PMID- 36811472 OWN - NLM STAT- MEDLINE DCOM- 20230307 LR - 20240108 IS - 1938-3207 (Electronic) IS - 0002-9165 (Print) IS - 0002-9165 (Linking) VI - 117 IP - 3 DP - 2023 Mar TI - Mixed meal tolerance testing highlights in diabetes altered branched-chain ketoacid metabolism and pathways associated with all-cause mortality. PG - 529-539 LID - S0002-9165(23)00002-3 [pii] LID - 10.1016/j.ajcnut.2023.01.001 [doi] AB - BACKGROUND: Elevated BCAA levels are strongly associated with diabetes, but how diabetes affects BCAA, branched-chain ketoacids (BCKAs), and the broader metabolome after a meal is not well known. OBJECTIVE: To compare quantitative BCAA and BCKA levels in a multiracial cohort with and without diabetes after a mixed meal tolerance test (MMTT) as well as to explore the kinetics of additional metabolites and their associations with mortality in self-identified African Americans. METHODS: We administered an MMTT to 11 participants without obesity or diabetes and 13 participants with diabetes (treated with metformin only) and measured the levels of BCKAs, BCAAs, and 194 other metabolites at 8 time points across 5 h. We used mixed models for repeated measurements to compare between group metabolite differences at each timepoint with adjustment for baseline. We then evaluated the association of top metabolites with different kinetics with all-cause mortality in the Jackson Heart Study (JHS) (N = 2441). RESULTS: BCAA levels, after adjustment for baseline, were similar at all timepoints between groups, but adjusted BCKA kinetics were different between groups for alpha-ketoisocaproate (P = 0.022) and alpha-ketoisovalerate (P = 0.021), most notably diverging at 120 min post-MMTT. An additional 20 metabolites had significantly different kinetics across timepoints between groups, and 9 of these metabolites-including several acylcarnitines-were significantly associated with mortality in JHS, irrespective of diabetes status. The highest quartile of a composite metabolite risk score was associated with higher mortality (HR:1.57; 1.20, 2.05, P = 0.00094) than the lowest quartile. CONCLUSIONS: BCKA levels remained elevated after an MMTT among participants with diabetes, suggesting that BCKA catabolism may be a key dysregulated process in the interaction of BCAA and diabetes. Metabolites with different kinetics after an MMTT may be markers of dysmetabolism and associated with increased mortality in self-identified African Americans. CI - Copyright (c) 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved. FAU - Mi, Michael Y AU - Mi MY AD - Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. Electronic address: mmi@bidmc.harvard.edu. FAU - Whitlock, Mark AU - Whitlock M AD - Early Clinical Development, Pfizer, Cambridge, UK. FAU - Shi, Xu AU - Shi X AD - Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. FAU - Farrell, Laurie A AU - Farrell LA AD - Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. FAU - Bhambhani, Victoria M AU - Bhambhani VM AD - Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. FAU - Quadir, Juweria AU - Quadir J AD - Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. FAU - Blatnik, Matthew AU - Blatnik M AD - Early Clinical Development, Pfizer, Groton, CT, USA. FAU - Wald, Kyle P AU - Wald KP AD - Early Clinical Development, Pfizer, Groton, CT, USA. FAU - Tierney, Brendan AU - Tierney B AD - Early Clinical Development, Pfizer, Groton, CT, USA. FAU - Kim, Albert AU - Kim A AD - Internal Medicine Research Unit, Pfizer, Cambridge, MA, USA; Cytel, Cambridge, MA, USA. FAU - Loudon, Peter AU - Loudon P AD - Early Clinical Development, Pfizer, Cambridge, UK; Tenpoint Therapeutics, Cambridge, UK. FAU - Chen, Zsu-Zsu AU - Chen ZZ AD - Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA. FAU - Correa, Adolfo AU - Correa A AD - Department of Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA. FAU - Gao, Yan AU - Gao Y AD - Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA. FAU - Carson, April P AU - Carson AP AD - Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA. FAU - Bertoni, Alain G AU - Bertoni AG AD - Department of Epidemiology & Prevention, Wake Forest School of Medicine, Winston Salem, NC, USA. FAU - Roth Flach, Rachel J AU - Roth Flach RJ AD - Internal Medicine Research Unit, Pfizer, Cambridge, MA, USA. FAU - Gerszten, Robert E AU - Gerszten RE AD - Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. LA - eng GR - T32 HL007208/HL/NHLBI NIH HHS/United States GR - R01 DK081572/DK/NIDDK NIH HHS/United States GR - HHSN268201800013I/MD/NIMHD NIH HHS/United States GR - HHSN268201800014I/HB/NHLBI NIH HHS/United States GR - HHSN268201800015I/HB/NHLBI NIH HHS/United States GR - HHSN268201800010I/HB/NHLBI NIH HHS/United States GR - HHSN268201800011I/HB/NHLBI NIH HHS/United States GR - HHSN268201800012I/HB/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20230107 PL - United States TA - Am J Clin Nutr JT - The American journal of clinical nutrition JID - 0376027 RN - 0 (Amino Acids, Branched-Chain) SB - IM MH - Humans MH - *Amino Acids, Branched-Chain/metabolism MH - *Diabetes Mellitus MH - Risk Factors MH - Obesity/metabolism MH - Metabolome PMC - PMC10356557 OTO - NOTNLM OT - African Americans OT - Jackson Heart Study OT - all-cause mortality OT - branched-chain amino acid OT - branched-chain ketoacid OT - diabetes OT - metabolomics OT - mixed meal tolerance test EDAT- 2023/02/23 06:00 MHDA- 2023/03/08 06:00 PMCR- 2024/01/07 CRDT- 2023/02/22 15:41 PHST- 2022/07/06 00:00 [received] PHST- 2022/12/22 00:00 [revised] PHST- 2023/01/03 00:00 [accepted] PHST- 2023/02/23 06:00 [pubmed] PHST- 2023/03/08 06:00 [medline] PHST- 2023/02/22 15:41 [entrez] PHST- 2024/01/07 00:00 [pmc-release] AID - S0002-9165(23)00002-3 [pii] AID - 10.1016/j.ajcnut.2023.01.001 [doi] PST - ppublish SO - Am J Clin Nutr. 2023 Mar;117(3):529-539. doi: 10.1016/j.ajcnut.2023.01.001. Epub 2023 Jan 7.