Abstract
The transcription factor 7-like 2 (TCF7L2) gene confers one of the strongest genetic predispositions to type 2 diabetes, but diabetes development can be modified by diet. The aim of our study was to evaluate postprandial metabolic alterations in healthy men with a high genetic risk of diabetes, after two meals with varying macronutrient content. The study was conducted in 21 homozygous nondiabetic men carrying the high-risk (HR, n=8, age: 31.2±6.3 y, body mass index (BMI, kg/m2) 28.5±8.1) or low-risk (LR, n=13, age: 35.2±10.3 y, BMI: 28.1±6.4) genotypes at the rs7901695 locus. During two meal challenge test visits subjects received standardized isocaloric (450 kcal) liquid meals: high-carbohydrate (HC, carbohydrates: 89% of energy) and normo-carbohydrate (NC, carbohydrates: 45% of energy). Fasting (0 min) and postprandial (30, 60, 120, 180 min) plasma samples were analyzed for metabolite profiles through untargeted metabolomics. Metabolic fingerprinting was performed on an ultra-high-performance liquid chromatography (UHPLC) system connected to an iFunnel quadrupole-time-of-flight (Q-TOF) mass spectrometer. In HR-genotype men, after the intake of an HC-meal, we noted a significantly lower area under the curves (AUCs) of postprandial plasma concentrations of most of the phospholipids (-37% to -53%, variable importance in the projection (VIP)=1.2-1.5), lysophospholipids (-29% to -86%, VIP=1.1-2.6), sphingolipids (-32% to -47%, VIP=1.1-1.3), as well as arachidonic (-36%, VIP=1.4) and oleic (-63%, VIP=1.3) acids, their metabolites: keto- and hydoxy-fatty acids (-38% to -78%, VIP=1.3-2.5), leukotrienes (-65% to -83%, VIP=1.4-2.2), uric acid (-59%, VIP=1.5), and pyroglutamic acid (-65%, VIP=1.8). The AUCs of postprandial sphingosine concentrations were higher (125-832%, VIP=1.9-3.2) after the NC-meal, AUCs of acylcarnitines were lower (-21% to -61%, VIP=1.1-2.4), and AUCs of fatty acid amides were higher (51-508%, VIP=1.7-3.1) after the intake of both meals. In nondiabetic men carrying the TCF7L2 HR genotype, subtle but detectable modifications in intermediate lipid metabolism are induced by an HC-meal. This trial was registered at www.clinicaltrials.gov as NCT03792685.
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