Metabolic flexibility across the spectrum of glycemic regulation in youth

JCI Insight. 2021 Feb 22;6(4):e146000. doi: 10.1172/jci.insight.146000.


BACKGROUNDMetabolic 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.METHODSWe investigated the determinants of MF (increased respiratory exchange ratio [ΔRER] 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)].RESULTSYouth with prediabetes and type 2 diabetes had lower ΔRER and oxidative and nonoxidative glucose disposal compared with NW, with no significant difference in ΔRER between NW and obese with normal glucose tolerance. In multiple regression analysis, ISFFM (β = 0.4, P = 0.004), percentage suppression of FFAs (r = 0.26, P = 0.007), and race/ethnicity (β = -0.23, P = 0.02) contributed to the variance in ΔRER (R2 = 0.30, P < 0.001) independent of percentage body fat (or VAT), sex, Tanner stage, and hemoglobin A1c.ConclusionMF is defective at the extreme of the metabolic phenotype in obese youth with dysglycemia related to a defect in IS limiting substrate utilization.FUNDINGUSDA/ARS Project Number 3092-51000-057.

Keywords: Diabetes; Insulin; Metabolism; Obesity.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipose Tissue / metabolism
  • Adolescent
  • Blood Glucose / metabolism*
  • Body Composition
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / metabolism
  • Fatty Acids, Nonesterified / metabolism
  • Female
  • Glucose / metabolism*
  • Glucose Clamp Technique
  • Glycated Hemoglobin / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance
  • Intra-Abdominal Fat / metabolism
  • Lipolysis
  • Male
  • Obesity / blood
  • Obesity / metabolism*
  • Oxidation-Reduction


  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Glycated Hemoglobin A
  • Insulin
  • hemoglobin A1c protein, human
  • Glucose