The Effect of TCF7L2 on Glucose Metabolism

描述（由申请人提供）：本申请的总体目标是更好地了解导致糖尿病的机制。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大，并可能为推动糖尿病前期发展为糖尿病的各种不同机制提供见解。TCF7L2的产物是wnt信号级联的重要组成部分，最初被证明可以调节胰高血糖素原基因的表达。然而，很明显，TCF7L2调节了多个调节代谢过程的基因，所有这些基因都可能在糖尿病的发病机制中起重要作用。β细胞的功能已被量化的处置指数（DI）表示胰岛素分泌作为胰岛素的功能

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.