Glucagon suppression and diabetes-associated variation in TCF7L2

本申请的总体目的是更好地理解受损的胰高血糖素抑制在糖尿病中的作用。 导致糖尿病的机制。与2型糖尿病相关的各种常见遗传变异 在TCF 7 L2中，对疾病易感性有最强的影响，并可能提供对各种疾病的了解。 糖尿病前期发展为糖尿病的多种机制。我们发现了一种效应， TCF 7 L2对胰高血糖素抑制的糖尿病相关变化。这个轨迹的产物是一个重要的 WNT信号级联的组成部分，其最初显示调节胰高血糖素原基因表达。在 此外，如通过处置指数（DI）量化的β细胞功能也受损。我们建议研究 正常血糖人群中该位点对α细胞和β细胞功能影响的时间关系 耐受性或前驱糖尿病，以帮助检查胰高血糖素抑制受损是否有助于增加 β细胞功能障碍或两个过程是否独立发展。由于α细胞功能障碍以前曾被 我们将利用马约的尸检资源来检查胰岛 在该基因座具有和不具有糖尿病相关变异的人类中的形态学。我们的初步数据 提示，α细胞大小和胰高血糖素表达在具有rs7903146的T等位基因的受试者中增加， TCF 7 L2位点。最后，我们希望提高口腔最小模型的能力-用于 测量体内β细胞功能-通过掺入 描述了胰高血糖素的分泌和作用。这将有助于阐明TCF 7 L2导致 2型糖尿病，但也将提供深入了解胰高血糖素在发病机制中的作用， 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.