PMID- 32880388 OWN - NLM STAT- MEDLINE DCOM- 20210323 LR - 20210919 IS - 1470-8736 (Electronic) IS - 0143-5221 (Print) IS - 0143-5221 (Linking) VI - 134 IP - 17 DP - 2020 Sep 18 TI - Metabolomics reveals the impact of Type 2 diabetes on local muscle and vascular responses to ischemic stress. PG - 2369-2379 LID - 10.1042/CS20191227 [doi] AB - 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 beta-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, beta-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. CI - (c) 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. FAU - Beckman, Joshua A AU - Beckman JA AD - Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A. AD - Vanderbilt Translational and Clinical Cardiovascular Research Center (VTRACC), Vanderbilt University Medical Center, Nashville TN, U.S.A. FAU - Hu, Jiun-Ruey AU - Hu JR AD - Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A. AD - Vanderbilt Translational and Clinical Cardiovascular Research Center (VTRACC), Vanderbilt University Medical Center, Nashville TN, U.S.A. FAU - Huang, Shi AU - Huang S AD - Vanderbilt Translational and Clinical Cardiovascular Research Center (VTRACC), Vanderbilt University Medical Center, Nashville TN, U.S.A. AD - Department of Biostatistics, Vanderbilt University Medical Center, Nashville TN, U.S.A. FAU - Farber-Eger, Eric AU - Farber-Eger E AD - Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A. AD - Vanderbilt Translational and Clinical Cardiovascular Research Center (VTRACC), Vanderbilt University Medical Center, Nashville TN, U.S.A. FAU - Wells, Quinn S AU - Wells QS AD - Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A. AD - Vanderbilt Translational and Clinical Cardiovascular Research Center (VTRACC), Vanderbilt University Medical Center, Nashville TN, U.S.A. FAU - Wang, Thomas J AU - Wang TJ AD - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas TX, U.S.A. FAU - Gerszten, Robert E AU - Gerszten RE AD - Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, U.S.A. FAU - Ferguson, Jane F AU - Ferguson JF AD - Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A. AD - Vanderbilt Translational and Clinical Cardiovascular Research Center (VTRACC), Vanderbilt University Medical Center, Nashville TN, U.S.A. LA - eng GR - R01 DK117144/DK/NIDDK NIH HHS/United States GR - R01 HL131977/HL/NHLBI NIH HHS/United States GR - R01 HL142856/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Clin Sci (Lond) JT - Clinical science (London, England : 1979) JID - 7905731 RN - 107-73-3 (Phosphorylcholine) SB - IM CIN - Clin Sci (Lond). 2021 Feb 12;135(3):589-591. PMID: 33565585 MH - Brachial Artery/pathology/physiopathology MH - Case-Control Studies MH - Diabetes Mellitus, Type 2/*metabolism/physiopathology MH - Endothelium, Vascular/pathology/physiopathology MH - Extremities/blood supply/pathology/physiopathology MH - Female MH - Humans MH - Ischemia/*metabolism/*pathology/physiopathology MH - Male MH - Metabolome MH - *Metabolomics MH - Middle Aged MH - Muscle, Skeletal/*metabolism/*pathology/physiopathology MH - Phosphorylcholine/metabolism MH - Regional Blood Flow MH - Signal Transduction MH - Vasodilation PMC - PMC8176641 MID - NIHMS1704149 OTO - NOTNLM OT - cardiovascular physiology OT - ischemia OT - metabolomics OT - type 2 diabetes COIS- The authors have no relevant conflicts of interest to disclose. EDAT- 2020/09/04 06:00 MHDA- 2021/03/24 06:00 PMCR- 2021/09/18 CRDT- 2020/09/04 06:00 PHST- 2019/11/28 00:00 [received] PHST- 2020/08/24 00:00 [revised] PHST- 2020/09/03 00:00 [accepted] PHST- 2020/09/04 06:00 [pubmed] PHST- 2021/03/24 06:00 [medline] PHST- 2020/09/04 06:00 [entrez] PHST- 2021/09/18 00:00 [pmc-release] AID - 226294 [pii] AID - 10.1042/CS20191227 [doi] PST - ppublish SO - Clin Sci (Lond). 2020 Sep 18;134(17):2369-2379. doi: 10.1042/CS20191227.