The role of dimethylguanidino valeric acid (DMGV)-related metabolic pathways in carbohydrate and lipid metabolism

Dimethylguanidino valeric acid (DMGV), including isomers ADGV and SDGV, is an emerging risk factor for metabolic syndrome (MetS) and has garnered research attention. However, the unavailability of DMGV commercial standards poses challenges for its mechanism study and potential clinical application. This PhD project aimed to synthesize DMGV standards with high purity, determine its absolute concentrations in healthy subjects and MetS patients, and evaluate its potential as a clinical biomarker. Additionally, we attempted to investigate the functional roles of DMGV in the occurrence and development of MetS to provide insights into novel intervention strategies. In Chapter 2, a biocatalytic synthesis method for DMGV was developed for the first time. Furthermore, a quantitative method based on high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was established and extensively validated according to guidelines. This method was applied to determine the DMGV concentrations in healthy human plasma with high sensitivity, precision, and accuracy. In Chapter 3, the relationship between the circulating levels of DMGV-related metabolites and clinical features in two Chinese cohorts (a cross-sectional and a longitudinal cohort) was investigated. A close correlation between ADGV and blood triglycerides was found and validated. Cell experiments further proved the stimulatory role of ADGV in lipid accumulation, especially fatty acid synthesis. These findings suggest that ADGV plays an important role in triglyceride synthesis and may have clinical value in MetS prevention and control. In Chapter 4, the association of ADGV with other key clinical features of MetS was explored. It was found that under hyperuricemia and impaired insulin sensitivity, the content of ADGV and relevant metabolites was upregulated, implying the importance of ADGV in the progression of MetS.To sum up, this PhD project provides a comprehensive understanding of DMGV's role in MetS and its potential as a biomarker. These findings have significant implications for developing new therapeutic strategies and their potential application in clinics.