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

定义导致 2 型糖尿病的胰岛功能障碍的分子和生理机制

• 批准号: MR/L020149/1
• 负责人: Mark Maccarthy
• 金额: $ 314.63万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL020149%2F1
• 关键词: Defining; molecular; physiological; mechanisms; pancreatic

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.

2型糖尿病（T2 D）在全球范围内的日益流行代表了未来几十年对全球健康的巨大挑战，迫切需要预防和治疗这种疾病的新策略。人们普遍认为，T2 D是由于产生胰岛素的胰腺β细胞不能充分响应由年龄和肥胖相关的胰岛素抵抗引起的增加胰岛素产生的需求而引起的。然而，这种失败的原因仍然知之甚少：例如，不知道这在多大程度上是β细胞本身问题的结果，而不是外部影响的影响。目前可用于T2 D的许多治疗方法旨在促进胰腺的胰岛素释放，但它们在大多数患者中仅部分有效。希望更好地了解导致β细胞性能下降的过程将为更强大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。虽然对这些模型的研究产生了许多有用的见解，但与人类状况的相关性总是受到质疑。次优模型的使用可能在某种程度上解释了当新的、有前途的药物首次在人体中进行测试时所看到的高失败率。本研究的动机是认为解决方案至少部分在于在糖尿病研究中延长使用人类受试者。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T2 D发展机制直接相关的见解。我们寻求回答的具体问题是：“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遗传研究的数据来确定DNA序列差异（a）与T2 D和/或相关性状的个体易感性明显相关的DNA变体（“DNA变体”）;- 第二，我们将选择一个与糖尿病相关的DNA变异子集，我们可以显示它们对糖尿病的影响，通过胰岛产生的胰岛素缺陷而影响。我们将利用对人类受试者和最近可用的人源性胰腺细胞系的研究来实现这一目标;第三，在该计划的核心，我们将从至少12，000名同意参加此类研究的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，以及具有相似特征的个体，并将进行详细的生理学测试，旨在梳理出两组之间微妙的代谢差异。- 最后，我们将进行进一步的研究，涉及人类受试者和人源性细胞，以确定这些DNA变体的作用机制，以及改变的基因功能如何改变个体的T2 D风险。这项研究将为开发针对高质量靶点的新药铺平道路，这些靶点从治疗潜力和副作用特征的角度来看已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志物，这些标志物在监测疾病进展、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，但它代表了一种强有力的战略，可以提供精确的生物学见解，这是减少T2 D对全球健康影响的原则性和系统性努力的重要组成部分。

项目成果

Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation.

使用多维功能数据有助于临床解释，HNF1A中错义变体的无监督聚类。

• DOI: 10.1016/j.ajhg.2020.08.016
• 发表时间: 2020-10-01
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: Althari S;Najmi LA;Bennett AJ;Aukrust I;Rundle JK;Colclough K;Molnes J;Kaci A;Nawaz S;van der Lugt T;Hassanali N;Mahajan A;Molven A;Ellard S;McCarthy MI;Bjørkhaug L;Njølstad PR;Gloyn AL
• 通讯作者: Gloyn AL

Vertical sleeve gastrectomy normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice.

• DOI: 10.3389/fendo.2022.1020576
• 发表时间: 2022
• 期刊: FRONTIERS IN ENDOCRINOLOGY
• 影响因子: 5.2
• 作者: Akalestou, Elina;Lopez-Noriega, Livia;Christakis, Ioannis;Hu, Ming;Miras, Alexander D.;Leclerc, Isabelle;Rutter, Guy A.
• 通讯作者: Rutter, Guy A.