Centre for Global Health, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Cardiovasc Diabetol. 2022 Apr 27;21(1):62. doi: 10.1186/s12933-022-01493-w.
Atherosclerotic cardiovascular diseases (CVD) is the leading cause of death in diabetes, but the full range of biomarkers reflecting atherosclerotic burden and CVD risk in people with diabetes is unknown. Metabolomics may help identify novel biomarkers potentially involved in development of atherosclerosis. We investigated the serum metabolomic profile of subclinical atherosclerosis, measured using ankle brachial index (ABI), in people with type 2 diabetes, compared with the profile for symptomatic CVD in the same population.
The Edinburgh Type 2 Diabetes Study is a cohort of 1,066 individuals with type 2 diabetes. ABI was measured at baseline, years 4 and 10, with cardiovascular events assessed at baseline and during 10 years of follow-up. A panel of 228 metabolites was measured at baseline using nuclear magnetic resonance spectrometry, and their association with both ABI and prevalent CVD was explored using univariate regression models and least absolute shrinkage and selection operator (LASSO). Metabolites associated with baseline ABI were further explored for association with follow-up ABI and incident CVD.
Mean (standard deviation, SD) ABI at baseline was 0.97 (0.18, N = 1025), and prevalence of CVD was 35.0%. During 10-year follow-up, mean (SD) change in ABI was + 0.006 (0.178, n = 436), and 257 CVD events occurred. Lactate, glycerol, creatinine and glycoprotein acetyls levels were associated with baseline ABI in both univariate regression [βs (95% confidence interval, CI) ranged from - 0.025 (- 0.036, - 0.015) to - 0.023 (- 0.034, - 0.013), all p < 0.0002] and LASSO analysis. The associations remained nominally significant after adjustment for major vascular risk factors. In prospective analyses, lactate was nominally associated with ABI measured at years 4 and 10 after adjustment for baseline ABI. The four ABI-associated metabolites were all positively associated with prevalent CVD [odds ratios (ORs) ranged from 1.29 (1.13, 1.47) to 1.49 (1.29, 1.74), all p < 0.0002], and they were also positively associated with incident CVD [ORs (95% CI) ranged from 1.19 (1.02, 1.39) to 1.35 (1.17, 1.56), all p < 0.05].
Serum metabolites relating to glycolysis, fluid balance and inflammation were independently associated with both a marker of subclinical atherosclerosis and with symptomatic CVD in people with type 2 diabetes. Additional investigation is warranted to determine their roles as possible etiological and/or predictive biomarkers for atherosclerotic CVD.
动脉粥样硬化性心血管疾病（CVD）是糖尿病患者死亡的主要原因，但反映糖尿病患者动脉粥样硬化负担和 CVD 风险的完整生物标志物范围尚不清楚。代谢组学可能有助于确定潜在参与动脉粥样硬化发展的新生物标志物。我们研究了踝臂指数（ABI）测量的 2 型糖尿病患者亚临床动脉粥样硬化的血清代谢组学特征，并与同一人群中症状性 CVD 的特征进行了比较。
爱丁堡 2 型糖尿病研究是一项包含 1066 例 2 型糖尿病患者的队列研究。ABI 在基线、第 4 年和第 10 年进行测量，心血管事件在基线和 10 年随访期间进行评估。使用核磁共振光谱法在基线时测量了 228 种代谢物，使用单变量回归模型和最小绝对值收缩和选择算子（LASSO）探索它们与 ABI 和常见 CVD 的相关性。与基线 ABI 相关的代谢物进一步探索与随访 ABI 和 CVD 事件的相关性。
基线时的平均（标准差，SD）ABI 为 0.97（0.18，N=1025），CVD 的患病率为 35.0%。在 10 年随访期间，ABI 的平均（SD）变化为+0.006（0.178，n=436），并发生了 257 例 CVD 事件。在单变量回归分析中[β（95%置信区间，CI）范围从-0.025（-0.036，-0.015）到-0.023（-0.034，-0.013），所有 p<0.0002]和 LASSO 分析中，乳酸、甘油、肌酐和糖蛋白乙酰水平与基线 ABI 相关。在调整主要血管危险因素后，这些关联仍然具有统计学意义。在前瞻性分析中，在调整基线 ABI 后，乳酸与第 4 年和第 10 年测量的 ABI 具有名义相关性。与 ABI 相关的四种代谢物均与常见 CVD 呈正相关[比值比（ORs）范围从 1.29（1.13，1.47）到 1.49（1.29，1.74），所有 p<0.0002]，并且它们也与新发 CVD 呈正相关[比值比（95%CI）范围从 1.19（1.02，1.39）到 1.35（1.17，1.56），所有 p<0.05]。
与糖酵解、体液平衡和炎症相关的血清代谢物与 2 型糖尿病患者的亚临床动脉粥样硬化和症状性 CVD 均独立相关。需要进一步研究以确定它们作为动脉粥样硬化性 CVD 潜在病因和/或预测生物标志物的作用。
