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Context Metabolic flexibility is the physiologic acclimatization to differing energy availability and requirement states. Effectively maintaining metabolic flexibility remains challenging, particularly since metabolic dysregulations in meal consumption during cardiometabolic disease (CMD) pathophysiology are incompletely understood. Objective We compared metabolic flexibility following consumption of a standardized meal challenge among adults with or without CMDs. Design, Setting, and Participants Study participants (n = 349; age 37-54 years, 55% female) received a standardized meal challenge (520 kcal, 67.4 g carbohydrates, 24.3 g fat, 8.0 g protein; 259 mL). Blood samples were collected at baseline and 2 hours postchallenge. Plasma samples were assayed by high-resolution, nontargeted metabolomics with dual-column liquid chromatography and ultrahigh-resolution mass spectrometry. Metabolome-wide associations between features and meal challenge timepoint were assessed in multivariable linear regression models. Results Sixty-five percent of participants had ≥1 of 4 CMDs: 33% were obese, 6% had diabetes, 39% had hypertension, and 50% had metabolic syndrome. Log2-normalized ratios of feature peak areas (postprandial:fasting) clustered separately among participants with versus without any CMDs. Among participants with CMDs, the meal challenge altered 1756 feature peak areas (1063 reversed-phase [C18], 693 hydrophilic interaction liquid chromatography [HILIC]; all q &amp;lt; 0.05). In individuals without CMDs, the meal challenge changed 1383 feature peak areas (875 C18; 508 HILIC; all q &amp;lt; 0.05). There were 108 features (60 C18; 48 HILIC) that differed by the meal challenge and CMD status, including dipeptides, carnitines, glycerophospholipids, and a bile acid metabolite (all P &amp;lt; 0.05). Conclusions Among adults with CMDs, more metabolomic features differed after a meal challenge, which reflected lower metabolic flexibility relative to individuals without CMDs.

Metabolomic Profiling After a Meal Shows Greater Changes and Lower Metabolic Flexibility in Cardiometabolic Diseases