V průběhu čtyřiceti let vývoje se transplantace pankreatu stala v České republice běžnou léčebnou metodou, která je zvláště vhodná pro pacienty současně podstupující transplantaci ledviny z důvodu dlouho trvajícího diabetu 1. typu. Oproti samostatné transplantaci ledviny zlepšuje kvalitu života i dlouhodobé přežití. Vede k téměř úplné normalizaci glykemií bez potřeby injekčního inzulinu a bez rizika hypoglykemií. Jako samostatný výkon suverénně léčí syndrom porušeného vnímání hypoglykemie u osob, u nichž edukace a použití dostupných technických prostředků nebyly dostatečně efektivní. V současné době existuje v České republice komplexní program, který dovoluje využít nabídku pankreatů od zemřelých dárců a různým typům příjemců s diabetem 1. a výjimečně i 2. typu poskytnout efektivní a relativně bezpečnou náhradu nefunkčních beta buněk s přihlédnutím k jejich celkovému zdravotnímu stavu, operačnímu riziku a také jejich volbě. Popisujeme dlouhodobé zkušenosti s transplantační léčbou diabetu v IKEM, na které se podílí odborníci z řad transplantačních chirurgů, diabetologů, nefrologů, imunologů a dalších specialistů.
During 40 years of development, pancreas transplantation has become a common treatment method in the Czech Republic, which is particularly suitable for patients undergoing simultaneous kidney transplantation due to long-standing type 1 diabetes. Compared to kidney transplantation alone, it improves quality of life and long-term survival. It leads to almost complete normalisation of glycaemia without the need for insulin injections and without the risk of hypoglycaemia. As a stand-alone procedure, it sovereigny treats the syndrome of impaired hypoglycaemia perception in people for whom education and the use of available technical means have not been sufficiently effective. Currently, there is a comprehensive program in the Czech Republic that allows to use the supply of pancreases from deceased donors and to provide various types of recipients with type 1 and, exceptionally, type 2 diabetes with an effective and relatively safe replacement of non-functioning beta cells, taking into account their overall health status, surgical risk and also their choice. We describe the long-term experience with transplantation treatment of diabetes at IKEM, involving experts from transplant surgeons, diabetologists, nephrologists, immunologists and other specialists.
Osteoporosis occurs in every third individual after simultaneous pancreas kidney transplantation (SPKT). Currently used bone measures insufficiently predict their fracture risk. Lumbar spine Trabecular bone score (TBS) and distal radius areal and volumetric bone mineral density (BMD) were monitored for the first time in patients with type 1 diabetes and chronic renal failure after SPKT with steroid-sparing protocol. In 33 subjects (mean age 43.4 ± 9.8 years), dual-energy X-ray absorptiometry and peripheral quantitative computed tomography were performed just after SPKT (baseline) and one and three years later. While TBS Z-scores increased (-1.1 ± 1.2 and -0.3 ± 1.0; p˂0.001, at baseline and year three, respectively), trabecular volumetric BMD Z-scores at distal radius metaphysis did not change during the study (-1.3 ± 1.3 and -1.3 ± 1.0; p = 0.38). Similarly, areal BMD Z-scores increased at lumbar spine, total hip and femoral neck (all p < 0.01), but not at the distal radius. SPKT induced bone measures' improvement at lumbar spine and hip but not at distal radius. Before suggesting changes in current clinical care, predictive value of individual bone measures or its combination for fracture risk assessment remains to be elucidated.
- Publikační typ
- časopisecké články MeSH
Diabetická retinopatie je obávanou komplikací diabetu, která je velmi často zastoupena u kandidátů transplantační léčby diabetu. Po úspěšné transplantaci pankreatu se u těchto pacientů obnoví endogenní regulace metabolismu glukózy a dosahují fyziologické nebo téměř fyziologické hodnoty glykemie. Pokud jde o retinopatii, většina kandidátů kombinované transplantace pankreatu a ledviny má již v době indikace velmi pokročilá stadia retinopatie s proliferací (70-80 % pacientů). U kandidátů transplantace samotného pankreatu či Langerhansových ostrůvků nacházíme spektrum nálezů širší a jsou častěji zastoupené i méně závažné formy. Podle dosavadních poznatků sice mohou v období časně po transplantaci ještě doznívat rozběhnuté patologické procesy v sítnici, avšak z dlouhodobého hlediska se zpravidla projevuje pozitivní vliv normoglykemie s následnou stabilizací či dokonce zlepšením sítnicových změn.
Diabetic retinopathy is a feared complication of diabetes very often present in transplant therapy candidates. After successful transplantation, endogenous regulation of glucose metabolism is restored, and these patients can reach normal (or near-normal) glycaemia levels. As for retinopathy, majority of pancreas and kidney transplant recipients (70-80 %) have already very advanced stages of retinopathy with proliferative changes. In pancreas transplant alone and pancreatic islet transplant recipients, the variety of retinopathy stages is wider, where also milder stages are seen more frequently. According to the evidence so far, some of the pathological processes in the retina may continue and gradually fade in the early posttransplant period, nevertheless in the long-term horizon we can observe beneficial effects of normoglycaemia with stabilisation or even improvement.
NEUROD1 is a transcription factor that helps maintain a mature phenotype of pancreatic β cells. Disruption of Neurod1 during pancreatic development causes severe neonatal diabetes; however, the exact role of NEUROD1 in the differentiation programs of endocrine cells is unknown. Here, we report a crucial role of the NEUROD1 regulatory network in endocrine lineage commitment and differentiation. Mechanistically, transcriptome and chromatin landscape analyses demonstrate that Neurod1 inactivation triggers a downregulation of endocrine differentiation transcription factors and upregulation of non-endocrine genes within the Neurod1-deficient endocrine cell population, disturbing endocrine identity acquisition. Neurod1 deficiency altered the H3K27me3 histone modification pattern in promoter regions of differentially expressed genes, which resulted in gene regulatory network changes in the differentiation pathway of endocrine cells, compromising endocrine cell potential, differentiation, and functional properties.
We previously developed a deep learning-based web service (IsletNet) for an automated counting of isolated pancreatic islets. The neural network training is limited by the absent consensus on the ground truth annotations. Here, we present a platform (IsletSwipe) for an exchange of graphical opinions among experts to facilitate the consensus formation. The platform consists of a web interface and a mobile application. In a small pilot study, we demonstrate the functionalities and the use case scenarios of the platform. Nine experts from three centers validated the drawing tools, tested precision and consistency of the expert contour drawing, and evaluated user experience. Eight experts from two centers proceeded to evaluate additional images to demonstrate the following two use case scenarios. The Validation scenario involves an automated selection of images and islets for the expert scrutiny. It is scalable (more experts, images, and islets may readily be added) and can be applied to independent validation of islet contours from various sources. The Inquiry scenario serves the ground truth generating expert in seeking assistance from peers to achieve consensus on challenging cases during the preparation for IsletNet training. This scenario is limited to a small number of manually selected images and islets. The experts gained an opportunity to influence IsletNet training and to compare other experts' opinions with their own. The ground truth-generating expert obtained feedback for future IsletNet training. IsletSwipe is a suitable tool for the consensus finding. Experts from additional centers are welcome to participate.
BACKGROUND: Glucose homeostasis is dependent on functional pancreatic α and ß cells. The mechanisms underlying the generation and maturation of these endocrine cells remain unclear. RESULTS: We unravel the molecular mode of action of ISL1 in controlling α cell fate and the formation of functional ß cells in the pancreas. By combining transgenic mouse models, transcriptomic and epigenomic profiling, we uncover that elimination of Isl1 results in a diabetic phenotype with a complete loss of α cells, disrupted pancreatic islet architecture, downregulation of key ß-cell regulators and maturation markers of ß cells, and an enrichment in an intermediate endocrine progenitor transcriptomic profile. CONCLUSIONS: Mechanistically, apart from the altered transcriptome of pancreatic endocrine cells, Isl1 elimination results in altered silencing H3K27me3 histone modifications in the promoter regions of genes that are essential for endocrine cell differentiation. Our results thus show that ISL1 transcriptionally and epigenetically controls α cell fate competence, and ß cell maturation, suggesting that ISL1 is a critical component for generating functional α and ß cells.
- Publikační typ
- časopisecké články MeSH
Infusing pancreatic islets into the portal vein currently represents the preferred approach for islet transplantation, despite considerable loss of islet mass almost immediately after implantation. Therefore, approaches that obviate direct intravascular placement are urgently needed. A promising candidate for extrahepatic placement is the omentum. We aimed to develop an extracellular matrix skeleton from the native pancreas that could provide a microenvironment for islet survival in an omental flap. To that end, we compared different decellularization approaches, including perfusion through the pancreatic duct, gastric artery, portal vein, and a novel method through the splenic vein. Decellularized skeletons were compared for size, residual DNA content, protein composition, histology, electron microscopy, and MR imaging after repopulation with isolated islets. Compared to the other approaches, pancreatic perfusion via the splenic vein provided smaller extracellular matrix skeletons, which facilitated transplantation into the omentum, without compromising other requirements, such as the complete depletion of cellular components and the preservation of pancreatic extracellular proteins. Repeated MR imaging of iron-oxide-labeled pancreatic islets showed that islets maintained their position in vivo for 49 days. Advanced environmental scanning electron microscopy demonstrated that islets remained integrated with the pancreatic skeleton. This novel approach represents a proof-of-concept for long-term transplantation experiments.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Islet transplantation represents an established therapeutic option for people with type 1 diabetes who have hypoglycemia unawareness syndrome and frequent problematic hypoglycemic episodes when other methods comprising diabetes education and use of technological support fail. Because the current standard method of islet infusion into the liver has some limitations, novel approaches are under investigation. METHODS: We report our first results with 2 cases of islet transplantation into an omental pouch using a biocompatible plasma-fibrin gel. The recipients received 12,350 and 5,350 islet equivalents per kilogram that were mixed with autologous plasma, seeded during a laparoscopic procedure on the omentum, overlaid with human thrombin solution, and fixed by flapping the omentum over. RESULTS: During a 9-month follow-up, neither patient experienced any moderate or severe hypoglycemia. Their glucose control significantly improved, insulin dose decreased by approximately 50%, and C-peptide at 1 year was 0.22 and 0.14 pmol/mL, respectively. The postoperative course was uneventful, but C-peptide production in the first patient progressively declined at 1 year and hypoglycemic episodes recurred. CONCLUSIONS: Though the results for these first 2 cases are not fully satisfactory, we have demonstrated the feasibility, safety, and ability of this novel method to restore insulin production. Further refinements to improve immediate islet survival seem necessary.
- MeSH
- biomedicínský výzkum * MeSH
- C-peptid MeSH
- diabetes mellitus 1. typu * farmakoterapie chirurgie MeSH
- hypoglykemie * farmakoterapie MeSH
- hypoglykemika terapeutické užití MeSH
- inzulin terapeutické užití MeSH
- krevní glukóza MeSH
- Langerhansovy ostrůvky * MeSH
- lidé MeSH
- omentum chirurgie MeSH
- thrombin terapeutické užití MeSH
- transplantace Langerhansových ostrůvků * škodlivé účinky metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Transplantace Langerhansových ostrůvků představuje zavedenou metodu léčby pacientů s diabetem 1. typu se syndromem porušeného vnímání hypoglykemie, u kterých selhává použití moderních technologických postupů. Nejčastěji se jedná o radiointervenční metodu, při které se suspenze pankreatických ostrůvků podává perkutánně zavedeným katétrem do větve portální žíly. Ačkoliv se na rozdíl od orgánové transplantace pankreatu jedná o výkon jen minimálně invazivní, řada technických problémů zůstává nevyřešena. Mezi možné komplikace patří zejména krvácení a trombóza portální žíly. Na rozdíl od svého přirozeného umístění disperzně ve tkáni exokrinního pankreatu jsou izolované transplantované ostrůvky v jaterním parenchymu vystaveny bezprostřední hypoxii, přímému působení toxinů a imunosupresivních léčiv. Přímý kontakt s krví příjemce vyvolává bezprostřední zánětlivou reakci, tzv. IBMIR (instant blood mediated inflammatory reaction), díky které i více než polovina transplantovaných buněk po aplikaci zaniká. Velikost ostrůvkového štěpu je proto často nedostatečná a řada pacientů potřebuje po výkonu určité množství exogenního inzulinu. To všechno jsou důvody, proč hledáme pro ostrůvkový štěp jiné místo transplantace s příznivějšími podmínkami pro dlouhodobé přežívání. V experimentálním i klinickém výzkumu byla zkoušena různá aplikační místa, jejichž výhody a nevýhody shrneme v tomto sdělení. Jako nejnadějnější se v současné době jeví transplantace do velkého omenta, která již byla na několika pracovištích klinicky použita.
Pancreatic islets transplantation is an established treatment method for type 1 diabetic patients with the hypoglycemia unawareness syndrome in whom a therapy with modern technologies fails. Islet transplantation is most commonly done using an interventional radiology method: a tissue suspension of pancreatic islets is applied into a branch of the portal vein through a percutaneously installed catheter. Although being minimally invasive unlike pancreas organ transplant, this method is associated with many technical difficulties. Possible complications of the procedure include hemorrhage and portal vein thrombosis. Unlike their natural dispersed localization in exocrine pancreas, isolated pancreatic islets are exposed to hypoxia, toxins and immunosuppressive drugs in the liver parenchyma. Direct contact with the recipient’s blood causes an instant blood mediated inflammatory reaction (IBMIR) resulting in the death of more than half of the pancreatic islets shortly after their application. Therefore the size of the islet graft is often insufficient and a number of transplanted patients require administration of exogenous insulin. All of these are reasons for seeking an alternative transplantation site with more hospitable conditions for long-term islet survival. Various transplantation sites have been tested in experimental and clinical research. The advantages and disadvantages of some of them are summarized in this paper. Currently, transplantation into the greater omentum seems most promising, which has already been used in clinical practice at several institutions.
- Klíčová slova
- syndrom porušeného vnímání hypoglykemie,
- MeSH
- diabetes mellitus 1. typu chirurgie MeSH
- lidé MeSH
- omentum MeSH
- transplantace Langerhansových ostrůvků * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
