Metabolic and Genetic Determinants of Glucose Shape After Oral Challenge in Obese Youths: A Longitudinal Study

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CONTEXT: The time-to-glucose-peak following the oral glucose tolerance test (OGTT) is a highly reproducible marker for diabetes risk. In obese youths, we lack evidence for the mechanisms underlying the effects of the TCF7L2 rs7903146 variant on glucose peak. METHODS: We analyzed the metabolic phenotype and the genotype for the TCF7L2 rs7903146 in 630 obese youths with normal (NGT) and impaired (IGT) glucose tolerance. Participants underwent a 3-hour, 9-point OGTT to estimate, using the oral minimal model, the disposition index (DI), the static (φstatic) and dynamic (φdynamic) components β-cell responsiveness and insulin sensitivity (SI). In a subgroup (n = 241) longitudinally followed for 2 years, we estimated the effect of time-to-glucose-peak on glucose tolerance change. RESULTS: Participants were grouped into early (<30 minutes) and late (≥30 minutes) glucose peakers. A delayed glucose peak was featured by a decline in φstatic (P < .001) in the absence of a difference in φdynamic. The prevalence of T-risk allele for TCF7L2 rs7903146 variant significantly increased in the late peak group. A lower DI was correlated with higher glucose concentration at 1 and 2 hours, whereas SI was inversely associated with 1-hour glucose. Glucose peak <30 minutes was protective toward worsening of glucose tolerance overtime (odds ratio 0.35 [0.15-0.82]; P = .015), with no subjects progressing to NGT or persisting IGT, in contrast to the 40% of progressor in those with late glucose peak. CONCLUSION: The prevalence of T-risk allele for the TCF7L2 rs7903146 prevailed in the late time-to-glucose peak group, which in turn is associated with impaired β-cell responsiveness to glucose (φ), thereby predisposing to prediabetes and diabetes in obese youths.


  • Alfonso Galderisi
  • Domenico Tricò
  • Chiara Dalla Man
  • Nicola Santoro
  • Bridget Pierpont
  • Leif Groop
  • Claudio Cobelli
  • Sonia Caprio
Enheter & grupper
Externa organisationer
  • Yale University
  • University of Padova
  • Scuola Superiore Sant’Anna

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Endokrinologi och diabetes
  • Pediatrik


TidskriftThe Journal of clinical endocrinology and metabolism
Utgåva nummer2
StatusPublished - 2020
Peer review utfördJa