Joshua A Beckman1,2, Jiun-Ruey Hu1,2, Shi Huang2,3, Eric Farber-Eger1,2, Quinn S Wells1,2, Thomas J Wang4, Robert E Gerszten5, Jane F Ferguson1,2. 1. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A. 2. Vanderbilt Translational and Clinical Cardiovascular Research Center (VTRACC), Vanderbilt University Medical Center, Nashville TN, U.S.A. 3. Department of Biostatistics, Vanderbilt University Medical Center, Nashville TN, U.S.A. 4. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas TX, U.S.A. 5. Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, U.S.A.
Abstract
OBJECTIVE: Type 2 diabetes mellitus (T2DM) reduces exercise capacity, but the mechanisms are incompletely understood. We probed the impact of ischemic stress on skeletal muscle metabolite signatures and T2DM-related vascular dysfunction. METHODS: we recruited 38 subjects (18 healthy, 20 T2DM), placed an antecubital intravenous catheter, and performed ipsilateral brachial artery reactivity testing. Blood samples for plasma metabolite profiling were obtained at baseline and immediately upon cuff release after 5 min of ischemia. Brachial artery diameter was measured at baseline and 1 min after cuff release. RESULTS: as expected, flow-mediated vasodilation was attenuated in subjects with T2DM (P<0.01). We confirmed known T2DM-associated baseline differences in plasma metabolites, including homocysteine, dimethylguanidino valeric acid and β-alanine (all P<0.05). Ischemia-induced metabolite changes that differed between groups included 5-hydroxyindoleacetic acid (healthy: -27%; DM +14%), orotic acid (healthy: +5%; DM -7%), trimethylamine-N-oxide (healthy: -51%; DM +0.2%), and glyoxylic acid (healthy: +19%; DM -6%) (all P<0.05). Levels of serine, betaine, β-aminoisobutyric acid and anthranilic acid were associated with vessel diameter at baseline, but only in T2DM (all P<0.05). Metabolite responses to ischemia were significantly associated with vasodilation extent, but primarily observed in T2DM, and included enrichment in phospholipid metabolism (P<0.05). CONCLUSIONS: our study highlights impairments in muscle and vascular signaling at rest and during ischemic stress in T2DM. While metabolites change in both healthy and T2DM subjects in response to ischemia, the relationship between muscle metabolism and vascular function is modified in T2DM, suggesting that dysregulated muscle metabolism in T2DM may have direct effects on vascular function.
OBJECTIVE:Type 2 diabetes mellitus (T2DM) reduces exercise capacity, but the mechanisms are incompletely understood. We probed the impact of ischemic stress on skeletal muscle metabolite signatures and T2DM-related vascular dysfunction. METHODS: we recruited 38 subjects (18 healthy, 20 T2DM), placed an antecubital intravenous catheter, and performed ipsilateral brachial artery reactivity testing. Blood samples for plasma metabolite profiling were obtained at baseline and immediately upon cuff release after 5 min of ischemia. Brachial artery diameter was measured at baseline and 1 min after cuff release. RESULTS: as expected, flow-mediated vasodilation was attenuated in subjects with T2DM (P<0.01). We confirmed known T2DM-associated baseline differences in plasma metabolites, including homocysteine, dimethylguanidino valeric acid and β-alanine (all P<0.05). Ischemia-induced metabolite changes that differed between groups included 5-hydroxyindoleacetic acid (healthy: -27%; DM +14%), orotic acid (healthy: +5%; DM -7%), trimethylamine-N-oxide (healthy: -51%; DM +0.2%), and glyoxylic acid (healthy: +19%; DM -6%) (all P<0.05). Levels of serine, betaine, β-aminoisobutyric acid and anthranilic acid were associated with vessel diameter at baseline, but only in T2DM (all P<0.05). Metabolite responses to ischemia were significantly associated with vasodilation extent, but primarily observed in T2DM, and included enrichment in phospholipid metabolism (P<0.05). CONCLUSIONS: our study highlights impairments in muscle and vascular signaling at rest and during ischemic stress in T2DM. While metabolites change in both healthy and T2DM subjects in response to ischemia, the relationship between muscle metabolism and vascular function is modified in T2DM, suggesting that dysregulated muscle metabolism in T2DM may have direct effects on vascular function.
Authors: Thomas J Wang; Debby Ngo; Nikolaos Psychogios; Andre Dejam; Martin G Larson; Ramachandran S Vasan; Anahita Ghorbani; John O'Sullivan; Susan Cheng; Eugene P Rhee; Sumita Sinha; Elizabeth McCabe; Caroline S Fox; Christopher J O'Donnell; Jennifer E Ho; Jose C Florez; Martin Magnusson; Kerry A Pierce; Amanda L Souza; Yi Yu; Christian Carter; Peter E Light; Olle Melander; Clary B Clish; Robert E Gerszten Journal: J Clin Invest Date: 2013-09-16 Impact factor: 14.808
Authors: Jose E Galgani; Leonie K Heilbronn; Koichiro Azuma; David E Kelley; Jeanine B Albu; Xavier Pi-Sunyer; Steven R Smith; Eric Ravussin Journal: Diabetes Date: 2008-02-19 Impact factor: 9.461
Authors: Brian J Bennett; Thomas Q de Aguiar Vallim; Zeneng Wang; Diana M Shih; Yonghong Meng; Jill Gregory; Hooman Allayee; Richard Lee; Mark Graham; Rosanne Crooke; Peter A Edwards; Stanley L Hazen; Aldons J Lusis Journal: Cell Metab Date: 2013-01-08 Impact factor: 27.287
Authors: Geoffrey A Walford; Yong Ma; Clary Clish; Jose C Florez; Thomas J Wang; Robert E Gerszten Journal: Diabetes Date: 2016-02-09 Impact factor: 9.461
Authors: Mingjian Shi; Chuan Wang; Hao Mei; Marinella Temprosa; Jose C Florez; Mark Tripputi; Jordi Merino; Loren Lipworth; Xiao-Ou Shu; Robert E Gerszten; Thomas J Wang; Joshua A Beckman; Jorge L Gamboa; Jonathan D Mosley; Jane F Ferguson Journal: J Am Heart Assoc Date: 2022-05-27 Impact factor: 6.106