The Effect of TCF7L2 on Glucose Metabolism

描述(申请人提供)：本申请的总体目标是确定最近与2型糖尿病相关的TCF7L2的常见基因变异改变葡萄糖代谢的机制(S)。我们希望这样做，以便为预防和治疗糖尿病制定合理的方法。2型糖尿病是一种常见的代谢紊乱，由基因和环境之间的复杂相互作用引起。糖尿病前期患者的空腹或餐后血糖浓度升高，但不符合糖尿病的诊断标准。糖尿病前期患者进展为糖尿病的风险很高。对糖尿病预防计划参与者的分析也独立证实，在糖耐量受损的人中，TCF7L2的常见变异与糖尿病风险增加有关。虽然关于KCNJ11和PPARG的变异如何改变葡萄糖代谢有一些了解，但关于TCF7L2如何改变葡萄糖稳态还知之甚少。TCF7L2是一种转录因子，可能调节血糖稳态所需的信号通路。研究表明，在口服葡萄糖耐量试验中，携带该基因疾病相关变异(S)的个体分泌的胰岛素较少。然而，尽管该基因与2型糖尿病之间存在可重复的关联，但人们对该基因的变异如何影响空腹血糖和/或糖耐量受损的人的血糖稳态，以及最终该基因如何促进糖尿病的发生知之甚少。TCF7L2的产物是WNT信号通路中的一个重要组成部分，它调节原胰高血糖素基因的表达。胰高血糖素原的蛋白产物在肠道L细胞中被分化处理，产生胰升糖素样肽-1(GLP-1)，GLP-1是一种有效的胰岛素促分泌剂，GLP-1的分泌缺陷与2型糖尿病和糖耐量减低有关。预测糖尿病发展的能力将使有针对性的预防战略成为可能。已有研究表明，TCF7L2中常见的基因变异易患糖尿病。了解该基因对葡萄糖代谢和GLP-1分泌的影响将无可估量地增加我们针对易患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.