Metabolic Flexibility Across the Spectrum of Glycemic Regulation in Youth

Authors

Fida Bacha
Sara Klinepeter Bartz
Maurice Puyau
Anne Adolph
Susan Sharma

Publication Date

2-22-2021

Journal

JCI Insight

DOI

10.1172/jci.insight.146000

PMID

33616083

PMCID

PMC7934924

PubMedCentral® Posted Date

2-22-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

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

Abstract

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.