Abstract 15241: Mixed Meal Tolerance Test Elicits Distinct Metabolite Kinetics for Individuals With and Without Diabetes

Abstract

Introduction: Branched chain amino acids (BCAA) are strongly associated with incident diabetes and CVD, and drugs that target their metabolism, especially in the context of a meal, are emerging treatments for diabetes given supportive genetic data. However, little is known about how BCAA, their breakdown metabolites—branched chain ketoacids (BCKA), and other metabolites change after a meal. Hypothesis: BCAA and BCKA levels are higher in individuals with diabetes after a mixed meal tolerance test (MMTT) than in those without diabetes, and a MMTT will uncover additional metabolites involved in dysregulated metabolic pathways secondary to diabetes. Methods: We administered a MMTT to 13 adults with diabetes treated by metformin alone and 11 age and sex matched controls. We measured BCKA, BCAA, and 194 metabolites at 8 timepoints across 6 hours. We used a mixed model for repeated measurements to compare between group differences at each timepoint with adjustment for baseline levels. Results: Across the participants (57 ± 8 years, 71% female, BMI 28 ± 4 kg/m 2 ), adjusted BCAA levels were similar at all timepoints between groups, but adjusted BCKA levels were higher in those with diabetes at 120 minutes (Figure). An additional 9 metabolites had 4 or more timepoints with significant between group differences (Figure). Acylcarnitine, palmitic acid, and linoleic acid showed slower rates of decrease and recovery in those with diabetes, altogether supportive of impaired fatty acid uptake and oxidation. Glycocholic acid showed no increase in those with diabetes, a finding that requires further study given growing recognition of bile acids’ paracrine effects on the liver. Conclusions: In contrast to BCAA, BCKA remained elevated after a MMTT in those with diabetes, suggesting that BCKA catabolism may be a key dysregulated process in the link between BCAA and diabetes. Other metabolites with different kinetics after a MMTT may be markers of dysmetabolism and impaired nutrient handling.