2409-P: Circulating N-lactoyl Amino Acids, GCKR Variant, and Risk of Type 2 Diabetes in the Hispanic Community Health Study/Study of Latinos

Introduction and Objective: N-lactoyl-phenylalanine (Lac-Phe) is the most abundant member of N-lactoyl-amino acids (Lac-AAs) family that can be induced by metformin use and reduce appetite. We investigated prospective associations of serum Lac-AAs and related genetic variation with risk of T2D. Methods: In 13814 participants, we examined cross-sectional associations of Lac-AAs with glycemic status and metformin use and prospective associations with incident T2D among diabetes-free persons. GWAS of Lac-Phe was conducted and the identified variants were further linked with triglycerides, fasting glucose, and incident T2D. Results: Lac-AA levels were highest among individuals with T2D and metformin use and associated with unfavorable cardiometabolic traits. Higher Lac-AAs were associated with higher risk of incident T2D, even further adjusted for fasting glucose. GWAS identified the lead variant rs1260326 in GCKR, a known functional variant in glycolipid metabolism, with T-allele paradoxically associated with higher Lac-Phe and triglycerides but lower fasting glucose and T2D risk. Moreover, stronger protective associations of this variant with fasting glucose and T2D risk were observed among individuals with higher Lac-Phe. Conclusion: Lac-AAs may play an important role in GCKR variant-mediated glucose-lipid interconversion influencing risk of T2D, and the paradoxical associations need to be elucidated by future research. Disclosure P. Wu: None. K. Luo: None. H. Yang: None. B. Peters: None. B. Yu: None. R. Kaplan: None. Q. Qi: None.