Defining the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes

全球2型糖尿病(T2D)的日益流行对未来几十年的全球健康构成了巨大的挑战，迫切需要新的战略来预防和治疗这种疾病。人们普遍认为，T2D是由于产生胰岛素的胰岛β细胞未能对年龄和肥胖相关的胰岛素抵抗引起的胰岛素产生增加的需求做出充分反应而导致的。然而，失败的原因仍然鲜为人知：例如，我们不知道这在多大程度上是β细胞自身问题的结果，而不是外部影响的影响。目前可用于T2D的许多治疗方法旨在促进胰岛素从胰腺释放，但它们对大多数患者只有部分有效。人们希望，更好地理解导致β细胞表现不佳的过程，将为更有效的治疗方案打开大门。从历史上看，定义这些过程的大部分工作都依赖于在各种糖尿病动物和细胞模型中进行的研究。虽然对这类模型的研究产生了许多有用的见解，但它与人类状况的相关性总是会受到质疑。使用次优模型可能在某种程度上解释了当新的、有希望的药物首次在人类身上进行测试时出现的高失败率。本研究的动机是这样一种观点，即解决方案至少部分在于扩大人类受试者在糖尿病研究中的使用。我们的研究整合了几个新的研究机会和策略，旨在提供与人类T2D发展机制直接相关的见解。我们试图回答的具体问题是：导致2型糖尿病的胰岛功能障碍的分子和生理机制是什么？我们的研究计划包括四个主要步骤--首先，我们将利用目前正在进行的大量基因研究的数据，确定与个人对T2D和/或相关特征的易感性明显相关的DNA序列差异(“DNA变体”)；-其次，我们将选择那些与糖尿病相关的DNA变体的子集，我们可以通过胰岛分泌缺陷的胰岛素来显示其对糖尿病的影响。我们将利用对人类受试者和最近可用的人类来源胰腺细胞系的研究来实现这一目标；-第三，也是该计划的核心，我们将从至少12,000名同意参与此类研究的个人中招募健康的人类志愿者。我们将选择携带感兴趣的DNA变体的志愿者，以及特征相似的不携带的志愿者，并将进行详细的生理学测试，以梳理出两组之间微妙的新陈代谢差异。-最后，我们将进行涉及人类受试者和人类衍生细胞的进一步研究，以确定这些DNA变体发挥作用的机制，以及基因功能改变如何改变个体患T2D的风险。通过更好地理解与T2D相关的胰岛功能障碍所涉及的过程，这项研究将为开发针对高质量靶点的新药铺平道路，这些新药已经从治疗潜力和副作用的角度在人类受试者中得到验证。这项工作还可能导致识别新的胰岛功能标记物，这些标记物在监测疾病进展、预测疾病风险和评估治疗反应方面具有临床价值。这项研究计划的实施将具有挑战性，但它代表了一种强大的战略，可以提供精确的生物学见解，形成原则性和系统性努力的重要组成部分，以减少T2D对全球健康的影响。

The growing prevalence of Type 2 diabetes (T2D) worldwide represents a massive challenge to global health in the decades to come, and novel strategies for the prevention and the treatment of this condition are urgently required. It is widely accepted that T2D results from a failure of the insulin-producing pancreatic beta-cells to respond adequately to demands for increased insulin production resulting from age- and obesity-related insulin resistance. However, the reasons for that failure remain poorly understood: it is not known for example how far this is the consequence of problems within the beta-cells themselves as opposed to the impact of external influences. Many of the treatments currently available for T2D are designed to bolster insulin release from the pancreas but they are only partially effective in most patients. The hope is that a better understanding of the processes responsible for the failing beta-cell performance will open the door to more powerful options for treatment. Historically, much of the work to define these processes has relied on studies conducted in a variety of animal and cellular models of diabetes. Whilst studies in such models have generated many useful insights, the relevance to the human situation can always be questioned. The use of suboptimal models may go some way to explaining the high failure rates seen when new, promising drugs are first tested in man.The present study is motivated by the view that the solution lies, at least in part, in the extended use of human subjects in diabetes research. Our research integrates several novel research opportunities and strategies, and aims to deliver insights that are of direct relevance to the mechanisms driving development of T2D in man.The specific question we seek to answer is this: "What are the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes?". Our research plan involved four main steps- First, we will exploit data from a number of massive genetic studies that are currently underway to identify sets of DNA sequence differences ("DNA variants") that are clearly associated with individual predisposition to T2D and/or related traits; - Second, we will select a subset of those diabetes-associated DNA variants that we can show exert their diabetes-effect via defective insulin production from the pancreatic islets. We will use studies of human subjects and of recently-available human-derived pancreatic cell-lines to achieve this;- Third, and at the core of the program, we will recruit healthy human volunteers from a pool of at least 12,000 individuals who have agreed to participate in studies such as these. We will select volunteers who carry the DNA variants of interest, and individuals with similar characteristics who do not, and will conduct detailed tests of physiology designed to tease out subtle metabolic differences beween the two groups. - Finally, we will perform further rounds of studies involving both human subjects and human-derived cells to define the mechanisms through which those DNA variants are acting, and how altered gene function is modifying an individual's risk of T2D.By delivering an improved understanding of the processes involved in T2D-associated islet dysfunction, this research will pave the way for development of novel drugs acting against high-quality targets that have been validated, from the perspectives of both therapeutic potential and side-effect profile, in human subjects. The work may also lead to identification of new markers of islet function that have clinical value in monitoring of disease progression, prediction of disease risk and evaluating treatment response. This research program will be challenging to implement, but it represents a powerful strategy for delivering the precise biological insights that form an essential part of a principled and systematic effort to reduce the impact of T2D on global health.