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The incidence of specific islet cell autoantibodies in patients with HNF1A-MODY and HNF4A-MODY
Urbanová, Jana ; Anděl, Michal (advisor) ; Štechová, Kateřina (referee) ; Bém, Robert (referee)
Islet cell autoantibodies are associated with autoimmune insulitis and belong to the diagnostic criteria of Type 1 diabetes mellitus. However, growing evidence suggests that autoantibodies are present in other types of diabetes. Here, we focus on the autoantibody incidence in Czech patients with maturity-onset diabetes of the young (MODY) and analyze their functional relevance in terms of diabetes onset and control. Autoantibodies against glutamic acid decarboxylase 65 (GADA) and protein tyrosine phosphatase islet antigen 2 (IA-2A) were measured in a cohort of 28 Czech patients with MODY (all confirmed by genetic testing). Selected clinical data were correlated to the status and kinetics of autoantibodies. One quarter of patients with MODY examined (7/28; 25%) was positive for GADA or IA-2A. GADA were more prevalent (7/7) than IA-2A (1/7). The incidence of autoantibodies did not correlate with human leukocyte antigen status, nor with particular mutation in MODY genes. The patients who were positive for the autoantibodies developed diabetes later than those who were autoantibody- negative, but had worse glycaemic control. Expression of autoantibodies decreased with any improvement of diabetes compensation. Only one patient did not correspond to the above and displayed signs of combined signs of MODY...
Immunointerventional therapy of autoimmune diabetes with recent oncet in NOD mice.
Vargová, Lenka ; Saudek, František (advisor) ; Štechová, Kateřina (referee) ; Mráz, Miloš (referee)
Introduction: Type 1 diabetes mellitus is a chronic metabolic disease caused by autoimmune destruction of pancreatic beta cells. The theory of the disease onset is derived from study of a disease course in non-obese diabetic (NOD) mice, in which the diabetes occurs due to a dysregulation of the immune system. Experimental and clinical studies showed that the autoimmunity may be abrogated by immune intervention, which if initiated early enough may at least slow down the ongoing beta cells lost and preserve residual insulin secretion. But immune intervention alone is not sufficient to restore normoglycemia in the majority of cases. Several interventional studies showed that stimulation of proliferation and/or regeneration of beta cells are necessary to restore normoglycemia in animal models. Aim of the study: To find out, if the combination of a potent immunosuppression (murine anti-thymocyte globulin (mATG), gusperimus) together with stimulation of islet regeneration (sitagliptin) will be able to slow down or reverse the course of the disease. Another aim is to identify the mechanism by which the substances act. Material and methods: All experiments were performed in female NODShiLtJ (H2g7 ) mice. The following parameters were examined at day 0, 7, 14 and 28: blood glucose, subpopulations of...
Possibilities of prediction and immunointervention in type 1 diabetes
Sklenářová, Jana ; Štechová, Kateřina (advisor) ; Saudek, František (referee) ; Pavlínková, Gabriela (referee)
Type 1 diabetes mellitus (T1D) is an organ-specific autoimmune disease characterised by autoimmune destruction of insulin-producing beta cells in the islets of Langerhans. It is a long-term process initiated months or even years prior to the clinical onset. The main role in the pathogenesis is played by T lymphocytes but other cell types are involved as well. The presence of autoantibodies in the circulation is typical even before the disease onset. Nowadays, intensive research is focused on finding individuals at risk and developing an effective prevention. During my postgraduate studies I was involved mainly in the research of T1D prediction and prevention. We investigated the relationship of established autoimmune markers - autoantibodies - and the cellular reactivity to GAD65 and IA2 autoantigens. We discovered that the reaction to autoantigens is very individual and it is influenced by the patient's autoantibody profile. These results could be relevant in planning antigen-specific immunointervention studies and improving their efficacy. We also made an attempt to improve specificity and sensitivity of a beta cell destruction marker (specifically demethylated DNA), which would enable better understanding of the beta cell decline and identification of individuals at risk of T1D development. In...
Differentiation of pancreatic stem cells into insulin producing β-cells.
Leontovyč, Ivan ; Saudek, František (advisor) ; Štechová, Kateřina (referee) ; Holáň, Vladimír (referee)
Diabetes mellitus (DM) is a severe and frequent disease with increasing prevalence. It is not possible to achieve long term cure without late complications. Recent advances in cell fate modifications open a pathway to alternative cell therapies for DM cure. My doctoral thesis "Differentiation of pancreatic stem cells into insulin producing β- cells" is focused on the development of a new source of insulin secreting cells for transplantation. Combinatorial testing of numerous potential transcription factors and epigenetic modifiers resulted in a final protocol for the reprogramming pancreatic of exocrine cells into insulin secreting cells. The key transcriptional factors TF (Pdx1, Ngn3 a MafA) were applied in the form of synthetic mRNA. In four independent experiments we applied transcriptional factors in a specific sequence, thus obtaining 14.3 ± 1.9 % insulin positive cells. When challenged in vitro by the glucose levels of 2.5 and 20 mmol/l glucose, respectively, these cells exhibited glucose-sensitivity of insulin secretion (842 ± 72 and 1 157 ± 58 pg insulin/µg DNA/ml, n=5). They also demonstrated a sensitivity of insulin secretion (863 ± 78 and 1 025 ± 66 pg insulin/µg DNA/ml, n=5) to the concentration of depolarization agent KCl applied at 0 and 30 mmol/l, respectively together with 2.5...
Epigenetic regulation of HLA class II genes and their role in autoimmune diseases
Čepek, Pavel ; Černá, Marie (advisor) ; Štechová, Kateřina (referee) ; Reiniš, Milan (referee)
(EN) Type 1 diabetes (T1D) belongs among polygenic multifactorial autoimmune diseases. The highest risk is associated with HLA (human leukocyte antigen) class II genes, including HLA-DQA1 gene. Our aim was to investigate DNA methylation of HLA-DQA1 promoter alleles (QAP) and correlate methylation status with individual HLA-DQA1 allele expression of T1D patients and healthy controls. DNA methylation is one of the epigenetic modifications, that regulate gene expression and is known to be shaped by the environment. 61 T1D patients and 39 healthy controls were involved in this study. Isolated DNA was treated with sodium bisulfite and HLA-DQA1 promoter sequence was amplified using nested PCR. After sequencing, DNA methylation of HLA-DQA1 promoter alleles was analyzed. Individual mRNA HLA-DQA1 relative allele expression was assessed using two different endogenous controls (PPIA, DRA). We have found statistically significant differences in HLA-DQA1 allele 02:01 expression (PPIA normalization, Pcorr=0.041; DRA normalization, Pcorr=0.052) between healthy controls and T1D patients. The complete methylation profile of the HLA-DQA1 promoter was gained with the most methylated allele DQA1*02:01 and the least methylated DQA1*05:01 in both studied groups. Methylation profile observed in T1D patients and healthy...
The incidence of specific islet cell autoantibodies in patients with HNF1A-MODY and HNF4A-MODY
Urbanová, Jana ; Anděl, Michal (advisor) ; Štechová, Kateřina (referee) ; Bém, Robert (referee)
Islet cell autoantibodies are associated with autoimmune insulitis and belong to the diagnostic criteria of Type 1 diabetes mellitus. However, growing evidence suggests that autoantibodies are present in other types of diabetes. Here, we focus on the autoantibody incidence in Czech patients with maturity-onset diabetes of the young (MODY) and analyze their functional relevance in terms of diabetes onset and control. Autoantibodies against glutamic acid decarboxylase 65 (GADA) and protein tyrosine phosphatase islet antigen 2 (IA-2A) were measured in a cohort of 28 Czech patients with MODY (all confirmed by genetic testing). Selected clinical data were correlated to the status and kinetics of autoantibodies. One quarter of patients with MODY examined (7/28; 25%) was positive for GADA or IA-2A. GADA were more prevalent (7/7) than IA-2A (1/7). The incidence of autoantibodies did not correlate with human leukocyte antigen status, nor with particular mutation in MODY genes. The patients who were positive for the autoantibodies developed diabetes later than those who were autoantibody- negative, but had worse glycaemic control. Expression of autoantibodies decreased with any improvement of diabetes compensation. Only one patient did not correspond to the above and displayed signs of combined signs of MODY...
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-...
Immunointerventional therapy of autoimmune diabetes with recent oncet in NOD mice.
Vargová, Lenka ; Saudek, František (advisor) ; Štechová, Kateřina (referee) ; Mráz, Miloš (referee)
Introduction: Type 1 diabetes mellitus is a chronic metabolic disease caused by autoimmune destruction of pancreatic beta cells. The theory of the disease onset is derived from study of a disease course in non-obese diabetic (NOD) mice, in which the diabetes occurs due to a dysregulation of the immune system. Experimental and clinical studies showed that the autoimmunity may be abrogated by immune intervention, which if initiated early enough may at least slow down the ongoing beta cells lost and preserve residual insulin secretion. But immune intervention alone is not sufficient to restore normoglycemia in the majority of cases. Several interventional studies showed that stimulation of proliferation and/or regeneration of beta cells are necessary to restore normoglycemia in animal models. Aim of the study: To find out, if the combination of a potent immunosuppression (murine anti-thymocyte globulin (mATG), gusperimus) together with stimulation of islet regeneration (sitagliptin) will be able to slow down or reverse the course of the disease. Another aim is to identify the mechanism by which the substances act. Material and methods: All experiments were performed in female NODShiLtJ (H2g7 ) mice. The following parameters were examined at day 0, 7, 14 and 28: blood glucose, subpopulations of...
Immunological markers for type 1 diabetes prediction
Včeláková, Jana ; Štechová, Kateřina (advisor) ; Černá, Marie (referee) ; Kverka, Miloslav (referee)
5 Abstract Type 1 diabetes (T1D) is an organ specific autoimmune disorder characterised by the immune-mediated destruction of insulin-producing pancreatic beta cells. Beta-cell destruction is mediated primarily by cellular components of the immune system, especially auto-reactive T cells. Nowadays, a goal of many studies is built up the best system for identification of individuals in prediabetes stage and to treat them to preserve sufficient amount of insulin producing beta cells. We identified several candidate pathways and proteins which could be important in pathology of T1D, like an antiviral responses and differentiation of Th17 pathways. We observed differences in dendritic cells count and in their cytokines production. Our data support the notion that the establishment of proinflammatory environment in genetically predisposed individuals along with the involvement of non-specific immune mechanisms is critical for the initiation of autoimmune, destructive insulitis. Nonetheless, patient's autoantibody profile reflects the type of cellular immune response and should be take in a count as well. This finding may be useful in design of immunointervention studies to prevent T1D. Considering the heterogeneity of the clinical course of this disease and perhaps different mechanisms of molecular pathology,...

National Repository of Grey Literature : 36 records found   previous11 - 20nextend  jump to record:
See also: similar author names
1 ŠTĚCHOVÁ, Karolina
4 ŠTĚCHOVÁ, Kristýna
4 Štěchová, Kristýna
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