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

Abstract

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 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; 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 two hours post-challenge. Plasma samples were assayed by high-resolution, non-targeted metabolomics with dual column liquid chromatography and ultra-high-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 ≥ one of four CMDs; 33% were obese, 6% had diabetes, 39% had hypertension, and 50% had metabolic syndrome. Log2-normalized ratios of feature peak areas (post-prandial:fasting) clustered separately among participants with versus without any CMDs. Among participants with CMDs, the meal challenge altered 1,756 feature peak areas (1,063 C18, 693 HILIC; all q<0.05). In individuals without CMDs, the meal challenge changed 1,383 feature peak areas (875 C18, 508 HILIC; all q<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<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.

Investigating the Postprandial Metabolome after Challenge Tests to Assess Metabolic Flexibility and Dysregulations Associated with Cardiometabolic Diseases

“…Therefore, other meal tests able to vehiculate several nutrients in a single bolus were designed [ 14 ]. Using a metabolomics approach, liquid mixed meals containing all the macronutrients were used to challenge the metabolism during the postprandial period [ 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ].…”

“…Overall, most studies reported a decrease in phenotypic flexibility after the meal challenge in populations with increased cardiometabolic risk [ 56 , 57 , 58 , 59 , 62 , 63 , 66 , 69 , 70 ]. A decrease in flexibility was characterized by an altered response of the lipid and energy postprandial metabolism consisting of a blunted suppression of lipolysis and ketogenesis in the early hours following food intake and later on, in the post-absorptive state, of a blunted shift back to lipid oxidation and ketogenesis for energy fueling ( Figure 1 ).…”

“…In addition to metabolic dysregulations specifically associated with T2D, Yu et al compared healthy controls ( n = 123) with subjects with a range of cardiometabolic abnormality ( n = 226), including obesity, hypertension, T2D and metabolic syndrome, 2 h after the ingestion of a mixed liquid meal [ 59 ]. The meal challenge resulted in changes in 1756 features in the cardiometabolic group vs. 1383 in the control group.…”

Several Metabolite Families Display Inflexibility during Glucose Challenge in Patients with Type 2 Diabetes: An Untargeted Metabolomics Study

“…Adipose tissue has been recognized as an important player in this pathological process [ 3 ]. Metabolic inflexibility is traditionally investigated through indirect calorimetry during hyperinsulinemic clamp [ 4 ] and has been associated with cardiometabolic diseases [ 5 ].…”