Glucagon suppression and diabetes-associated variation in TCF7L2

胰高血糖素抑制和糖尿病相关的 TCF7L2 变异

• 批准号: 10215489
• 负责人: Adrian Vella
• 金额: $ 53.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215489
• 关键词: Alleles; Alpha Cell; Apoptosis; Area; Automobile Driving; Autopsy; Beta Cell; Cell Size; Cell physiology; Cell surface; Cellular Morphology; Clinic; Data; Defect; Diabetes Mellitus; Disease; Early Diagnosis; Enteroendocrine Cell; Exhibits; Functional disorder; Gene Expression; Genetic Variation; Genotype; Glucagon; Glucose; Gold; Human; Hyperglycemia; Impaired fasting glycaemia; Impairment; Individual; Insulin; Islets of Langerhans; Lead; Life Style; Measurement; Measures; Messenger RNA; Methods; Modeling; Morphology; Non-Insulin-Dependent Diabetes Mellitus; Oral; Pathogenesis; Play; Prediabetes syndrome; Predisposition; Prevention strategy; Process; Reporting; Resources; Role; TCF7L2 gene; Time; Variant; WNT Signaling Pathway; blood glucose regulation; diabetes risk; genetic variant; genome wide association study; glucagon-like peptide 1; glucose metabolism; glucose production; glucose tolerance; impaired glucose tolerance; improved; in vivo; indexing; insight; insulin secretion; islet; non-diabetic; novel; proglucagon; transcription factor

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.

本申请的总体目标是更好地了解胰高血糖素抑制受损在 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 TCF7L2 中，对疾病易感性的影响最强，并可能提供对各种疾病的深入了解 驱动糖尿病前期进展为糖尿病的多种机制。我们发现了一个效果 糖尿病相关的 TCF7L2 胰高血糖素抑制变异。该基因座的产物是一个重要的 wnt 信号级联的组成部分，最初被证明可以调节胰高血糖素原基因表达。在 此外，通过处置指数 (DI) 量化的 β 细胞功能也受损。我们建议审查 该基因座对血糖正常人群的 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会导致糖尿病发生率增加 β 细胞功能障碍或两个过程独立发展。由于 α 细胞功能障碍先前已被 在糖尿病前期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 在该位点有或没有糖尿病相关变异的人类的形态学。我们的初步数据 表明在 rs7903146 处带有 T 等位基因的受试者中，α 细胞大小和胰高血糖素表达增加 TCF7L2 基因座。最后，我们希望提高口腔最小模型的能力——过去的黄金标准 测量体内 β 细胞功能 – 通过加入以下成分来测量葡萄糖稳态 描述胰高血糖素的分泌和作用。这将有助于阐明 TCF7L2 导致的机制 人类 2 型糖尿病，但也将提供关于胰高血糖素在 2 型糖尿病发病机制中的作用的见解。 糖尿病前期和进展为糖尿病。