beta-cell function
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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 2. typu etiologie genetika MeSH
- draslíkové kanály fyziologie genetika chemie MeSH
- finanční podpora výzkumu jako téma MeSH
- geny genetika MeSH
- Langerhansovy buňky patologie sekrece MeSH
- lidé MeSH
- mutace MeSH
- polymorfismus genetický MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie 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
- beta-buňky metabolismus MeSH
- diabetes mellitus 1. typu genetika metabolismus patologie MeSH
- diabetes mellitus 2. typu genetika metabolismus patologie MeSH
- dospělí MeSH
- homeostáza genetika MeSH
- IGFBP-3 genetika metabolismus MeSH
- imunoblotting MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové proteiny genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- myši inbrední NOD MeSH
- myši knockoutované MeSH
- myši transgenní MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- regulace genové exprese * MeSH
- signální transdukce genetika MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
... graft monitoring and imaging / Christian Toso and Thierry Berney -- Metabolic measures of islet function ... ... Johnson -- Key factors to consider in setting up clinical trials in islet cell transplantation: a nursing ... ... Salomon -- Approaches to [beta]-cell regeneration and neogenesis / Susan C. ... ... Campbell and Wendy Macfarlane -- Stem cell approaches for [beta]-cell replacement / Enrique Roche and ...
xi, 361 s. : il., portrét ; 24 cm
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- diabetologie
- NLK Publikační typ
- 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
- beta-buňky * účinky léků metabolismus MeSH
- buněčné linie MeSH
- homeostáza * účinky léků MeSH
- inzulin * metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- organofosfáty toxicita MeSH
- organofosforové sloučeniny * toxicita MeSH
- proinsulin metabolismus MeSH
- retardanty hoření * toxicita MeSH
- sekrece inzulinu účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Acta Universitatis upsaliensis. Comprehensive summaries of Uppsala dissertations from the Faculty of Medicine, ISSN 0282-7476 379
53 s. : il. ; 24 cm
Scandinavian journal of clinical and laboratory investigation, ISSN 0085-591X vol. 46, suppl. 183, 1986
47 s. : il., tab., grafy ; 24 cm
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-katenin metabolismus MeSH
- buněčná adheze MeSH
- duktální karcinom prsu genetika metabolismus patologie MeSH
- fosforylace MeSH
- imunoprecipitace MeSH
- kaseinkinasa Iepsilon chemie genetika metabolismus MeSH
- konformace proteinů MeSH
- lidé MeSH
- MAP kinasa-kinasa 4 metabolismus MeSH
- messenger RNA genetika MeSH
- mutace genetika MeSH
- nádorové buněčné linie MeSH
- nádory prsu genetika metabolismus patologie MeSH
- pohyb buněk MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proliferace buněk MeSH
- proteiny Wnt metabolismus MeSH
- rac1 protein vázající GTP metabolismus MeSH
- transkripční faktory NFATC metabolismus MeSH
- western blotting MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Acta endocrinologica, ISSN 0300-9750 vol. 108, suppl. 266, 1985
39 s. : tab., grafy ; 24 cm
Acta universitatis upsaliensis. Comprehensive summaries of Uppsala dissertations from the Faculty of Medicine, ISSN 0282-7476 860
70 s. : il. ; 24 cm
