All-optical deconstruction of the islet wiring patterns underlying insulin secretion in health and disease

英国国家医疗服务体系将其年度预算的9%用于治疗糖尿病及其相关并发症，人们普遍预计到2035年这一数字将翻一番。目前，英国成年人口中糖尿病患病率为5.1%，其中2型糖尿病占大多数（90%）。这种危及生命的疾病状态的典型特征是胰岛素分泌β细胞群无法适应外周抵抗的增加。由此产生的代谢失调增加了一系列并发症的发生率，包括心血管疾病、肾和肝衰竭、视网膜变性和癌症。尽管在过去二十年中进行了大量的研究投资，但疾病患病率仍在上升。为了制止这一趋势，迫切需要新的研究途径来确定治疗靶点。最近，我们发现了葡萄糖和其他分泌物调节朗格汉斯胰岛胰岛素分泌的新途径。通过将复杂的原位成像方法与电路神经科学方法相结合来绘制细胞-细胞连接，我们和其他人已经证明β细胞在胰岛内连接自己作为葡萄糖和胰岛素响应子网络，支持同步活动。这些子网络协调胰岛素释放的功能获得，当β细胞分离或电解耦时，胰岛素释放会丢失。β细胞连通性的一个显著特征是超级连接枢纽的存在，它通过在遥远的胰岛区域之间协调和起搏反应来主导胰岛动力学。由于中心细胞是罕见的（每个胰岛有几十个），它们在面对随机损伤时是强健的，但在有针对性的损伤后容易崩溃，这种情况对胰岛功能将是灾难性的。因此，胰岛内胰岛素释放的调节，特别是中枢细胞，可能是胰腺基础设施在T2DM期间失效的关键组成部分。利用光遗传学和光药理学对单个细胞进行精确的毫秒级光学控制，本建议的目的是：1)询问胰岛动力学产生的线路模式；2)定义了枢纽在胰岛素释放中的功能作用的第一个蓝图；3)了解这些细胞的特殊之处；4)显示胰岛回路和中枢细胞功能如何在T2DM期间影响胰岛素分泌。预计这些研究将导致胰岛素释放的新途径的特征，这可能最终通过恢复功能性β细胞群来逆转T2DM。

The NHS spends 9% of its annual budget on treating diabetes and its associated complications, a figure widely projected to double by 2035. Diabetes prevalence is currently 5.1% of the UK adult population, with T2DM accounting for the majority (90%) of cases. This life-threatening disease state is typified by a failure of the insulin-secreting beta cell mass to adapt to increased peripheral resistance. The resulting metabolic dysregulation increases the incidence of a wide range of complications including cardiovascular disease, renal and liver failure, retinal degeneration, and cancer. Despite considerable research investment over the last two decades, disease prevalence is increasing. To halt or stop this trend, new avenues of investigation are urgently required to identify therapeutic targets. Recently, we have uncovered a new pathway by which glucose and other secretagogues regulate insulin secretion from the islets of Langerhans. By combining sophisticated in situ imaging approaches with circuit neuroscience methodology to map cell-cell connectivity, we and others have shown that beta cells wire themselves within islets as glucose- and incretin-responsive subnetworks which support synchronised activity. These subnetworks orchestrate a gain-of-function in insulin release that is lost when beta cells are dissociated or electrically uncoupled. A striking feature of beta cell connectivity is the existence of superconnected hubs that dominate islet dynamics by coordinating and pacemaking responses between distant islet regions. Since hub cells are rare events (dozens per islet), they are robust in the face of random insult but are prone to collapse following targeted insult, a scenario that would be catastrophic for islet function. Thus, the intraislet regulation of insulin release, and in particular hub cells, may be key components of the pancreatic infrastructure which fails during T2DM. Using optogenetics and photopharmacology to yield precise millisecond optical control over single cells, the aims of the present proposal are to: 1) interrogate the wiring patterns underlying generation of islet dynamics; 2) define the first blueprint for a functional role of hubs in insulin release; 3) understand what is special about such cells; and 4) show how the islet circuitry and hub cell function may be targeted during T2DM to impact insulin secretion. It is anticipated that these studies will lead to the characterisation of a novel route of insulin release, which may eventually allow the reversal of T2DM through restoration of the functional beta cell mass.