Epigenetic changes and methylglyoxal adducts induced by metabolic regulation in patients with type 1 diabetes that develop complications

抽象的。 近几十年来，1型糖尿病（T1 D）的发病率每年增加多达3-4%。此外，委员会认为， T1 D患者易发生微血管和大血管并发症，这是T1 D的主要原因。 死亡在这个人口。为了降低T1 D患者的死亡率，迫切需要识别易感的 在并发症发作之前，对人群进行预防性治疗，以便能够实施预防性治疗。为了做到这一点， 我们必须确定与疾病病因有关的特定细胞因子。一个有前途的来源，这些调解 细胞因子是血糖控制不良，这是显着相关的并发症。识别和 为了表征这些因素，我们与我们的合作研究者拉马Natarajan博士一起，沿着访问了来自 一项研究血糖控制对并发症进展的作用的已确立的纵向临床研究。 对并发症发生前采集的样本进行分析，发现特定代谢物和表观遗传 与血糖控制不良相关的特征;我们假设这些特征可能具有预测 并发症的生物标志物，并将在目标1中探讨这一点。并发症后采集的样本分析 研究显示，这些相同的代谢和表观遗传标记随着时间的推移仍然升高， 在血糖得到有效控制后我们假设这些标志物是长期的 血糖控制不佳，将在目标2中对此进行探讨。我们的目标1和2是建立一个预测模型， 并确定代谢和表观遗传标记与不良 血糖控制除了代谢和表观遗传标记用于预测和监测疾病之外 随着研究进展，我们发现它们影响特定的细胞途径，如糖酵解，脂解， 蛋白水解和炎症。我们假设这些通路中相互关联的成分在以下方面发挥作用： 并发症病因，并将在目标3中对此进行探讨。我们在目标3中的目标是建立基础信息 探讨特异性通路组分在并发症病因和进展中的作用。这项工作 该提案是第一个合并分析代谢和表观遗传标记在并发症病因的例子。

Abstract. The incidence of type 1 diabetes (T1D) has increased as much as 3-4% annually in recent decades. Furthermore, patients with T1D are vulnerable to developing micro- and macrovascular complications, the leading cause of death in this population. To reduce mortality in patients with T1D, there is a critical need to identify susceptible populations prior to the onset of complications so that preventative therapies can be implemented. To do this, we must identify the specific cellular factors involved in disease etiology. A promising source of these mediatory cellular factors is poor glycemic control, which is significantly associated with complications. To identify and characterize these factors, we, along with our Co-Investigator Dr. Rama Natarajan, have accessed samples from an established, longitudinal clinical study investigating the role of glycemic control on complication progression. Analysis of samples collected pre-complication development revealed specific metabolites and epigenetic signatures associated with poor glycemic control; we hypothesize that these may have utility as predictive biomarkers of complications and will explore this in Aim 1. Analysis of samples collected post-complication development revealed that these same metabolic and epigenetic markers remained elevated over time, even after strong glycemic control was established. We hypothesize that these markers are indicative of long-term poor glycemic control and will explore this in Aim 2. Our goals for Aims 1 and 2 are to build a predictive model for complications and determine the extent to which metabolic and epigenetic markers are associated with poor glycemic control. Beyond the utility of metabolic and epigenetic markers for predicting and monitoring disease progression, we discovered that they influence specific cellular pathways such as glycolysis, lipolysis, proteolysis, and inflammation. We hypothesize that interrelated components of these pathways play a role in complication etiology and will explore this in Aim 3. Our goal in Aim 3 is to establish the foundational information to explore the role of specific pathway components in complication etiology and progression. The work in this proposal is the first example of combined analysis of metabolic and epigenetic markers in complication etiology.