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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...
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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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Factors affecting glucose metabolism and inflammatory response in critically ill patients
Kotulák, Tomáš ; Haluzík, Martin (advisor) ; Maruna, Pavel (referee) ; Šenolt, Ladislav (referee)
Hyperglycemia in critically ill patients was considered for many years an adaptive response to stress conditions being present in both patients with and without previous history of diabetes. Hyperglycemia is caused mainly by peripheral insulin resistance induced by the factors acting counteracting insulin signalling at the postreceptor level. Furthermore, hyperglycemia itself can then increase serum levels of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (Il-6) and interleukin-8 (Il- 8) and others. On the contrary, peripheral insulin resistance induced by pro- inflammatory cytokines may further potentiate hyperglycemia. White adipose tissue represents in addition to its energy storage function also a very active endocrine active organ. In addition to regulation of a number of metabolic processes it also significantly modulates the inflammatory response. In critically ill patients, adipose tissue changes its morphology, i.e. the adipocytes are shrinking and adipose tissue is abundantly infiltrated by macrophages. Paradoxically, overweight and obese critically ill patients have lower mortality than underweight, lean and morbidly obese subjects. In our studies, we selected population of the patients undergoing elective major cardiac surgery with extracorporeal...
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Neural mechanisms in the pathogenesis of spontaneous hypertension in the rat
Vavřínová, Anna ; Zicha, Josef (advisor) ; Haluzík, Martin (referee) ; Neckář, Jan (referee)
Both sympathoneural and sympathoadrenal systems are involved in the regulation of arterial blood pressure and in the pathogenesis of hypertension. Spontaneously hypertensive rats (SHR), the mostly used animal model of genetic hypertension, is characterized by multiple molecular, morphological and functional alterations at different levels of sympathoneural and sympathoadrenal systems. The study of young prehypertensive SHR allows to reveal the abnormalities preceding hypertension development, whereas adult SHR with established hypertension offers a better model for the treatment of human essential hypertension. The aim of my PhD Thesis was to describe abnormalities in sympathoneural and sympathoadrenal systems in SHR under different conditions. Firstly, ontogenetic differences which might contribute to hypertension development were determined. Secondly, the effect of chemical sympathectomy induced by guanethidine in adulthood on cardiovascular parameters and on the compensatory mechanisms counteracting the reduction of blood pressure were studied. Thirdly, stress-induced cardiovascular response and stress-induced changes of sympathoneural and sympathoadrenal systems were described in adult SHR. My Thesis brought several important results. The increased adrenal catecholamine content and the...
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Regulatory mechanisms affecting etiopathogenesis of obesity, insulin resistance and type 2 diabetes mellitus.
Cinkajzlová, Anna ; Haluzík, Martin (advisor) ; Krčma, Michal (referee) ; Kříž, Jan (referee)
Subclinical inflammation plays a pivotal role in the development of obesity- related complications including type 2 diabetes mellitus, hypertension and cardiovascular diseases. Macrophages are considered important players participating in the initiation and progression of subclinical inflammation within as well as outside of adipose tissue. The first part of this dissertation thesis was focused on macrophage characterization and their quantitative and qualitative changes accompanying metabolic improvements after bariatric surgery. We have demonstrated that the number of macrophages in subcutaneous adipose tissue is reduced regardless of their M1 or M2 polarization manifested as positivity of both the M1- associated CD40 antigen and the M2-associated CD163 and CD206 antigens 6 months after bariatric surgery. Thus, as suggested by previously published data, subcutaneous adipose tissue macrophages seem to have a mixed phenotype. We further confirmed a higher number of non- classical monocytes, which play a role in the control of vascular integrity, in obese subjects as well as a classical monocyte-derived origin of CD163 positive monocytes. Our data also support the previous suggestion of the soluble form of CD163 antigen being a suitable marker of metabolic complications of obesity. The second part...
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The influence of very-low calorie diet and pharmacologic interventions on adipose tissue metabolism in patients with type 2 diabetes mellitus and obesity.
Gregová, Monika ; Haluzík, Martin (advisor) ; Kunešová, Marie (referee) ; Žourek, Michal (referee)
(EN) Obesity and type 2 diabetes mellitus (T2DM) are among metabolic disease with increasing incidence and prevalence. Last decade has been devoted to intensive research focused on pathophysiological mechanisms underlying development of these diseases. Besides environmental factors, lifestyle and amount and composition of food, adipose tissue is a key player in the pathogenesis of obesity and its metabolic complications including insulin resistance (IR) and T2DM. Primary aim of our work was to evaluate the role of recently discovered adipokine omentin and the role of mitochondrial dysfunction in subcutaneous adipose tissue (SCAT) and in peripheral monocytes (PM) in patients with obesity and T2DM with respect to the development of insulin resistance and diabetes. A total number of 118 subjects enrolled in the study were divided into three groups: patients with obesity and T2DM (T2DM group), obese non-diabetics (OB) and healthy lean subjects as a control group (KO). Study subjects underwent several types of interventions - 2 to 3 weeks of very-low calorie diet (VLCD, energy intake 600 kcal per day), regular physical activity program or bariatric surgery (laparoscopic sleeve gastrectomy, LSG). Results indicate that low serum omentin concentrations may contribute to development of obesity-associated...
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The changes in endocrine function and inflammatory profile of adipose tissue and peripheral monocytes of patients with obesity: the influence of physical activity and bariatric surgery
Trachta, Pavel ; Haluzík, Martin (advisor) ; Maruna, Pavel (referee) ; Štechová, Kateřina (referee)
(EN) Research in the field of obesity, diabetes mellitus and their complications in recent years is increasingly focused on pathophysiological mechanisms of their onset and potential prevention and treatment. The aim of the present work was to evaluate the effects of two different interventions - sleeve gastrectomy and physical activity - on anthropometric, biochemical, hormonal parameters and mRNA expression of proinflammatory factors in subcutaneous adipose tissue along with mRNA expression in peripheral blood monocytes in patients who underwent sleeve gastrectomy. A total of 15 obese women with hypertension were included into the physical activity study. These patients underwent a 3-month training program, which included 30 minutes of aerobic exercise three times a week. 13 obese women were included into sleeve gastrectomy study and were followed-up for 2 years after surgery. Our results indicate that in both studies obese groups had at baseline significantly increased mRNA expression of proinflammatory cytokines, adipokines, chemokines and chemokine receptors relative to control groups. Both interventions decreased body weight and low-grade inflammation. Physical activity had no significant effect on blood pressure, lipid profile and mRNA expression of the components of the renin-...
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Molecular mechanisms of metabolic syndrome with focus on new hormones produced by adipose tissue, liver and skeletal muscle
Kloučková, Jana ; Haluzík, Martin (advisor) ; Šenolt, Ladislav (referee) ; Bužga, Marek (referee)
1 Abstract The cluster of obesity, insulin resistance and other associated comorbidities represents a significant health risk for the affected individuals as well as the whole population. Chronic low-grade inflammation of adipose tissue is considered one of the main mechanisms respon- sible for the progression from simple obesity to a fully developed metabolic syndrome. The aim of our study was to explore two different approaches that could potentially ameliorate adipose tissue inflammation - therapeutic hypothermia and the adipocytokine clusterin. In the first part, we showed that a period of deep hypothermia associated with the an- oxic phase of cardiac surgery significantly delayed the onset of systemic inflammatory re- sponse induced by surgery. The relative gene expression of the studied genes was not altered during the hypothermic period, but was significantly increased in five out of ten studied genes (IL-6, MCP-1, TNF-α, HIF1-α, GLUT1) and decreased in two genes (IRS1, GPX1) at the end of surgery. We conclude that deep hypothermia delays the onset of local adipose tissue hy- poxia and inflammation. These results could partially explain the positive effects of therapeu- tic deep hypothermia on postoperative morbidity and mortality in cardiac surgery patients. In the second part, we examined plasma...
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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...
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