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(T1D)的发病率以每年3-4%的速度递增。此外， 患有T1D的患者容易发生微血管和大血管并发症，这是 在这群人中死亡。为了降低T1D患者的死亡率，迫切需要确定易感人群 在并发症发生前对人群进行干预，以便能够实施预防性治疗。要做到这点， 我们必须确定疾病病因学中涉及的特定细胞因素。这些调解的一个很有希望的来源 细胞因子是血糖控制不良的因素，与并发症密切相关。以识别和 这些因素的特征，我们和我们的合作调查员Rama Natarajan博士一起从 一项已建立的纵向临床研究，调查血糖控制在并发症进展中的作用。 对并发症发生前采集的样本的分析显示了特定的代谢物和表观遗传学 与血糖控制不佳相关的信号；我们假设这些信号可能具有预测作用 并发症的生物标志物，并将在目标1中探索这一点。对并发症后采集的样本进行分析 研究表明，随着时间的推移，这些相同的新陈代谢和表观遗传标记物仍保持升高，甚至 在建立了强有力的血糖控制之后。我们假设这些标记物是长期的 血糖控制不佳，并将在目标2中探讨这一点。我们的目标1和2的目标是建立预测模型 用于并发症，并确定代谢和表观遗传标记与不良相关的程度 血糖控制。超越代谢和表观遗传标记物对疾病预测和监测的效用 进展，我们发现它们影响特定的细胞通路，如糖酵解，脂肪分解， 蛋白分解和炎症。我们假设这些通路的相互关联的组成部分在 并将在目标3中探讨这一点。我们在目标3中的目标是建立基础信息 探讨特殊通路成分在并发症、病因和进展中的作用。这里面的工作 Proposal是并发症病因学中代谢和表观遗传标记物联合分析的第一个例子。

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.