Mechanistic Insights Into the Heterogeneity of Glucose Response Classes in Youths With Obesity: A Latent Class Trajectory Approach

Abstract

Objective: In a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT).

Research design and methods: Latent class trajectory analysis was used to identify various glucose response profiles to a nine-point OGTT in 2,378 participants in the Yale Pathogenesis of Youth-Onset T2D study, of whom 1,190 had available TCF7L2 genotyping and 358 had multiple OGTTs over a 5 year follow-up. Insulin sensitivity, clearance, and β-cell function were estimated by glucose, insulin, and C-peptide modeling.

Results: Four latent classes (1 to 4) were identified based on increasing areas under the curve for glucose. Participants in class 3 and 4 had the worst metabolic and genetic risk profiles, featuring impaired insulin sensitivity, clearance, and β-cell function. Model-predicted probability to be classified as class 1 and 4 increased across ages, while insulin sensitivity and clearance showed transient reductions and β-cell function progressively declined. Insulin sensitivity was the strongest determinant of class assignment at enrollment and of the longitudinal change from class 1 and 2 to higher classes. Transitions between classes 3 and 4 were explained only by changes in β-cell glucose sensitivity.

Conclusions: We identified four glucose response classes in youths with obesity with different genetic risk profiles and progressive impairment in insulin kinetics and action. Insulin sensitivity was the main determinant in the transition between lower and higher glucose classes across ages. In contrast, transitions between the two worst glucose classes were driven only by β-cell glucose sensitivity.

Trial registration: ClinicalTrials.gov NCT01967849.

© 2022 by the American Diabetes Association.

Figures

Figure 1

Observed (solid lines) and predicted (dashed lines) glucose profiles (A), plasma insulin (B), and C-peptide (C) profiles; WBISI (D), insulin secretion rate profile (E), total insulin secretion as a function of insulin sensitivity (F), and achieved plasma glucose levels (G); β-cell glucose sensitivity (H), rate sensitivity (I), and potentiation (J); total insulin clearance (K); and prevalence of the T risk allele for the common TCF7L2 variant rs7903146 (L) in the four latent classes of glucose response patterns identified. Data are mean ± SEM (A–C, E, G) or median (IQR) (D, F, H–L). Different letters between groups indicate statistically significant differences (P < 0.05).

Figure 2

Model-predicted cumulative probability (risk) to be assigned to each of the four identified latent glucose pattern classes across ages in the longitudinal cohort (A) and in the subgroups of participants carrying the CT/TT or CC genotype (B). Probabilities are adjusted for sex and race/ethnicity.

Figure 3

Longitudinal changes in insulin sensitivity (WBISI) (A), insulin clearance (Clins) (B), β-cell glucose sensitivity (β-GS) (C), and β-cell rate sensitivity (β-RS) (D) across ages in males and females, adjusted for race/ethnicity and BMI. Odds ratios (95% CIs) for the transition from lower to higher latent glucose pattern classes for each 1-SD decrease in WBISI, Clins, β-GS, and β-RS adjusted for sex and race/ethnicity (E). Sqroot, square root.