Optimising islet transplantation therapy by targeting the liver niche to promote the long-term engraftment and function of human islets.

糖尿病是最常见的慢性疾病之一，影响7%的人口。大约15%的糖尿病患者患有1型糖尿病，依赖胰岛素注射来控制血糖水平，由于注射胰岛素的需要，超过25%的人反复出现低血糖读数需要帮助（严重低血糖），同时与低血糖相关的警告症状（颤抖、头晕出汗）消失，使他们的生命处于危险之中。胰岛移植是将含有胰岛素分泌细胞的胰岛从供体胰腺中纯化出来，移植到1型糖尿病患者体内，持续有效地稳定血糖控制，降低低血糖，挽救生命。我们的NHS资助的苏格兰胰岛移植项目成立于2009年，从那时起，我们完成了英国60%的移植手术。我们的移植患者低血糖发作次数减少，低血糖意识恢复，血糖控制更加稳定，注射胰岛素量显著减少，生活质量得到改善。此外，有证据表明糖尿病相关并发症的进展延迟。然而，患者需要来自至少两个供体胰腺的胰岛：胰岛在首次移植时没有血液供应，超过60%的胰岛因易在血液供应建立之前死亡而丢失。随着时间的推移，胰岛移植功能也逐渐恶化；胰岛数量有限的胰腺不能使用，因为它们不会影响血糖控制，而且患者目前在全国等待名单上等待不止一个。迫切需要提高胰岛移植效率的策略。包括血管内皮生长因子（VEGF）在内的生长因子可用于促进血管形成，并已在实验中以不同的方式用于修复血管，现在计划已将这些因子推进临床试验。角质细胞生长因子（KGF）是另一种生长因子，被许可用于人类。我们在诺丁汉大学和爱丁堡大学的实验室已经产生了重要的实验数据。首先，人类KGF可以配制成针对肝脏的特定颗粒。通过小鼠模型，我们已经证明这些颗粒可以促进肝脏内细胞的增殖，而其他器官中没有其他细胞显示出增殖。用1型糖尿病小鼠模型，我们将装载KGF的颗粒的小鼠胰岛移植到肝脏中，结果表明，与单独接受胰岛的小鼠相比，这导致了胰岛在肝脏中的更多保留，以及在短期和长期内更好的血糖控制，糖尿病的治愈率更高。我们目前正在检查胰岛移植部位，以调查其中是否有更多的血管，这将支持KGF不仅促进肝脏内细胞增殖，而且还导致胰岛和肝脏之间血管形成的概念。值得注意的是，这些微粒可以用于人体。这些实验的目的是用人体胰岛（局部分离的人类胰岛）测试这些颗粒，并确定将装载KGF的颗粒与胰岛一起移植到小鼠肝脏中，是否会在长期控制血糖水平方面产生益处，从而导致移植的功能更长。我们将进行研究，了解这些颗粒是如何工作的，并将通过灵敏的成像技术跟踪颗粒，以确定它们的目标。这些研究可能会导致首次人体研究，使更多的糖尿病患者得到治疗。

Diabetes mellitus is one of the most common chronic conditions affecting 7% of the population. Approximately 15% of people with diabetes have Type 1 diabetes and are dependent on insulin injections to control blood glucose levels and due to inject insulin requirements, over 25 percent of people suffered repeated episodes of low blood glucose readings requiring help (severe hypoglycaemia) and at the time the warning symptoms associated with the hypoglycaemia (shakiness, dizziness sweating) are lost putting their lives at risk.Islet transplantation whereby islets which contain insulin secreting cells are purified from donor pancreases and transplanted into subjects with Type 1 diabetes, consistently and effectively stabilises blood glucose control reducing hypoglycaemia iand saves lives. Our NHS funded islet transplant programme for Scotland was established in 2009 and since this time we have done 60% of the transplants in the UK. Our transplanted patients have had fewer episodes of hypoglycaemia, regained awareness of hypoglycaemia and experienced more stable blood glucose control With significant reductions the amount of insulin they inject and reported improved quality-of-life. Additionally there is evidence of delayed progression from diabetes related complications.However patients require islets from at least 2 donor pancreases: islets do not have a blood supply when first transplanted and over 60% of islets are lost as they are susceptible to dying before a blood supply is established. There is also a gradual deterioration in islet graft function over time; pancreases with marginal numbers of islets cannot be used because they will not impact on blood glucose control and patients are currently awaiting more than onethe national waiting list. Strategies to improve the efficiency of islet transplantation are urgently needed.Growth factors including vascular endothelial derived growth factor (VEGF) can be used to promote blood vessel formation and have been utilised in different ways to repair blood vessels experimentally and now programmes have taken these factors forward into clinical trials. Keratinocyte Growth Factor (KGF) is another growth factor, licensed for specific use in man. Our laboratories at the University of Nottingham and University of Edinburgh have generated important experimental data. Firstly human KGF can be formulated into specific particles which target the liver. Using a mouse model we have shown that these particles can promote multiplication (=proliferation) of cells within the liver with no other cells in other organs demonstrating proliferation. Using a mouse model of Type 1 diabetes we have transplanted mouse islets with these particles loaded with KGF into the liver and have shown that this results in greater retention of the islets in the liver as well as better blood glucose control in the short and longer term with greater cure rate of diabetes versus those mice that received the islets alone. We are currently examining the islet transplant site to investigate if there are more blood vessels in it, which would support the concept that KGF promotes not only cells within the liver to proliferate but also that it causes blood vessel formation between the islets and the liver. Significantly these particles can be used in man.The aim of these experiments is to test these particles with human islets,(human islets isolated locally) and determine whether transplanting the particles loaded with KGF along with the islets into the liver of a mouse produces benefit in terms of controlling blood glucose levels in the long term leading to transplants which would function for longer. We will perform studies to understand how these particles work and will track the particles by sensitive imaging techniques to confirm where they target. These studies will potentially lead to first-in-man studies allowing more people with diabetes to be treated.