Identifying Metabolite Signatures of Type 2 Diabetes Risk, Etiology, and Therapy Using Data from Large Human Cohorts
- Begzati, Arjana
- Advisor(s): Majithia, Amit R;
- Jain, Mohit
Abstract
Type 2 diabetes (T2D) is a growing global health challenge. The underlying mechanisms driving T2D onset, progression and therapy response are complex, heterogeneous, and not fully elucidated. Blood-based metabolites, which reflect both endogenous physiology and external exposures, offer a promising window into these processes. Therefore, metabolomic profiling has the potential to improve risk stratification, determine the cause of diseases, and identify the effects of treatments, ultimately guiding more personalized and effective preventative treatments and interventions. In this dissertation, I use high-throughput untargeted metabolomics data generated from the plasma samples of large human cohorts to identify metabolites and metabolic pathways that predict T2D risk, etiology, and medication effects. Chapter 1 utilizes metabolite profiling of two large population-based cohorts to identify diacylglycerol and phosphatidylcholine metabolites as robust, race-independent biomarkers of incident T2D, which capture distinct aspects of disease etiology beyond conventional glycemic measures. Chapter 2 describes how long-term metformin use induces widespread, dose-dependent changes in circulating metabolites—including amino acid and related metabolites, triglycerides, very long-chain fatty acid-derived lipids, phospholipids, and linoleic acid-derived lipids— highlighting novel metabolic pathways that may underlying its glycemic and immune-modulatory effects. Chapter 3 presents a novel approach to metabolite identification using mass isotopomer distributions from isotope-labeled reference materials. Using the method, we identity the previously uncharacterized metabolite trimethylglycyl-lysine which is altered in human muscle tissue in response to lifestyle changes. Collectively, this body of work highlights the utility of metabolomics for uncovering novel insights into T2D development and therapeutic response and provides a new method for the discovery previously uncharacterized metabolites which could have important physiological roles.