The Effect of TCF7L2 on Glucose Metabolism

描述（由申请人提供）：本申请的总体目的是更好地了解导致糖尿病的机制。在TCF7L2中与2型糖尿病相关的各种常见遗传变异中，对疾病易感性的影响最大，并可能提供对推动前驱糖尿病进展为糖尿病的各种不同机制的深入了解。TCF7L2的产物是wnt信号级联的重要组成部分，其最初显示调节胰高血糖素原基因表达。然而，很明显，TCF7L2调节多个调节代谢过程的基因，所有这些基因在糖尿病的发病机制中可能都很重要。β细胞功能已通过处置指数（DI）进行定量，该指数将胰岛素分泌表示为胰岛素的函数 行动上然而，这两个参数之间的关系已经被假设为在葡萄糖耐量的各种状态下是一致的，并且实际上在β细胞储备的不同状态下是一致的。直接测量响应于胰岛素作用的急性降低的分泌反应验证或改善DI作为β细胞功能的表征以及TCF 7L2中的糖尿病相关变化对该测量的影响。此外，肠促胰岛素激素（由TCF 7L2调节）被认为是对胰岛素作用急性降低的代偿反应的一部分。在糖尿病前期发病的早期，肝脏胰岛素作用受损，其特征是对胰岛素生成的抑制受损。TCF 7L2中糖尿病相关变异对这些过程的贡献尚不清楚。最后，胰岛素分泌和胰岛素作用在整个糖尿病前期范围内平行下降。该观察结果的机制尚不清楚。动物实验支持的一种可能的解释是，消化间期胰岛素脉动性降低导致肝脏胰岛素作用降低。调节胰岛素分泌的幅度和频率的过程是复杂的，并且已经显示在与糖尿病易感性增加相关的许多状态中是异常的。糖尿病相关的TCF 7L2变异对胰岛素脉动性和分泌幅度的直接影响尚不清楚。实验设计还将允许人类消化间期胰岛素分泌与肝脏胰岛素作用的直接相关性。拟议的实验将直接解决TCF7L2如何改变葡萄糖稳态，并提供对糖尿病前期和糖尿病进展的发病机制的见解。

DESCRIPTION (provided by applicant): The overall aim of this application is to better understand the mechanism(s) that lead to diabetes. Of the various common genetic variants associated with type 2 diabetes that in TCF7L2, has the strongest effect on disease predisposition and might provide insight into various diverse mechanisms that drive the progression of prediabetes to diabetes. The product of TCF7L2 is an important constituent of the wnt-signaling cascade that was originally shown to regulate proglucagon gene expression. However, it is apparent that TCF7L2 regulates multiple genes regulating metabolic processes, all of which may be important in the pathogenesis of diabetes. Beta-cell function has been quantified by the Disposition Index (DI) which expresses insulin secretion as a function of insulin action. However, the relationship between these 2 parameters has been assumed to be uniform across various states of glucose tolerance, and indeed different states of beta-cell reserve. Direct measurement of the secretory response in response to an acute decrease in insulin action validate or improve DI as a characterization of beta-cell function and the effect of diabetes-associated variation in TCF7L2 on this measurement. Moreover, incretin hormones (regulated by TCF7L2 have been suggested to be part of the compensatory response to acute decreases in insulin action. Hepatic insulin action is impaired early in the pathogenesis of prediabetes and is characterized by impaired suppression of gluconeogenesis. The contribution of diabetes-associated variation in TCF7L2 to these processes is unknown. Finally, insulin secretion and insulin action decline in parallel across the spectrum of prediabetes. The mechanism(s) underlying this observation are unknown. One potential explanation, supported by animal experiments, is that decreased interdigestive insulin pulsatility leads to decreased hepatic insulin action. The processes regulating the amplitude and frequency of insulin secretion are complex and have been shown to be abnormal in many states associated with increased predisposition to diabetes. A direct effect of diabetes-associated variation in TCF7L2 on insulin pulsatility and amplitude of secretion is unknown. The experimental design will also allow direct correlation of interdigestive insulin secretion with hepatic insulin action in humans. The proposed experiments will directly address how TCF7L2 alters glucose homeostasis and provide insights into the pathogenesis of prediabetes and progression to diabetes.