BACKGROUND: Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown. METHODS: In this phase 3, randomized, placebo-controlled trial, we assessed β-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in β-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events. RESULTS: Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval [CI], 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome. CONCLUSIONS: Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of β-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.).

• MeSH
• antigeny CD3 antagonisté a inhibitory   imunologie   MeSH
• beta-buňky účinky léků   imunologie   MeSH
• C-peptid analýza   MeSH
• diabetes mellitus 1. typu * diagnóza   imunologie   terapie   MeSH
• dítě MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky * škodlivé účinky   farmakologie   terapeutické užití   MeSH
• hypoglykemika aplikace a dávkování   terapeutické užití   MeSH
• inzulin aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• mladiství MeSH
• progrese nemoci MeSH
• T-lymfocyty účinky léků   imunologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

• MeSH
• beta-buňky fyziologie   patologie   účinky léků   MeSH
• cévy patologie   účinky léků   MeSH
• diabetes mellitus 2. typu * epidemiologie   etiologie   komplikace   mortalita   patofyziologie   MeSH
• diabetické angiopatie etiologie   MeSH
• endotel patofyziologie   účinky léků   MeSH
• inzulinová rezistence MeSH
• kouření patofyziologie   škodlivé účinky   MeSH
• lidé MeSH
• nikotin * škodlivé účinky   MeSH
• oxidační stres fyziologie   účinky léků   MeSH
• rizikové faktory MeSH
• sekrece inzulinu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• Klíčová slova
• systémový zánět,
• MeSH
• beta-buňky účinky léků   MeSH
• diabetes mellitus 2. typu patofyziologie   MeSH
• diabetes mellitus * farmakoterapie   patofyziologie   MeSH
• lidé MeSH
• oxidační stres MeSH
• zánět farmakoterapie   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Many compounds have the potential to harm pancreatic beta-cells; organochlorine pollutants belong to those compounds. In this work, we aimed to find markers of acute toxicity of p,p'-DDT exposure among proteins expressed in NES2Y human pancreatic beta-cells employing 2-D electrophoresis. We exposed NES2Y cells to a high concentration (150 μM, LC96 after 72 hours) of p,p'-DDT for 24 and 30 hours and determined proteins with changed expression using 2-D electrophoresis. We have found 22 proteins that changed their expression. They included proteins involved in ER stress (GRP78, and endoplasmin), mitochondrial proteins (GRP75, ECHM, IDH3A, NDUS1, and NDUS3), proteins involved in the maintenance of the cell morphology (EFHD2, TCPA, NDRG1, and ezrin), and some other proteins (HNRPF, HNRH1, K2C8, vimentin, PBDC1, EF2, PCNA, biliverdin reductase, G3BP1, FRIL, and HSP27). The proteins we have identified may serve as indicators of p,p'-DDT toxicity in beta-cells in future studies, including long-term exposure to environmentally relevant concentrations.

• MeSH
• 2D gelová elektroforéza MeSH
• beta-buňky cytologie   účinky léků   metabolismus   MeSH
• biologické markery metabolismus   MeSH
• buněčné linie MeSH
• DDT toxicita   MeSH
• hmotnostní spektrometrie MeSH
• lidé MeSH
• proteomika metody   MeSH
• regulace genové exprese účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Transcript levels for selected ATP synthase membrane FO-subunits-including DAPIT-in INS-1E cells were found to be sensitive to lowering glucose down from 11 mM, in which these cells are routinely cultured. Depending on conditions, the diminished mRNA levels recovered when glucose was restored to 11 mM; or were elevated during further 120 min incubations with 20-mM glucose. Asking whether DAPIT expression may be elevated by hyperglycemia in vivo, we studied mice with hyaluronic acid implants delivering glucose for up to 14 days. Such continuous two-week glucose stimulations in mice increased DAPIT mRNA by >5-fold in isolated pancreatic islets (ATP synthase F1α mRNA by 1.5-fold). In INS-1E cells, the glucose-induced ATP increment vanished with DAPIT silencing (6% of ATP rise), likewise a portion of the mtDNA-copy number increment. With 20 and 11-mM glucose the phosphorylating/non-phosphorylating respiration rate ratio diminished to ~70% and 96%, respectively, upon DAPIT silencing, whereas net GSIS rates accounted for 80% and 90% in USMG5/DAPIT-deficient cells. Consequently, the sufficient DAPIT expression and complete ATP synthase assembly is required for maximum ATP synthesis and mitochondrial biogenesis, but not for insulin secretion as such. Elevated DAPIT expression at high glucose further increases the ATP synthesis efficiency.

• MeSH
• adenosintrifosfát metabolismus   MeSH
• beta-buňky cytologie   účinky léků   metabolismus   MeSH
• buněčné kultury MeSH
• buněčné linie MeSH
• glukosa aplikace a dávkování   farmakologie   MeSH
• konformace proteinů MeSH
• krysa rodu rattus MeSH
• kyselina hyaluronová chemie   MeSH
• membránové proteiny chemie   genetika   metabolismus   MeSH
• mitochondriální DNA účinky léků   genetika   MeSH
• mitochondrie účinky léků   genetika   metabolismus   MeSH
• molekulární modely MeSH
• myši MeSH
• upregulace * MeSH
• variabilita počtu kopií segmentů DNA účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Persistent organochlorine pollutants (POPs) gradually accumulate in the human organism due to their presence in the environment. Some studies have described a correlation between the level of POPs in the human body and the incidence of diabetes, but we know little about the direct effect of POPs on pancreatic beta-cells. We exposed pancreatic beta-cells INS1E to non-lethal concentrations of p,p'-DDT (1,1'-(2,2,2-Trichloroethane-1,1-diyl)bis(4-chlorobenzene)) and p,p'-DDE (1,1'-(2,2-dichloroethene-1,1-diyl)bis(4-chlorobenzene)) for 1 month, and assessed changes in protein expression and the intracellular insulin level. 2-D electrophoresis revealed 6 proteins with changed expression in cells exposed to p,p'-DDT or p,p'-DDE. One of the detected proteins - vitamin D-binding protein (VDBP) - was upregulated in both cells exposed to p,p'-DDT, and cells exposed to p,p'-DDE. Both exposures to pollutants reduced the intracellular level of insulin mRNA, proinsulin, and insulin monomer; p,p'-DDT also slightly reduced the level of hexameric insulin. Overexpression of VDBP caused by the stable transfection of beta-cells with the gene for VDBP decreased both the proinsulin and hexameric insulin level in beta-cells similarly to the reduction detected in cells exposed to p,p'-DDT. Our data suggest that in the cells exposed to p,p'-DDT and p,p'-DDE, the increased VDBP protein level decreased the proinsulin expression in an unknown mechanism.

• MeSH
• beta-buňky účinky léků   metabolismus   MeSH
• buněčné linie MeSH
• DDT toxicita   MeSH
• dichlordifenyldichlorethylen toxicita   MeSH
• inzulin metabolismus   MeSH
• krysa rodu rattus MeSH
• látky znečišťující životní prostředí toxicita   MeSH
• protein vázající vitamin D metabolismus   MeSH
• testy subchronické toxicity MeSH
• upregulace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Pancreatic β-cells are vulnerable to oxidative stress due to their low content of redox buffers, such as glutathione, but possess a rich content of thioredoxin, peroxiredoxin, and other proteins capable of redox relay, transferring redox signaling. Consequently, it may be predicted that cytosolic antioxidants could interfere with the cytosolic redox signaling and should not be recommended for any potential therapy. In contrast, mitochondrial matrix-targeted antioxidants could prevent the primary oxidative stress arising from the primary superoxide sources within the mitochondrial matrix, such as at the flavin (IF) and ubiquinone (IQ) sites of superoxide formation within respiratory chain complex I and the outer ubiquinone site (IIIQ) of complex III. Therefore, using time-resolved confocal fluorescence monitoring with MitoSOX Red, we investigated various effects of mitochondria-targeted antioxidants in model pancreatic β-cells (insulinoma INS-1E cells) and pancreatic islets. Both SkQ1 (a mitochondria-targeted plastoquinone) and a suppressor of complex III site Q electron leak (S3QEL) prevented superoxide production released to the mitochondrial matrix in INS-1E cells with stimulatory glucose, where SkQ1 also exhibited an antioxidant role for UCP2-silenced cells. SkQ1 acted similarly at nonstimulatory glucose but not in UCP2-silenced cells. Thus, UCP2 can facilitate the antioxidant mechanism based on SkQ1+ fatty acid anion- pairing. The elevated superoxide formation induced by antimycin A was largely prevented by S3QEL, and that induced by rotenone was decreased by SkQ1 and S3QEL and slightly by S1QEL, acting at complex I site Q. Similar results were obtained with the MitoB probe, for the LC-MS-based assessment of the 4 hr accumulation of reactive oxygen species within the mitochondrial matrix but for isolated pancreatic islets. For 2 hr INS-1E incubations, some samples were influenced by the cell death during the experiment. Due to the frequent dependency of antioxidant effects on metabolic modes, we suggest a potential use of mitochondria-targeted antioxidants for the treatment of prediabetic states after cautious nutrition-controlled tests. Their targeted delivery might eventually attenuate the vicious spiral leading to type 2 diabetes.

• MeSH
• antioxidancia farmakologie   MeSH
• beta-buňky účinky léků   metabolismus   patologie   MeSH
• fenantridiny MeSH
• kultivované buňky MeSH
• mitochondriální membrány účinky léků   metabolismus   patologie   MeSH
• mitochondrie účinky léků   metabolismus   patologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• organofosforové sloučeniny MeSH
• oxidace-redukce MeSH
• oxidační stres účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• uncoupling protein 2 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Reprogramming of non-endocrine pancreatic cells into insulin-producing cells represents a promising therapeutic approach for the restoration of endogenous insulin production in diabetic patients. In this paper, we report that human organoid cells derived from the pancreatic tissue can be reprogrammed into the insulin-producing cells (IPCs) by the combination of in vitro transcribed modified mRNA encoding transcription factor neurogenin 3 and small molecules modulating the epigenetic state and signalling pathways. Upon the reprogramming, IPCs formed 4.6 ± 1.2 % of the total cells and expressed typical markers (insulin, glucokinase, ABCC8, KCNJ11, SLC2A2, SLC30A8) and transcription factors (PDX1, NEUROD1, MAFA, NKX2.2, NKX6.1, PAX4, PAX6) needed for the proper function of pancreatic β-cells. Additionally, we have revealed a positive effect of ALK5 inhibitor RepSox on the overall reprogramming efficiency. However, the reprogrammed IPCs possessed only a partial insulin-secretory capacity, as they were not able to respond to the changes in the extracellular glucose concentration by increasing insulin secretion. Based on the achieved results we conclude that due to the incomplete reprogramming, the IPCs have immature character and only partial properties of native human β-cells.

• MeSH
• antigen AC133 metabolismus   MeSH
• beta-buňky cytologie   účinky léků   MeSH
• dospělí MeSH
• genetická transkripce účinky léků   MeSH
• inzulin biosyntéza   MeSH
• knihovny malých molekul farmakologie   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• organoidy cytologie   MeSH
• přeprogramování buněk účinky léků   genetika   MeSH
• proliferace buněk MeSH
• proteiny nervové tkáně genetika   metabolismus   MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• beta-buňky metabolismus   sekrece   účinky léků   MeSH
• diabetes mellitus 2. typu farmakoterapie   MeSH
• diabetická kardiomyopatie epidemiologie   komplikace   MeSH
• hodnocení rizik MeSH
• léková kontraindikace MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• thiazolidindiony aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Standardní léčbou diabetu vyvolaného ztrátou endogenní produkce inzulinu je dnes tzv. intenzifikovaná inzulinová léčba. Zavedení nových technologických metod aplikace inzulinu a monitorování koncentrací krevního cukru v podkoží posunulo možnosti dobré metabolické kontroly, ale problematiku rozvoje pozdních komplikací diabetu ani riziko problematických hypoglykemií neodstranilo. Cílem transplantace inzulin produkující tkáně, v současné době pomocí transplantace celého pankreatu či izolovaných Langerhansových ostrůvků, je obnova glukózou regulované inzulinové sekrece, zastavení progrese diabetických komplikací a zlepšení kvality života. Transplantace je většinou indikována u pacientů s již rozvinutými progresivními komplikacemi, kterým každodenní výkyvy glykemií výrazně narušují kvalitu života. Základním předpokladem je, že riziko transplantačního výkonu a trvalé imunosuprese bude vyváženo metabolickou stabilizací, kterou endogenní sekrece zajistí. Institut klinické a experimentální medicíny v Praze nabízí několik modalit, jejichž výběr závisí na stupni orgánového postižení, nebezpečí hypoglykemií a také na pacientově rozhodnutí.

Intensified insulin therapy represents currently the standard of care for diabetic subjects with loss of endogenous insulin production. Implementation of novel technological was of insulin Administration and glucose monitoring improved the level of metabolic control, however has not still prevented the develomment of organ compcilations and the risk of problematic hypoglycemias. The aims pancreas or pancreatic islet transplantaton are to restore glucose‑regulated insulin production, halt the progression of microangiopatic complication and to improve the patient´s qualiti of live. Transplantation is usually performed only in subjects with advanced aibetes complication, in thome the day to day glycemic excursions significantly impair the quality of life. Principal presumption is, that the risk of the transplant procedure and life‑long immunosupression will be compensated by stable metabolic controle due to restored endogenous insulin production. The Institute for Clinical and Experimental Medicine in Prague now offers several transplant modalities. Their selection depends ant he character of organ impairments, risk of hypoglycemia on standard insulin therapy and also on the patient´s decision.

• MeSH
• beta-buňky patologie   transplantace   účinky léků   MeSH
• biomedicínské technologie * metody   přístrojové vybavení   trendy   MeSH
• diabetes mellitus * prevence a kontrola   terapie   MeSH
• hypoglykemie prevence a kontrola   terapie   MeSH
• imunosupresivní léčba metody   trendy   využití   MeSH
• inzulinová rezistence fyziologie   imunologie   MeSH
• komplikace diabetu prevence a kontrola   terapie   MeSH
• Langerhansovy buňky imunologie   transplantace   MeSH
• Langerhansovy ostrůvky imunologie   MeSH
• lidé MeSH
• statistika jako téma MeSH
• transplantace buněk metody   využití   MeSH
• transplantace Langerhansových ostrůvků * metody   trendy   využití   MeSH
• transplantace tkání metody   trendy   využití   MeSH
• transplantační imunologie genetika   imunologie   účinky léků   MeSH
• výsledky a postupy - zhodnocení (zdravotní péče) MeSH
• Check Tag
• lidé MeSH