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

NHS将其年度预算的9%用于治疗糖尿病及其相关并发症，预计到2035年这一数字将翻一番。糖尿病患病率目前占英国成年人群的5.1%，其中T2 DM占大多数（90%）病例。这种危及生命的疾病状态的典型特征是分泌胰岛素的β细胞群不能适应增加的外周阻力。由此产生的代谢失调增加了各种并发症的发生率，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，但疾病的流行率仍在上升。为了制止或阻止这一趋势，迫切需要新的研究途径来确定治疗靶点。最近，我们发现了一个新的途径，葡萄糖和其他促分泌素调节胰岛素分泌的胰岛。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细胞在胰岛内作为葡萄糖和肠促胰岛素响应子网络连接起来，支持同步活动。这些子网络协调胰岛素释放中的功能获得，当β细胞解离或电解偶联时，该功能丧失。β细胞连接的一个显著特征是存在超级连接枢纽，其通过在遥远的胰岛区域之间协调和起搏反应来支配胰岛动力学。由于枢纽细胞是罕见的事件（每个胰岛几十个），它们在面对随机损伤时是稳健的，但在靶向损伤后容易崩溃，这种情况对胰岛功能来说是灾难性的。因此，胰岛内调节胰岛素释放，特别是中枢细胞，可能是T2 DM期间胰腺基础结构失效的关键组成部分。使用光遗传学和生物药理学来产生对单细胞的精确毫秒光学控制，本提案的目的是：1）询问胰岛动力学产生的基础布线模式; 2）定义枢纽在胰岛素释放中的功能作用的第一个蓝图; 3）理解这些细胞的特殊之处;和4）显示在T2 DM期间如何靶向胰岛回路和中枢细胞功能以影响胰岛素分泌。预计这些研究将导致对胰岛素释放新途径的表征，这可能最终允许通过恢复功能性β细胞群来逆转T2 DM。

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.