Impact of Metabolic Flexibility on Changes in Metabolic Health

Metabolic Syndrome, Obesity

Metabolic flexibility is the capacity to adapt fuel oxidation to fuel availability so that ATP synthesis can match its cellular demands. Thus, for example, increases in glucose availability after a meal would increase glucose oxidation, while increases in lipid availability during fasting would increase lipid oxidation. Enhanced metabolic flexibility has been proposed to protect humans from metabolic diseases. Nevertheless, most studies examining associations between metabolic flexibility and metabolic health outcomes have used cross-sectional designs. Whether impaired metabolic flexibility causes or results from metabolic health impairment is thus unclear. In this study, the investigators will use the data from a study conducted approximately 16 years ago in healthy participants without obesity. Using the data already collected in that study, the metabolic flexibility of each participant will be calculated. To test the association between metabolic flexibility and the change in metabolic health, the investigators will call back all the participants for a single follow-up visit to reassess several metabolic health outcomes. Thus, the main aim of the study is to test the association between metabolic flexibility and the change in metabolic health outcomes after 16 years in humans.

Metabolic flexibility is the capacity to adapt fuel oxidation to fuel availability so that ATP synthesis can match its cellular demands. Thus, for example, increases in glucose availability after a meal would increase glucose oxidation, while increases in lipid availability during fasting would increase lipid oxidation. Enhanced metabolic flexibility has been proposed to protect humans from ectopic lipid accumulation and the subsequent development of insulin resistance and metabolic syndrome. In humans, metabolic flexibility is assessed by measuring relative macronutrient oxidation (i.e., lipids and carbohydrates) in response to metabolic challenges that increase glucose or lipid availability. The respiratory exchange ratio (RER = CO2 production / O2 consumption) is used to determine relative macronutrient oxidation. The euglycemic-hyperinsulinemic clamp is a widely used challenge to assess metabolic flexibility as it increases glucose availability and thus relative glucose oxidation. Recently, other methods have been proposed to assess metabolic flexibility, including the relative lipid oxidation during an overnight fast or the difference between 24-hour RER and sleeping RER in non-exercise, energy balance conditions while staying in a metabolic chamber. The method most relevant for assessing the influence of metabolic flexibility and its effects on metabolic health outcomes is unknown. The influence of metabolic flexibility on metabolic health outcomes remains uncertain. The lack of agreement across studies is explained by the variability in the metabolic challenges, differences in the analytical approach to compute metabolic flexibility, and the loose use of the metabolic flexibility concept in the context of many different phenomena. Moreover, most studies examining associations between metabolic flexibility and metabolic health outcomes have used cross-sectional designs. Whether impaired metabolic flexibility causes or results from metabolic health impairment is thus unclear. Longitudinal studies using well-controlled methods are required to determine the impact of metabolic flexibility on prospective metabolic health. In this pilot and feasibility study, the investigators will use the data from a study conducted 16 years ago in 88 healthy participants without obesity (InSight study at Pennington Biomedical). The study included an euglycemic-hyperinsulinemic clamp, an overnight fasting assessment, a 24-hour stay in a metabolic chamber, and the measurement of metabolic health outcomes. Using the data already collected in the InSight study, the metabolic flexibility of each participant in the euglycemic-hyperinsulinemic clamp, the overnight fast, and the metabolic chamber will be calculated. To test the association between metabolic flexibility(ies) and the change in metabolic health outcomes, the investigators will call back all the participants for a single follow-up visit to reassess the metabolic health outcomes including body mass index, body composition, blood pressure, HOMA-IR, and the circulating concentrations of glucose, triglycerides, and cholesterol. Such data will shed light on the most informative method to assess metabolic flexibility in relationship to specific metabolic health outcomes. The investigators will use these preliminary data to design and power future projects to be submitted for funding to scientific federal agencies. Our specific aims are to: 1. Test the association between metabolic flexibility in response to a euglycemic-hyperinsulinemic clamp and the change in metabolic health outcomes after 16 years in humans. 2. Test the association between metabolic flexibility in response to overnight fasting and the change in metabolic health outcomes after 16 years in humans. 3. Test the association between metabolic flexibility in response to a 24-hour stay in a metabolic chamber and the change in metabolic health outcomes after 16 years in humans.

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