Glucagon suppression and diabetes-associated variation in TCF7L2

此应用程序的总体目标是更好地了解受损的胰高血糖素抑制在 导致糖尿病的机制。与2型糖尿病相关的各种常见基因变异 在TCF7L2中，对疾病易感性的影响最强，并可能为了解各种 推动糖尿病前期发展为糖尿病的多种机制。我们发现了一种影响 糖尿病相关的TCF7L2对胰高血糖素抑制的变异。这个轨迹的乘积是一个重要的 WNT-信号级联的组成部分，最初被证明调节原胰高血糖素基因的表达。在……里面 此外，用倾向性指数(DI)量化的β细胞功能也受到损害。我们建议研究 该基因座对正常血糖人群α细胞和β细胞功能影响的时间关系 耐受性或糖尿病前期，以帮助检查胰高血糖素抑制受损是否有助于增加 β-细胞功能障碍或这两个过程是否独立发展。因为α-细胞功能障碍之前 在前驱糖尿病的发病机制中被忽视，我们将利用梅奥尸检资源来检查胰岛 此基因座有糖尿病相关变异和无糖尿病相关变异的人的形态。我们的初步数据 提示在T等位基因位于rs7903146的受试者中，α细胞大小和胰升糖素的表达增加。 TCF7L2基因座。最后，我们希望提高口腔最小模型的能力，这是用于 测量β-体内细胞功能-通过加入一种成分来测量葡萄糖稳态 描述了胰升糖素的分泌和作用。这将有助于阐明TCF7L2导致 但也将提供对胰高血糖素在2型糖尿病发病机制中的作用的深入了解 糖尿病前期和进展为糖尿病。

The overall aim of this application is to better understand the role of impaired glucagon suppression in the mechanisms 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. We have discovered an effect of diabetes-associated variation in TCF7L2 on glucagon suppression. The product of this locus is an important constituent of the wnt-signaling cascade that was originally shown to regulate proglucagon gene expression. In addition, β-cell function as quantified by the Disposition Index (DI) is also impaired. We propose to examine the temporal relationship of the effects of this locus on α-cell and on β-cell function in people with normal glucose tolerance or prediabetes to help examine if impaired glucagon suppression contributes to an increased rate of β-cell dysfunction or if the two processes develop independently. Since α-cell dysfunction has previously been overlooked in the pathogenesis of prediabetes, we will harness the Mayo Autopsy resource to examine islet morphology in humans with and without diabetes-associated variation at this locus. Our preliminary data suggests that α-cell size and glucagon expression is increased in subjects with the T-allele at rs7903146 in the TCF7L2 locus. Finally we hope to improve the ability of the oral minimal model – the gold standard used to measure β-cell function in vivo – to measure glucose homeostasis by incorporating a component that describes glucagon secretion and action. This will help elucidate the mechanism by which TCF7L2 leads to type 2 diabetes in humans but will also provide insights into the role of glucagon in the pathogenesis of prediabetes and progression to diabetes.