Understanding the hepatic microenvironment to improve function and survival of transplanted pancreatic islets in diabetes

了解肝脏微环境以改善糖尿病患者移植胰岛的功能和存活率

• 批准号: MR/X00211X/1
• 负责人: Daniel Doherty
• 金额: $ 38.96万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX00211X%2F1
• 关键词: Understanding; hepatic; microenvironment; improve; function

A patient with Type 1 Diabetes Mellitus (T1DM) administers 65,000 insulin injections and checks their blood sugar 80,000 times during their lifetime. T1DM results from destruction of beta-cells by the body's own defensive cells. Beta-cells are specialist insulin producing cells in the Islets of Langerhans which are hormone producing sections scattered within the pancreas. Insulin is a signalling molecule which controls blood sugar levels. This destruction, prevents the beta-cells in the pancreas from producing insulin, meaning that blood sugar levels will rise out of control. As a result, patient's need to inject insulin regularly, throughout the day, to control their sugar levels. This affects approximately 400,000 people in the UK, 29,000 of whom are children with a predicted rise to 600,000 and 48,000 in 2035. Worldwide this figure is approximately 37 million. This represents a significant financial burden for the healthcare system and in 2010/11 the NHS spent £1 billion on direct patient care for T1DM. Severe T1DM can cause loss of vision, kidney failure, strokes and heart disease causing debilitating health problems and death at a young age.Islet transplantation offers an avenue to help these patients improve their sugar control by replacing the islet cells which have been destroyed. It allows patients to produce insulin again without injections. It involves taking islet cells from the pancreas of an organ donor and separating the insulin producing islet cells out, before adding them to the liver through an infusion. Islet transplant works well for some patients, but it is not perfect. It can stop patients from having dangerous levels of poor sugar control, but many patients will continue to need additional insulin injections even after islet transplant and some transplants will only work for a short period of time. Most patients will also need to have more than one islet transplant, meaning that less patients can benefit from this treatment as the number of organ donors is very limited. Many of the islet cells do not survive in the liver after transplant. We will investigate why this happens and how this can be improved, so that islet transplants can work better, for longer, for more people.We will look closely at islet cells in normal pancreas samples in the laboratory so I can establish the support they receive from other neighbouring cells which encourage them to work well in their normal environment. We will then compare what we discover to samples of islet cell infusions. This will allow us to see what supporting cells and pathways are present after the islets have been separated from their neighbouring cells and the rest of the pancreas. We will then also compare the islet cell environment after they have been placed into the liver and how the neighbouring liver cells influence islet cell survival and function. We hope to find ways to create a more supportive environment for islet cells after separation from the pancreas and after transplant, so that more cells survive and produce insulin more effectively. Answering these questions will make islet transplant available for more people as repeat transplants will not be required. Therefore, more patients suffering from the complications of severe T1DM can benefit from this treatment.Please follow the link to my video for a visual summary of my research.https://youtu.be/bWfo4JknIx8

一名 1 型糖尿病 (T1DM) 患者一生中注射了 65,000 次胰岛素，并检查了 80,000 次血糖。 T1DM 是由于人体自身防御细胞破坏 β 细胞所致。 β细胞是朗格汉斯岛中专门产生胰岛素的细胞，朗格汉斯岛是分散在胰腺内的激素产生部分。胰岛素是控制血糖水平的信号分子。这种破坏会阻止胰腺中的β细胞产生胰岛素，这意味着血糖水平将失控上升。因此，患者需要全天定期注射胰岛素，以控制血糖水平。这影响了英国约 400,000 人，其中 29,000 人是儿童，预计到 2035 年将增加到 600,000 人和 48,000 人。在全球范围内，这一数字约为 3700 万。这给医疗保健系统带来了巨大的财务负担，2010/2011 年，NHS 花费了 10 亿英镑用于 T1DM 患者的直接护理。严重的 T1DM 可导致视力丧失、肾衰竭、中风和心脏病，从而导致健康问题和年轻时死亡。胰岛移植提供了一种途径，通过替换已破坏的胰岛细胞来帮助这些患者改善血糖控制。它允许患者无需注射即可再次产生胰岛素。它涉及从器官捐献者的胰腺中取出胰岛细胞，并将产生胰岛素的胰岛细胞分离出来，然后通过输注将其添加到肝脏中。胰岛移植对某些患者效果良好，但并不完美。它可以阻止患者出现血糖控制不良的危险水平，但即使在胰岛移植后，许多患者仍需要额外注射胰岛素，并且某些移植只能在短时间内发挥作用。大多数患者还需要进行不止一次胰岛移植，这意味着由于器官捐献者的数量非常有限，能够从这种治疗中受益的患者较少。许多胰岛细胞在移植后无法在肝脏中存活。我们将研究为什么会发生这种情况以及如何改进，以便胰岛移植能够更好地、更长时间地为更多的人服务。我们将在实验室中仔细观察正常胰腺样本中的胰岛细胞，以便我可以确定它们从其他邻近细胞那里获得的支持，从而鼓励它们在正常环境中良好地工作。然后我们将把我们的发现与胰岛细胞输注样本进行比较。这将使我们能够看到胰岛与其邻近细胞和胰腺的其余部分分离后存在哪些支持细胞和通路。然后，我们还将比较胰岛细胞放入肝脏后的环境以及邻近肝细胞如何影响胰岛细胞的存活和功能。我们希望找到方法，为从胰腺分离和移植后的胰岛细胞创造一个更有支持性的环境，以便更多的细胞存活并更有效地产生胰岛素。回答这些问题将使更多的人可以进行胰岛移植，因为不需要重复移植。因此，更多患有严重 T1DM 并发症的患者可以从这种治疗中受益。请点击我的视频链接，查看我的研究的直观总结。https://youtu.be/bWfo4JknIx8

项目成果

Unlocking the post-transplant microenvironment for successful islet function and survival.

• DOI: 10.3389/fendo.2023.1250126
• 发表时间: 2023
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2