that protein wasting during starvation will be positively related to insulin effects on glucose disposal and negatively related to insulin antilipolytic and antiketogenic effects. In the light of this we designed an observational, prospective, in-hospital study, comparing the effects of 60 hours fast on various aspects of insulin resistance, endocrine regulation and metabolism in 10 patients with T2DM and 10 obese controls without diabetes (OB).
The influence of central serotoninergic and dopaminergic activity on nutritional and metabolic parameters
Brunerová, Ludmila ; Anděl, Michal (advisor) ; Haluzík, Martin (referee) ; Yamamotová, Anna (referee)
THE INFLUENCE OF CENTRAL SEROTONINERGIC AND DOPAMINERGIC ACTIVITY ON NUTRITIONAL AND METABOLIC PARAMETERS MUDr. Ludmila Brunerová SUMMARY Introduction: Neuromediators dopamine and serotonin play a significant role in homeostatic and hedonic regulation of food intake, may exert direct metabolic effects and particularly serotonin influences affectivity. Their central activity could be quantified by functional tests. Common regulatory mediators of metabolism and affectivity represent an interesting research goal. Aims of study: The first aim was to describe the relationship between central serotoninergic activity measured by citalopram challenge test, affectivity, preference of macronutrients in food and metabolic profile in healthy men. The second aim was to confirm the use of sublingual apomorphine test as a functional test for assessment of central dopaminergic activity. The third aim was to reveal the relationship between central dopaminergic activity measured by sublingual apomorphine test, preference of macronutrients and metabolic profile. Methods: The study was performed on 42 healthy men (average age 43.5 ± 7.4 years and average BMI 27.4 ± 5.7 kg/mš) within 4 days with a week interval in between them. Anthropometric and...
Diabetes mellitus and impairment of intestinal barier function
Hoffmanová, Iva ; Anděl, Michal (advisor) ; Haluzík, Martin (referee) ; Keil, Radan (referee)
Introduction: Impairment of intestinal barrier function is involved in pathogenesis of immune mediated diseases (such as type 1 diabetes mellitus or celiac disease) and metabolic diseases (such as type 2 diabetes mellitus). Aims of study: The first aim was to analyze impairment of mucosal part of intestinal barrier in both type of diabetes and to describe differences when compared to celiac disease, which is a typical condition associated with impairment of intestinal barrier function. The second aim was to find a correlation between duration or compensation of diabetes and intestinal barrier desintegration in patients with both type of diabetes, and to find a correlation between body mass index and intestinal barrier desintegration in patients with type 2 diabetes. The third aim was to assess influence of gluten-free diet on improvement of small intestinal mucosal integrity in patient with celiac disease. Methods: The study was performed on 166 individuals including healthy controls and five group of patients with: type 1 diabetes mellitus with fading insulitis (T1D), type 1 diabetes mellitus with ongoing insulitus (T1D/INS), type 2 diabetes mellitus (T2D), untreated celiac disease (CLD), and celiac disease on gluten-free diet (CLD-GFD). We tested the marker of epithelial apoptosis - cytokeratin 18...
The importance of endocrinefunction of adipose tissue in the development of insulin resistance syndrome
Kaválková, Petra ; Haluzík, Martin (advisor) ; Karásek, David (referee) ; Kuneš, Jaroslav (referee)
(AJ) Adipose tissue produces numerous adipokines, pro- and antiinflammatory cytokines and hormones which may influence the development of insulin resistance, type 2 diabetes mellitus and other comorbidities of the metabolic syndrome. The ability of adipose tissue to store lipids and thus protect other organs and tissues from ectopic lipid accumulation and development of insulin resistance (IR) is largely dependent on the adipogenic potential of preadipocytes. The amount and function of these cells may be the key factor in creating "healthy" adipose tissue or on the contrary "unhealthy" adipose tissue eventually leading to metabolic derangements. The regulation of the amount of body fat by converting preadipocytes into mature adipocytes may be crucial in the prevention and treatment of obesity and its comorbidities. One of the reasons for development of insulin resistance can be the inhibition of the differentiation process of preadipocytes into mature adipocytes with consequent ectopic lipid accumulation caused by the secretion of preadipocyte factor - 1 (Pref - 1). Pref - 1 has been discovered recently as a protein produced by preadipocytes but not by mature adipocytes. Pref - 1 is a member of the protein family sharing similarity with epidermal growth factors which regulate the differentiation of...
Functional genomic and pharmacogenomic analysis of metabolic syndrome aspects
Krupková, Michaela ; Šeda, Ondřej (advisor) ; Haluzík, Martin (referee) ; Polák, Jan (referee)
Metabolic syndrome is a prevalent disease characterized by concurrent manifestation of insulin resistance, obesity, dyslipidemia, hypertension and other hemodynamic and metabolic disorders. It has multifactorial type of inheritance and its resultant phenotype is determined by both environmental and genetic factors as well as their interactions. That is the main reason why comprehensive analysis of the genetic component of this syndrome is complicated in human population. Genetically designed experimental animal models are significant tools for analysis of genetic architecture of human complex conditions including the metabolic syndrome. The aim of this Thesis is utilization of functional and comparative genomic tools to uncover pathogenesis of metabolic syndrome aspects and their genetic determinants. We also studied pharmacogenetic interactions of these genetic determinants with drugs affecting particular components of the metabolic syndrome. Establishing and utilizing several genetically designed congenic rat strains, we undertook four different research projects focusing on pharmacogenetic interaction of all-trans retinoic acid and ondansetron with differential segment of rat chromosome 8, pharmacogenetic interaction of differential segment of rat chromosome 4 and dexamethasone, determining Plzf...
The role of GH/IGF-1 axis components in the etiopathogenesis of metabolic disturbances in type 2 diabetes mellitus and acromegaly
Toušková, Věra ; Haluzík, Martin (advisor) ; Müllerová, Dana (referee) ; Saudek, František (referee)
(EN) GH/IGF-1 axis components (GH, growth hormone receptor (GH-R), IGF-1, IGF-1 receptor (IGF-1R), IGF-binding proteins (IGFBPs)) participate in the control of glucose metabolism, inflammatory processes as well as cell proliferation and differentiation, including adipocytes and monocytes. The aim of the present study was to evaluate the role of local mRNA expression of GH/IGF-1 axis components in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) in the development of insulin resistance and differences of adipose tissue mass in following groups of patients: obese females with and without type 2 diabetes mellitus and subjects with active untreated acromegaly. A total number of 66 subjects were included in the study: obese females without type 2 diabetes mellitus (OB), obese females with type 2 diabetes mellitus (T2DM), acromegalic patients (AC) and healthy lean control subjects (C). T2DM underwent 2 weeks of very-low- calorie diet (VLCD - energy content 2500 kJ/day). According to our results we suggest that decreased mRNA expression of IGF-1, IGF-1R, IGFBP-2 and IGFBP-3 in adipose tissue of T2DM subjects may contribute to changes of fat differentiation capacity and the increased IGF-1R mRNA expression in peripheral monocytes in these patients may play a role in the regulation of...
Antiproliferative effects of heme catabolic pathway's products
Koníčková, Renata ; Vítek, Libor (advisor) ; Haluzík, Martin (referee) ; Farghali, Hassan (referee)
Presented work is focused on heme metabolism with the main interest in bile pigments. Recent data indicate that bilirubin is not only a waste product of the heme catabolic pathway, but also emphasize its important biological impacts, including possible antiproliferative effects. Until today metabolism of bilirubin has not been completely elucidated, which has prevented detailed evaluation of its potential anticancer action. The aim of this study was to clarify some aspects of heme catabolism with respect for antiproliferative properties of its products. Based on the fact that bilirubin potently affects carcinogenesis of the intestine, we initially investigated not properly known bilirubin metabolism by intestinal bacteria. We studied bilirubin neurotoxic effects in hyperbilirubinemic Gunn rats - its distribution in the brain tissue and its degradation during pathological conditions, such as severe newborn jaundice or Crigler-Najjar syndrome. Possible approaches to improve the treatment of severe unconjugated hyperbilirubinemias, combination of the phototherapy and human albumin administration were also investigated. The main reason of these studies was the fact that mechanisms of neurotoxic effects of bilirubin are predominantly identical with those, by which bilirubin inhibits cancer cells growth....
Novel metabolic regulators and proinflammatory factors in the etiopathogenesis of type 2 diabetes mellitus and obesity: the influence of pharmacological and dietary interventions
Mráz, Miloš ; Haluzík, Martin (advisor) ; Šenolt, Ladislav (referee) ; Hainer, Vojtěch (referee)
NOVEL METABOLIC REGULATORS AND PROINFLAMMATORY FACTORS IN THE ETIOPATHOGENESIS OF TYPE 2 DIABETES MELLITUS AND OBESITY: THE INFLUENCE OF PHARMACOLOGICAL AND DIETARY INTERVENTIONS MUDr. Miloš Mráz Doctoral Thesis ABSTRACT (EN) Identifying novel factors involved in the etiopathogenesis of obesity, diabetes mellitus and their complications has become one of the primary scopes of metabolic research in the last years. The aim of the present study was to evaluate the role of recently discovered metabolic and inflammatory regulators including fibroblast growth factors 19 and 21 and chemotactic cytokines in the development of obesity and type 2 diabetes mellitus (DM2). A total number of 182 patients were included into the study. They were divided into 3 groups - patients with obesity but without type 2 diabetes mellitus, individuals with obesity and type 2 diabetes mellitus and healthy control normal-weight subjects. Selected interventions included 2 to 3 weeks of very-low-calorie diet (VLCD - energy content 2500 kJ/day), 3 months of administration of PPARα receptor agonist fenofibrate and acute hyperinsulinemia during hyperinsulinemic isoglycemic clamp. Our results indicate that the increase of circulating FGF-21 levels after VLCD and fenofibrate treatment could contribute to positive metabolic effects of these...
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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