Diabetes mellitus 2. typu (DM2) je heterogenní onemocnění, na jehož rozvoji se podílejí genetické faktory i vnější prostředí. Přes značné úsilí, které je mapování genetického pozadí DM2 věnováno, nejsou genetické příčiny nejběžnějších forem diabetu objasněny. V posledních letech je v souvislosti s DM2 věnována velká pozornost draselným kanálům pankreatických beta buněk, neboť hrají stěžejní úlohu v regulaci inzulinové sekrece. Článek shrnuje poznatky o struktuře a funkci draselných kanálů se zaměřením na jejich zapojení do etiopatogeneze DM2. Zvláštní pozornost je věnována polymorfismu E23K, který je považován za jeden z nejvýznamnějších genetických rizikových faktorů,které byly v souvislosti s DM2 dosud odhaleny.

Type 2 diabetes mellitus (DM2) is generally perceived as a heterogeneous polygenic disorder influenced by both hereditary and environmental factors. Despite intensive investigations, little progress has been made in identifying genes that impart susceptibility to the common late-onset forms of the disease. Recently, genes encoding for components of ATP-sensitive K+ channels in pancreatic beta cells have been widely considered as DM2 targets. These channels control insulin secretion by coupling metabolism to membrane electrical activity. The article summarizes knowledge concerning structure and function of the channels with respect to DM2. A common E23K polymorphism in the pore-forming subunit of the channels, which belongs to the most important genetic risk factors for DM2 yet identified, is discussed here.

• MeSH
• Diabetes Mellitus, Type 2 etiology   genetics   MeSH
• Potassium Channels physiology   genetics   chemistry   MeSH
• Research Support as Topic MeSH
• Genes genetics   MeSH
• Langerhans Cells pathology   secretion   MeSH
• Humans MeSH
• Mutation MeSH
• Polymorphism, Genetic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Comparative Study MeSH

Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients' cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.

• MeSH
• Insulin-Secreting Cells metabolism   MeSH
• Diabetes Mellitus, Type 1 genetics   metabolism   pathology   MeSH
• Diabetes Mellitus, Type 2 genetics   metabolism   pathology   MeSH
• Adult MeSH
• Homeostasis genetics   MeSH
• Insulin-Like Growth Factor Binding Protein 3 genetics   metabolism   MeSH
• Immunoblotting MeSH
• Cells, Cultured MeSH
• Middle Aged MeSH
• Humans MeSH
• Membrane Proteins genetics   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Inbred NOD MeSH
• Mice, Knockout MeSH
• Mice, Transgenic MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Gene Expression Regulation * MeSH
• Signal Transduction genetics   MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• Diabetes Mellitus, Type 1 * MeSH
• Islets of Langerhans Transplantation * MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• diabetologie
• NML Publication type
• kolektivní monografie

Despite the fact that environmental pollution has been implicated in the global rise of diabetes, the research on the impact of emerging pollutants such as novel flame retardants remains limited. In line with the shift towards the use of non-animal approaches in toxicological testing, this study aimed to investigate the effects of two novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) in rat (INS1E) and human (NES2Y) pancreatic beta-cell lines. One-week exposure to 1 μM and 10 μM TDCIPP and TPhP altered intracellular insulin and proinsulin levels, but not the levels of secreted insulin (despite the presence of a statistically insignificant trend). The exposures also altered the protein expression of several factors involved in beta-cell metabolic pathways and signaling, including ATP citrate lyase, isocitrate dehydrogenase 1, perilipins, glucose transporters, ER stress-related factors, and antioxidant enzymes. This study has brought new and valuable insights into the toxicity of TDCIPP and TPhP on beta-cell function and revealed alterations that might impact insulin secretion after more extended exposure. It also adds to the scarce studies using in vitro pancreatic beta-cells models in toxicological testing, thereby promoting the development of non-animal testing strategy for identifying pro-diabetic effects of chemical pollutants.

• MeSH
• Insulin-Secreting Cells * drug effects   metabolism   MeSH
• Cell Line MeSH
• Homeostasis * drug effects   MeSH
• Insulin * metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Organophosphates toxicity   MeSH
• Organophosphorus Compounds * toxicity   MeSH
• Proinsulin metabolism   MeSH
• Flame Retardants * toxicity   MeSH
• Insulin Secretion drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Research Support as Topic MeSH
• Insulin secretion   MeSH
• Blood Glucose metabolism   MeSH
• Islets of Langerhans secretion   MeSH
• Humans MeSH
• Polycystic Ovary Syndrome physiopathology   MeSH
• Check Tag
• Humans MeSH
• Female MeSH

• MeSH
• Echocardiography methods   instrumentation   statistics & numerical data   MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Endothelins blood   MeSH
• Research Support as Topic MeSH
• Ventricular Function, Right physiology   MeSH
• Interleukin-6 blood   MeSH
• Catheterization methods   instrumentation   MeSH
• Humans MeSH
• Cardiac Output, Low diagnosis   etiology   ultrasonography   MeSH
• Ultrasonography, Doppler methods   instrumentation   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Comparative Study MeSH

• Conspectus
• Fyziologie člověka a srovnávací fyziologie
• NML Fields
• endokrinologie
• biologie
• biochemie

• MeSH
• Insulin MeSH
• Islets of Langerhans anatomy & histology   physiology   MeSH
• Pancreas anatomy & histology   physiology   MeSH
• Publication type
• Academic Dissertation MeSH

• Conspectus
• Fyziologie člověka a srovnávací fyziologie
• NML Fields
• endokrinologie
• chemie, klinická chemie

INTRODUCTION: Breast cancer is one of the most common types of cancer in women. One of the genes that were found mutated in breast cancer is casein kinase 1 epsilon (CK1epsilon). Because CK1epsilon is a crucial regulator of the Wnt signaling cascades, we determined how these CK1epsilon mutations interfere with the Wnt pathway and affect the behavior of epithelial breast cancer cell lines. METHODS: We performed in silico modeling of various mutations and analyzed the kinase activity of the CK1epsilon mutants both in vitro and in vivo. Furthermore, we used reporter and small GTPase assays to identify how mutation of CK1epsilon affects different branches of the Wnt signaling pathway. Based on these results, we employed cell adhesion and cell migration assays in MCF7 cells to demonstrate a crucial role for CK1epsilon in these processes. RESULTS: In silico modeling and in vivo data showed that autophosphorylation at Thr 44, a site adjacent to the breast cancer point mutations in the N-terminal lobe of human CK1epsilon, is involved in positive regulation of the CK1epsilon activity. Our data further demonstrate that, in mammalian cells, mutated forms of CK1epsilon failed to affect the intracellular localization and phosphorylation of Dvl2; we were able to demonstrate that CK1epsilon mutants were unable to enhance Dvl-induced TCF/LEF-mediated transcription, that CK1epsilon mutants acted as loss-of-function in the Wnt/beta-catenin pathway, and that CK1epsilon mutants activated the noncanonical Wnt/Rac-1 and NFAT pathways, similar to pharmacological inhibitors of CK1. In line with these findings, inhibition of CK1 promoted cell migration as well as decreased cell adhesion and E-cadherin expression in the breast cancer-derived cell line MCF7. CONCLUSIONS: In summary, these data suggest that the mutations of CK1epsilon found in breast cancer can suppress Wnt/beta-catenin as well as promote the Wnt/Rac-1/JNK and Wnt/NFAT pathways, thus contributing to breast cancer development via effects on cell adhesion and migration. In terms of molecular mechanism, our data indicate that the breast cancer point mutations in the N-terminal lobe of CK1epsilon, which are correlated with decreased phosphorylation activities of mutated forms of CK1epsilon both in vitro and in vivo, interfere with positive autophosphorylation at Thr 44.

• MeSH
• beta Catenin metabolism   MeSH
• Cell Adhesion MeSH
• Carcinoma, Ductal, Breast genetics   metabolism   pathology   MeSH
• Phosphorylation MeSH
• Immunoprecipitation MeSH
• Casein Kinase 1 epsilon chemistry   genetics   metabolism   MeSH
• Protein Conformation MeSH
• Humans MeSH
• MAP Kinase Kinase 4 metabolism   MeSH
• RNA, Messenger genetics   MeSH
• Mutation genetics   MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms genetics   metabolism   pathology   MeSH
• Cell Movement MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Cell Proliferation MeSH
• Wnt Proteins metabolism   MeSH
• rac1 GTP-Binding Protein metabolism   MeSH
• NFATC Transcription Factors metabolism   MeSH
• Blotting, Western MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

V posledních deseti letech došlo k mimořádně bouřlivému rozvoji molekulární biologie a genetiky. Denně přibývají nové poznatky umožněné nejen procesem vlastního výzkumu, ale též obrovským rozvojem jeho technologického zázemí. Uvedený rozvoj výzkumu přiblížil dobu, kdy výsledky výzkumu se stanou součástí praktické medicíny i jiných odvětví. Tak, jako jsme museli znát alespoň základy klasické biochemie, abychom porozuměli základům farmakologie, tak pro blízkou budoucnost bude nezbytné znát minimální základy molekulární biologie a genetiky, abychom byli schopni zodpovědně využívat možností diagnostiky a terapie nemocí, které nám současné výzkumy nabídnou. Proto se autor pokusil shrnout základní a zjednodušené informace o struktuře a funkci receptorů, o přenosu informace (signálu) z extracelulárního prostoru přes membránu do cytosolu a pak dále na úroveň transkripce. Na příkladu desenzitizace beta adrenoreceptoru je pak naznačena šíře složitosti popsaných procesů.

The extraordinary intensive development of the molecular biology and the genetics as well as the technological development supporting both sciences brought an unusual amount of our knowledges that were discovered in the past 10 years. The mentioned results of the research are still the closer part of the practical medicine. The basic knowledge of the molecular biology and the genetics became very important for the everyday medical practice. Therefore the author attempted to summarize and simplify the information about the structure and the function of the receptors and about the transduction of the signals from the extracellular side across the cell membranes to the cytosol and then to the transcriptional level. The example of the desensitization of beta 2-adrenoceptor was used to show the extensive difficulties of the described processes.

• MeSH
• Research Support as Topic MeSH
• Receptors, Cell Surface physiology   classification   MeSH
• Signal Transduction MeSH
• Publication type
• Review MeSH