KLF14, adipose dysfunction, insulin resistance and type 2 diabetes: from genetic discovery to biological mechanisms and translation.

2型糖尿病是一种主要的和不断增长的疾病和死亡的原因在世界各地。然而，对这种疾病发展过程的不完全理解阻碍了更好地治疗和预防这种疾病的方法的发展。在过去的几年里，人类基因发现的合作努力已经确定了人类基因组中超过50个位置，其中个体序列变异与2型糖尿病的风险相关。原则上，这些遗传“信号”中的每一个都拥有负责维持正常代谢健康的机制的重要线索。然而，在这些区域中的大多数，我们还没有确定负责信号的特定遗传变异，或者介导对糖尿病风险的影响的特定基因。因此，生物学见解的步伐落后于基因发现的步伐。该领域的一个关键挑战是制定策略，使这些遗传信号能够被挖掘，以获得它们可以提供的生物学线索。我们最近证明，这些糖尿病信号之一映射到一个名为KLF 14的基因附近，并且这种对糖尿病风险的影响是由胰岛素敏感组织（包括肌肉和肝脏）对胰岛素的反应能力降低驱动的。我们还表明，在脂肪组织中，KLF 14附近的相同变体对包括KLF 14本身在内的各种基因的表达水平具有广泛的影响。这些数据与KLF 14作为脂肪组织事件的主要调节剂的模型一致，KLF 14水平的这些改变通过尚未明确的机制导致外周胰岛素抵抗和2型糖尿病。本研究的总体目标是确定KLF 14与2型糖尿病之间关系的分子，细胞和生理机制。为此，我们将采取一些互补的研究策略，包括人类遗传学和生理学研究以及脂肪细胞的细胞研究。更具体地说，我们的工作旨在：（a）确定负责所有这些效应的特定序列变体，以及它们如何影响脂肪细胞内KLF 14的水平;（B）检测由KLF 14开启和关闭的基因组，并了解这些继发性变化对脂肪组织功能的影响;（c）了解脂肪组织中这些KLF 14依赖性变化如何导致远端组织（如肌肉和肝脏）对胰岛素反应能力的变化。我们希望，通过关注KLF 14的作用及其导致糖尿病风险增加的方式，我们将获得对脂肪事件在其他组织中产生广泛代谢影响的机制的有价值的一般性见解。这个问题的答案将有助于我们提高对肥胖和糖尿病之间联系的理解，这是一个至关重要的问题，因为世界各地糖尿病患病率的增加主要是由脂肪的数量，分布和功能的变化驱动的。这项研究提供了一个机会，利用人类遗传学的最新发现来促进对疾病生物学的理解。在申请中，我们解释了如何在直接翻译研究中利用该项目产生的生物信息来定义治疗，预防，诊断和监测2型糖尿病的新方法。

Type 2 diabetes is a major and growing cause of illness and death across the world. However, incomplete understanding of the processes involved in the development of this condition acts as a barrier to the development of better ways for treating and preventing the disease. In the past few years, collaborative efforts in human genetic discovery have identified over fifty positions in the human genome where individual sequence variation is associated with risk of type 2 diabetes. In principle, each of these genetic "signals" holds important clues to the mechanisms that are responsible for the maintenance of normal metabolic health. However, in most of these regions, we have yet to define the specific genetic variants responsible for the signal, or the particular genes through which the effects on diabetes-risk are mediated. As a result, the pace of biological insights has lagged behind that of genetic discovery. A key challenge for the field is to develop strategies that enable genetic signals such as these to be mined for the biological clues they can provide. We recently demonstrated that one of these diabetes signals maps near a gene named KLF14, and that this effect on risk of diabetes is driven by a reduced ability of insulin-sensitive tissues, including muscle and liver, to respond to insulin. We have also shown that, in fat tissue, the same variants near KLF14 have widespread effects on the levels of expression of a wide range of genes, including KLF14 itself. These data are consistent with a model whereby KLF14 acts as a major regulator of events in fat tissue, with these alterations in the levels of KLF14 leading, through as yet unspecified mechanisms, to peripheral insulin resistance and type 2 diabetes. The overall aim of this research is to define the molecular, cellular and physiological mechanisms which are responsible for the relationship between KLF14 and type 2 diabetes. To do this, we will pursue a number of complementary research strategies which include studies of human genetics and physiology and cellular studies in fat cells.More specifically, our work aims to:(a) define the specific sequence variants that are responsible for all of these effects, and how they influence levels of KLF14 within fat cells;(b) characterise the suite of genes that are turned on and off by KLF14, and understand the consequences of those secondary changes on the function of fat tissue; and(c) understand how it is that these KLF14-dependent changes in fat tissue lead to changes in the ability of remote tissues (such as muscle and liver) to respond to insulin. We expect that, by focusing on the role of KLF14 and the ways in which it leads to an increased risk of diabetes, we will gain valuable, generic insights into the mechanisms whereby events in fat have widespread metabolic effects in other tissues. An answer to this question would help us improve our understanding of the connections between obesity and diabetes, an issue of supreme importance given that much of the increase in diabetes prevalence around the world is driven by changes in the amount, distribution and function of fat. The research provides an opportunity to capitalise on recent discoveries in human genetics to advance understanding of disease biology. In the application, we explain how the biological information generated by this project can be exploited in directly translational studies to define novel approaches for treating, preventing, diagnosing and monitoring type 2 diabetes.