Measuring Postprandial Metabolic Flexibility to Assess Metabolic Health and Disease

Metabolic abnormalities substantially increase the risk of noncommunicable diseases, which are among the leading causes of mortality globally. Mitigating and preventing these adverse consequences remains challenging due to a limited understanding of metabolic health. Metabolic flexibility, a key tenet of metabolic health, encompasses the responsiveness of interrelated pathways to maintain energy homeostasis throughout daily physiologic challenges, such as the response to meal challenges. One critical underlying research gap concerns the measurement of postprandial metabolic flexibility, which remains incompletely understood. We concisely review the methodology for assessment of postprandial metabolic flexibility in recent human studies. We identify 3 commonalities of study design, specifically the nature of the challenge, nature of the response measured, and approach to data analysis. Primary interventions were acute short-term nutrition challenges, including single- and multiple-macronutrient tolerance tests. Postmeal challenge responses were measured via laboratory assays and instrumentation, based on a diverse set of metabolic flexibility indicators [e.g., energy expenditure (whole-body indirect calorimetry), glucose and insulin kinetics, metabolomics, transcriptomics]. Common standard approaches have been diabetes-centric with single-macronutrient challenges (oral-glucose-tolerance test) to characterize the postprandial response based on glucose and insulin metabolism; or broad measurements of energy expenditure with calculated macronutrient oxidation via indirect calorimetry. Recent methodological advances have included the use of multiple-macronutrient meal challenges that are more representative of physiologic meals consumed by free-living humans, combinatorial approaches for assays and instruments, evaluation of other metabolic flexibility indicators via precision health, systems biology, and temporal perspectives. Omics studies have identified potential novel indicators of metabolic flexibility, which provide greater granularity to prior evidence from canonical approaches. In summary, recent findings indicate the potential for an expanded understanding of postprandial metabolic flexibility, based on nonclassical measurements and methodology, which could represent novel dynamic indicators of metabolic diseases.