Metabolomics reveals the impact of Type 2 diabetes on local muscle and vascular responses to ischemic stress.
Metabolomics reveals the impact of Type 2 diabetes on local muscle and vascular responses to ischemic stress.
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DOI：
10.1042/cs20191227
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发表时间：
2020-09-18
期刊：
影响因子：
--
通讯作者：
Ferguson JF
中科院分区：
文献类型：
--
作者：
Beckman JA;Hu JR;Huang S;Farber-Eger E;Wells QS;Wang TJ;Gerszten RE;Ferguson JF
2型糖尿病（T2 DM）降低运动能力，但其机制尚不完全清楚。我们探讨了缺血应激对骨骼肌代谢物特征和T2 DM相关血管功能障碍的影响。我们招募了38名受试者（18名健康受试者，20名T2 DM受试者），放置肘前静脉导管，并进行同侧肱动脉反应性测试。在基线和缺血5分钟后释放袖带时立即采集用于血浆代谢物分析的血样。在基线和袖带释放后1分钟测量肱动脉直径。正如预期，T2 DM受试者的血流介导的血管舒张减弱（p<0.01）。我们证实了血浆代谢物中已知的T2 DM相关基线差异，包括同型半胱氨酸、二甲基胍基戊酸和β-丙氨酸（所有p<0.05）。两组间缺血诱导的代谢物变化不同，包括5-羟基吲哚乙酸（健康：-27%; DM +14%）、乳清酸（健康：+5%; DM-7%）、三甲胺-N-氧化物（健康：-51%; DM +0.2%）和乙醛酸（健康：+19%; DM-6%）（均p<0.05）。丝氨酸、甜菜碱、β-氨基异丁酸和邻氨基苯甲酸的水平与基线时的血管直径相关，但仅在T2 DM中（所有p<0.05）。对缺血的代谢反应与血管舒张程度显著相关，但主要在T2 DM中观察到，并且包括磷脂代谢的富集（p<0.05）。我们的研究强调了2型糖尿病患者在休息时和缺血性应激期间肌肉和血管信号的损伤。虽然代谢物在健康和T2 DM受试者中响应于缺血而发生变化，但T2 DM中肌肉代谢和血管功能之间的关系发生改变，表明T2 DM中肌肉代谢失调可能对血管功能有直接影响。
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. 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 minutes of ischemia. Brachial artery diameter was measured at baseline and 1 minute after cuff release. 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, 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). 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.
影响因子：
3.8
作者：
Milian, Jessica;Goldfine, Allison B.;Zuflacht, Jonah P.;Parmer, Caitlin;Beckman, Joshua A.
通讯作者：
Beckman, Joshua A.