Investigating the role of immature beta cells in insulin release from the intact islet

当胰岛β细胞不能释放足够的胰岛素来对抗激素抵抗时，就会发生2型糖尿病(T2 DM)。由此导致的血糖水平上升会导致一系列严重的并发症，包括心血管疾病、肾功能衰竭和肝功能衰竭、视网膜变性和癌症。因此，T2 DM被认为是一种迫在眉睫的医疗危机，在英国每10个成年人中就有1人受到影响，消耗了NHS年度预算的9%。尽管进行了密集的研究工作，T2 DM的发病率仍在继续上升，预计到2035年，NHS的支出将翻一番。为了有希望阻止这一趋势，我们迫切需要开辟新的研究途径，以确定机制和治疗靶点。我们和其他人在过去几年的研究表明，并不是所有的β细胞都是平等的。就像社会一样，β细胞具有不同的年龄、能力和能力。当这些不同的β细胞之间的比例变得不平衡时，例如在肥胖、衰老或糖尿病期间，胰岛素的释放就会下降。特别是，年轻或不成熟的β细胞占主导地位与产生更多的β细胞有关，但代价是胰岛素的释放。尽管如此，人们对健康成人胰腺中通常存在的未成熟β细胞几乎一无所知。我们最新的研究表明，与预期相反，未成熟的β细胞实际上可能在调节胰岛素释放方面发挥核心作用。我们现在的目标是：1)研究未成熟细胞的丧失如何影响其他更成熟的β细胞的行为；2)使用LIGH来控制单个β细胞的成熟状态，以直接探索它们对胰岛素释放的贡献；3)建立小鼠模型，在此模型中，使用食物中的药物可以使未成熟的β细胞变得更成熟；4)确定未成熟的β细胞的丧失是否易患T2 DM。预计这些研究将提供胰岛素释放的最新蓝图，与T2 DM治疗以及干细胞移植的胰岛生成相关。

Type 2 diabetes mellitus (T2DM) occurs when pancreatic beta-cells are unable to release enough insulin to combat resistance to the hormone. The resulting increase in blood glucose levels drives a range of severe complications including cardiovascular disease, renal and liver failure, retinal degeneration and cancer. As such T2DM is considered an immediate healthcare crisis, affecting 1 in 10 adults in the UK and consuming 9% of the NHS annual budget. Despite intensive research efforts, T2DM incidence continues to rise and NHS spend is projected to double by 2035. To have any hope of halting this trend, we urgently need to open up new research avenues to identify mechanisms and therapeutic targets. Research from us and others over the past few years has shown that not all beta-cells are equal. Much like society, beta-cells possess different ages, abilities and capacities. When the proportions between these different beta-cells become imbalanced, for example during obesity, ageing or diabetes, then insulin release declines. In particular, predominance of younger or immature beta-cells is associated with generation of more beta-cells, but at the expense of insulin release. Despite this, practically nothing is known about the immature beta-cells that are normally resident in the healthy adult pancreas. Our most recent studies have shown that, contrary to expectation, immature beta-cells might in fact play a central role in regulating insulin release. We now aim to: 1) investigate how loss of immature cells influences behaviour of the other, more mature beta-cells;2) control the maturity status of individual beta-cells using light to directly explore their contribution to insulin release; 3) develop a mouse model where immature beta-cells can be made to be more mature using drugs in the food; 4) determine whether loss of immature beta-cells predisposes to T2DM. It is anticipated that these studies will provide an updated blueprint for insulin release, with relevance for T2DM treatment as well as the generation of islets from stem cells for transplantation.