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

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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.