The Effect of TCF7L2 on Glucose Metabolism

描述(申请人提供)：本申请的总体目的是为了更好地了解导致糖尿病的机制(S)。在与2型糖尿病相关的各种常见遗传变异中，TCF7L2对疾病易感性的影响最强，并可能为推动糖尿病前期进展为糖尿病的各种不同机制提供洞察力。TCF7L2的产物是WNT信号级联的重要组成部分，最初被认为是调节胰高血糖素原基因表达的信号。然而，很明显，TCF7L2调节多个基因调节代谢过程，所有这些都可能在糖尿病的发病机制中发挥重要作用。胰岛β细胞功能由倾向指数(DI)量化，该指数将胰岛素分泌表示为胰岛素的函数 行动。然而，这两个参数之间的关系被认为在不同的糖耐量状态下是一致的，甚至在不同的β细胞储备状态下也是如此。直接测量对胰岛素作用急剧下降的分泌反应，验证或改善DI作为β细胞功能的特征，以及糖尿病相关的TCF7L2变异对这一测量的影响。此外，胰岛素激素(由TCF7L2调节)被认为是对胰岛素急剧下降的代偿反应的一部分。肝脏胰岛素作用在糖尿病前期发病早期就受到损害，其特点是糖异生受到抑制。糖尿病相关的TCF7L2变异对这些过程的作用尚不清楚。最后，在所有糖尿病前期患者中，胰岛素分泌和胰岛素作用同时下降。这一观察结果背后的机制(S)尚不清楚。一个得到动物实验支持的潜在解释是，消化间期胰岛素脉动性降低会导致肝脏胰岛素作用减弱。调节胰岛素分泌幅度和频率的过程是复杂的，已被证明在许多与糖尿病易感性增加相关的状态下是异常的。糖尿病相关的TCF7L2基因变异对胰岛素脉动性和分泌幅度的直接影响尚不清楚。该实验设计还将允许消化间期胰岛素分泌与人体肝脏胰岛素作用直接相关。拟议的实验将直接解决TCF7L2如何改变血糖稳态，并为糖尿病前期和糖尿病进展的发病机制提供见解。

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.