Metabolic flexibility across the spectrum of glycemic regulation in youth

Authors: BACHA, FIDA - Children'S Nutrition Research Center (CNRC); BARTZ, SARA - Children'S Nutrition Research Center (CNRC); PUYAU, MAURICE - Children'S Nutrition Research Center (CNRC); ADOLPH, ANNE - Children'S Nutrition Research Center (CNRC); SHARMA, SUSAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/13/2021
Publication Date: 2/22/2021
Citation: Bacha, F., Bartz, S.K., Puyau, M., Adolph, A., Sharma, S. 2021. Metabolic flexibility across the spectrum of glycemic regulation in youth. Journal of Clinical Investigation. 6(4):e146000. https://doi.org/10.1172/jci.insight.146000.
DOI: https://doi.org/10.1172/jci.insight.146000

Interpretive Summary: Metabolic flexibility (MF) refers to the ability to utilize different fuels (fats and sugars) and to transition between them in the fasting state and after a meal. Impairment in metabolic flexibility is related to metabolic disease. However, it is not clear whether MF is impaired in obese youth and who is at risk. In this study, we investigated the metabolic flexibility in youth with normal weight and overweight status to determine who is at risk for impairment of MF and what drives it. We studied 104 adolescents, mean age 15.6+/-1.8 years. Youth with obesity (n=80) had different glucose tolerance status form normal glucose tolerant to type 2 diabetes. They were compared to 24 normal weight (NW) controls. We measured their body composition (fat mass, %body fat), abdominal fat (VAT) (MRI), glucose levels, and insulin sensitivity. We also used the indirect calorimetry method to measure the respiratory exchange ratio. This allows us to determine which fuel is being used by the body by measuring the CO2 produced and oxygen consumed during respiration. We found that adolescents with prediabetes and type 2 diabetes had lower MF compared with normal weight children, with no significant difference in MF between NW and obese children with normal glucose regulation. Insulin sensitivity and increased fatty acids in the blood were the major drivers of this impairment in MF, independent of the sugar levels. We therefore demonstrated that MF is defective in obese youth with prediabetes and type 2 diabetes. This is due to their severe insulin resistance which impairs the transport into the cells and the use of available fuels appropriately. We can now target MF in future research and find which interventions may improve it.

Technical Abstract: Metabolic flexibility (MF) refers to the relative ability to utilize lipid and carbohydrate substrates and to transition between them. It is not clear whether MF is impaired in obese youth and what the determining factors are. We investigated the determinants of MF (increased respiratory exchange ratio [RER] under insulin-stimulated conditions) in pubertal youth (n = 104; 15.6 +/- 1.8 years) with obesity across the spectrum of glucose tolerance compared with normal weight (NW) controls, including body composition (fat-free mass [FFM], %body fat), visceral adipose fat (VAT) (MRI), glycemia, and insulin sensitivity (IS) [3-hour hyperinsulinemic-euglycemic clamp with measurement of lipolysis([2H5] glycerol), free fatty acids (FFAs), and RER (indirect calorimetry)]. Youth with prediabetes and type 2 diabetes had lower RER and oxidative and nonoxidative glucose disposal compared with NW, with no significant difference in RER between NW and obese with normal glucose tolerance. In multiple regression analysis, ISFFM (B = 0.4, P =0.004), percentage suppression of FFAs (r = 0.26, P = 0.007), and race/ethnicity (B = –0.23, P =0.02) contributed to the variance in deltaRER (R2 = 0.30, P < 0.001) independent of percentage body fat (or VAT), sex, Tanner stage, and hemoglobin A1C. MF is defective at the extreme of the metabolic phenotype in obese youth with dysglycemia related to a defect in IS limiting substrate utilization.