The Effect of TCF7L2 on Glucose Metabolism

描述（由申请人提供）：本申请的总体目的是确定最近与2型糖尿病相关的TCF 7 L2中常见遗传变异改变葡萄糖代谢的机制。我们希望这样做，以便制定预防和治疗糖尿病的合理办法。2型糖尿病是一种常见的代谢紊乱，是基因和环境之间复杂的相互作用引起的。它是由糖尿病前期进行的，其中受影响的受试者具有升高的空腹或餐后葡萄糖浓度，但不符合糖尿病诊断标准。糖尿病前期患者进展为糖尿病的风险很高。对糖尿病预防项目参与者的分析也独立证实，TCF 7 L2的常见变异与糖耐量受损人群患糖尿病的风险增加有关。虽然对KCNJ 11和PPARG的变异如何改变葡萄糖代谢有一些了解，但对TCF 7 L2如何改变葡萄糖稳态知之甚少。TCF 7 L2是一种转录因子，可调节血糖稳态所需的信号通路。已经表明，具有该基因的疾病相关变体的个体在口服葡萄糖耐量试验（OGTT）期间分泌较少的胰岛素。然而，尽管该基因座与2型糖尿病的可重复关联，但关于该基因座的变异如何影响空腹血糖受损和/或葡萄糖耐量受损的人的葡萄糖稳态以及最终该基因如何促进糖尿病的发展的知识很少。TCF 7 L2的产物是调节胰高血糖素原基因表达的wnt信号级联的重要组成部分。胰高血糖素原的蛋白质产物在肠L细胞中差异加工以产生胰高血糖素样肽-1（GLP-1），GLP-1是一种肠促胰岛素激素，其是有效的胰岛素促分泌素，并且GLP-1的分泌缺陷与2型糖尿病和葡萄糖耐量受损相关。预测糖尿病发展的能力将允许有针对性的预防策略。研究表明，TCF 7 L2中常见的遗传变异易患糖尿病。了解该基因对葡萄糖代谢和GLP-1分泌的影响将极大地提高我们针对易感个体的预防策略的能力。

DESCRIPTION (provided by applicant): The overall aim of this application is to determine the mechanism(s) by which common genetic variation in TCF7L2, recently associated with type 2 diabetes alters glucose metabolism. We wish to do so in order to develop rational approaches for the prevention and treatment of diabetes. Type 2 diabetes is a common metabolic disorder that arises out of a complex interaction between genes and the environment. It is proceeded by pre-diabetes where affected subjects have elevated fasting or postprandial glucose concentrations but do not fulfill the criteria for the diagnosis of diabetes. Individuals with prediabetes are at high risk of progression to diabetes. Analysis of participants in the diabetes prevention program has also independently confirmed that common variants in TCF7L2 are associated with increased risk of diabetes among persons with impaired glucose tolerance. Although there is some understanding as to how variation in KCNJ11 and PPARG alters glucose metabolism, little is known about how TCF7L2 alters glucose homeostasis. TCF7L2 is a transcription factor that may modulate signaling pathways necessary for blood glucose homeostasis. It has been shown that individuals with the disease-associated variant(s) of this gene secrete less insulin during an oral glucose tolerance test (OGTT). However, despite the reproducible association of this genetic locus with type 2 diabetes, there is very little knowledge of how variation in this locus affects glucose homeostasis in humans with and without impaired fasting glucose and / or impaired glucose tolerance and ultimately how this gene contributes to the development of diabetes. The product of TCF7L2 is an important constituent of the wnt-signaling cascade that regulates proglucagon gene expression. The protein product of proglucagon is differentially processed in intestinal L cells to produce glucagon-like peptide-1 (GLP-1), an incretin hormone that is a potent insulin secretagogue and defective secretion of GLP-1 has been associated with type 2 diabetes and impaired glucose tolerance. The ability to predict diabetes development will allow targeted prevention strategies. It has been shown that common genetic variation in TCF7L2 predisposes to diabetes. Understanding the effect of this gene on glucose metabolism and GLP-1 secretion will immeasurably increase our ability to target prevention strategies to predisposed individuals.