Response of circulating metabolites to an oral glucose challenge and risk of cardiovascular disease and mortality in the community

Abstract

Background New biomarkers to identify cardiovascular disease (CVD) risk earlier in its course are needed to enable targeted approaches for primordial prevention. We evaluated whether intraindividual changes in blood metabolites in response to an oral glucose tolerance test (OGTT) may provide incremental information regarding the risk of future CVD and mortality in the community. Methods An OGTT (75 g glucose) was administered to a subsample of Framingham Heart Study participants free from diabetes (n = 361). Profiling of 211 plasma metabolites was performed from blood samples drawn before and 2 h after OGTT. The log2(post/pre) metabolite levels (Δmetabolites) were related to incident CVD and mortality in Cox regression models adjusted for age, sex, baseline metabolite level, systolic blood pressure, hypertension treatment, body mass index, smoking, and total/high-density lipoprotein cholesterol. Select metabolites were related to subclinical cardiometabolic phenotypes using Spearman correlations adjusted for age, sex, and fasting metabolite level. Results Our sample included 42% women, with a mean age of 56 ± 9 years and a body mass index of 30.2 ± 5.3 kg/m2. The pre- to post-OGTT changes (Δmetabolite) were non-zero for 168 metabolites (at FDR ≤ 5%). A total of 132 CVD events and 144 deaths occurred during median follow-up of 24.9 years. In Cox models adjusted for clinical risk factors, four Δmetabolites were associated with incident CVD (higher glutamate and deoxycholate, lower inosine and lysophosphatidylcholine 18:2) and six Δmetabolites (higher hydroxyphenylacetate, triacylglycerol 56:5, alpha-ketogluturate, and lower phosphatidylcholine 32:0, glucuronate, N-monomethyl-arginine) were associated with death (P < 0.05). Notably, baseline metabolite levels were not associated with either outcome in models excluding Δmetabolites. The Δmetabolites exhibited varying cross-sectional correlation with subclinical risk factors such as visceral adiposity, insulin resistance, and vascular stiffness, but overall relations were modest. Significant Δmetabolites included those with established roles in cardiometabolic disease (e.g., glutamate, alpha-ketoglutarate) and metabolites with less defined roles (e.g., glucuronate, lipid species). Conclusions Dynamic changes in metabolite levels with an OGTT are associated with incident CVD and mortality and have potential relevance for identifying CVD risk earlier in its development and for discovering new potential therapeutic targets.

Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition

“…While the precise dietary exposures were different in nature and duration from our study, some metabolites were shared, including carnitines, select amino acids, ketones, and microbially products. Moreover, while we did not have access to long-term outcomes in the present report, acute metabolic responses to select substrates (e.g., oral glucose 11,[29][30][31] or mixed meal tolerance testing 32 ) may map to longerterm cardiometabolic outcomes 33 . Indeed, in the present report, we observed dynamic changes in metabolites (glycine 34 , glutamine 35 , DMGV [36][37][38] ) linked to cardiometabolic states in select dietary interventions (e.g., high-fat, fasting, high-protein), opening the potential for individualizing metabolic risk mitigation strategies by precision metabolic response to nutrition.…”

Maternal and Child Health, Non-Communicable Diseases and Metabolites

“…Specific metabolites shaped the glucose regulation in prediabetic people following 24 weeks (~5.5 months) of lifestyle intervention (hypocaloric diet and >150 min of physical activity per week) [ 4 ]. Dynamic altered metabolite levels in an OGTT were linked to cardiovascular disease and mortality and were relevant for the earlier identification of the cardiovascular disease risk and the discovery of novel therapeutic targets [ 5 ]. Metabolic responses to OGTTs, therefore, could identify high-risk individuals prior to the emergence of overt risk factors and can present targets for the earlier prevention of cardiovascular and cardiometabolic disease [ 5 ].…”

“…Dynamic altered metabolite levels in an OGTT were linked to cardiovascular disease and mortality and were relevant for the earlier identification of the cardiovascular disease risk and the discovery of novel therapeutic targets [ 5 ]. Metabolic responses to OGTTs, therefore, could identify high-risk individuals prior to the emergence of overt risk factors and can present targets for the earlier prevention of cardiovascular and cardiometabolic disease [ 5 ]. Defining the metabolite fluctuations during OGTTs could yield insights into the metabolite interplay during a glucose challenge, reaching glucose homeostasis, and reveal metabolites implicated in the onset of impaired glucose tolerance, insulin resistance and beta cell dysfunction that precede the onset of overt diabetes.…”

“…Further, metabolomics reveals insights into environmental factors (e.g., nutrition) [ 4 ], and many metabolites are derived from nutritional metabolism. Metabolites can be utilized for biomarker discovery to identify risks for diseases early, as they reflect a snapshot of diverse metabolic functions [ 5 ]. Altered metabolite profiles arise from nutrition, and with infrequent physiological events that can unravel potential mechanisms and novel approaches to prevent and treat diseases [ 6 ].…”