Glycaemic control in critically ill patients has been a topic of considerable attention for the past 20 years. In literature and at scientific meetings, there have been ongoing debates regarding the efficacy of glycaemic control in these patients with frequently entirely opposite opinions. These range from a strict invasive approach with target glycaemia 4-6 mmol/l to a liberal approach tolerating even values higher than 12 mmol/l. In the preview of this PhD thesis we have analysed so far published literature and describe the reasons for this inconsistency. According to the results of recent studies, the most significant efficacy of tight glycaemic control has been observed in cardiac surgical patients. If we consider the concept of tight glycaemic control as efficient strategy, there are three important questions remaining unanswered as follow. Does the specific algorithm-protocol play a key part in the concept of tight glycaemic control alongside the knowledge and skills of nursing staff in safe and efficient blood glucose control? What is the ideal timing of starting the strategy of tight glycaemic control (TGC) in cardiac surgical patient? And is there any benefit in outcome respect to mortality or morbidity? Do we have any more safe and efficient option or add-on to standard perioperative...

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are aging-associated diseases that have rising prevalence in all industrialized countries. AD is a neurodegenerative disease characterized by progressive loss of cognitive functions. It is a complex disease which formation involves both genetic factors and environmental factors. The most important marker associated with this disease is the risk allele ε4 in APOE gene. From the latest genome-wide association study emerged another ten candidate genes. As the most significant from those genes appears the minority G allele of rs744373 polymorphism in the gene BIN1. AD is connected with many metabolic and immune disorders. To the markers of interest belongs also the new parameter visfatin which can act as a pro-inflammatory cytokine. T2DM is a chronic disease characterized by raised levels of blood glucose, which is also characterized by neurological disorders. In the case of both of these diseases can be found a large number of metabolic disorders. One of the most important disorders is insulin resistance. This thesis consists of two parts - the biochemical and genetic one. The biochemical part of the thesis studies the visfatin level in patients with AD and healthly control and studies whether visfatin is related to AD. In this part of the...

The pathogenesis of insulin resistance is a complex and still intensively studied issue. Endocrine and paracrine activity of the adipose tissue together with mi- tochondrial dysfunction are the most discussed potential factors included in the development of insulin resistance. In the first part of our study we examined the involvement of the adipose tissue and its secretory products in the etiopathogenesis of insulin resistance in patients with Cushing's syndrome, acromegaly and simple obesity. We focused on three important regulators of metabolic homeostasis - fibroblast growth factors 21 and 19 (FGF-21 and FGF-19) and adipocyte fatty acid binding protein (FABP-4). We found significantly elevated circulating levels of FGF-21 and FABP-4 ac- companying insulin resistance in both patients with simple obesity and patients with obesity connected to Cushing's syndrome, as compared to healthy controls. The concentrations of both substances were comparable between hypercortisolic and obese patients. This finding together with the absence of correlation be- tween the levels of FGF-21 resp. FABP-4 and cortisol suggest that the reason for elevation of their concentrations is obesity and its metabolic consequences themselves rather then the effect of hypercortisolism on FGF-21 and FABP-4 production. We found no...

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...

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...

(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...

The project focuses on dietary interventions in type 2 diabetes(T2D). The aim was to investigate how glucose metabolism and other manifestations of insulin resistance should be influenced by a) the composition of macronutrients and b) frequency of meals; and to characterize the possible mechanisms of these dietary interventions in patients with T2D. A. In a randomized crossover study, 50 patients T2D and 50 age-matched healthy subjects underwent in a random order meal tolerance tests with three isocaloric meals (vegan sandwich; V-meal, hamburger; M-meal, or cheese sandwich; S-meal. Blood samples for analysis were taken at time 0 and after 30, 60, 120 and 180 minutes after meal ingestion. Plasma concentrations of plasma glucose, insulin, C-peptide, lipids, oxidative stress markers and gastrointestinal hormones (GIHs) were investigated. Both basal and postprandial plasma concentrations of glucose and insulin were significantly higher in patients with T2D (p<0.001); basal and postprandial concentrations of almost all other GIHs (except for ghrelin) and thiobarbituric acid reactive substances (TBARS) were significantly increased (p<0.001), while ascorbic acid, reduced glutathione and superoxide dismutase activity were decreased in patients with T2D compared to healthy controls (p<0.001). The meal rich...

Gestational diabetes (GDM) is a disorder of glucose metabolism arising for the first time in pregnancy and spontaneously receding after birth. The issue of GDM is very topical since, according to the latest update of diagnostic criteria, up to 17% of pregnant women is threatened by this disorder. The incidence of GDM correlates with the increasing prevalence of overweight/obesity and metabolic syndrome. It is proved that women who have had gestational diabetes have an enormously increased risk of developing type 2 diabetes mellitus (DM2T). The risk accosiated with a gestational diabetes pregnancy stretches beyond the host, and can affect the fetus both directly (e. g. macrosomia development), and epigenetically (increases susceptibility to obesity, DM2T development or cardiovascular disease). Significant influence on the development of GDM (or DM2T) is a body composition that is directly related to lifestyle (nutritional intake and physical activity) and genetic role i salso involved. Early intervention may help delay the risk of developing DM2T and other metabolic complications. In this diploma thesis we monitored metabolic profiles of glucose and lipids and body composition based on anthropometric examination and questionnaires of nutritional income and physical activity. For the complex...

The pathogenesis of insulin resistance is a complex and still intensively studied issue. Endocrine and paracrine activity of the adipose tissue together with mi- tochondrial dysfunction are the most discussed potential factors included in the development of insulin resistance. In the first part of our study we examined the involvement of the adipose tissue and its secretory products in the etiopathogenesis of insulin resistance in patients with Cushing's syndrome, acromegaly and simple obesity. We focused on three important regulators of metabolic homeostasis - fibroblast growth factors 21 and 19 (FGF-21 and FGF-19) and adipocyte fatty acid binding protein (FABP-4). We found significantly elevated circulating levels of FGF-21 and FABP-4 ac- companying insulin resistance in both patients with simple obesity and patients with obesity connected to Cushing's syndrome, as compared to healthy controls. The concentrations of both substances were comparable between hypercortisolic and obese patients. This finding together with the absence of correlation be- tween the levels of FGF-21 resp. FABP-4 and cortisol suggest that the reason for elevation of their concentrations is obesity and its metabolic consequences themselves rather then the effect of hypercortisolism on FGF-21 and FABP-4 production. We found no...

(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...