β-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to type 2 diabetes

Abstract

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired β-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled β-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. β-Cell function parameters were derived from established mathematical models yielding β-cell glucose sensitivity (βCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-βCGS to the 2-h hyperglycemic clamp-βCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, βCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia.

Figure 1

Incretin peptides during the OGTT; early- and late-phase responses in GLP-1 (A), GIP (B), and PP (C) in obese adolescents with NGT (n = 173), IGT (n = 48), and T2D (n = 34). Plots are mean ± SEM. P values are for group differences by ANOVA.

Figure 2

Dose-response of insulin secretion rates and plasma glucose concentrations in obese youth with NGT, IGT, and T2D. Plots are mean ± SEM; the mean slope of the dose-response function is βCGS.

Figure 3

βCGS (A) and incretin effect (B) in obese adolescents with NGT (n = 173), IGT (n = 48), and T2D (n = 34). Differences among the three groups within each of the OGTT-βCGS and clamp-βCGS were analyzed with ANOVA. Tukey post hoc test for significant (P < 0.05) differences between any two groups is indicated with the same letter. Paired Student t test P values between the OGTT-βCGS and clamp-βCGS are shown above the bar graphs.

Figure 4

Relationship between βCGS and oral and intravenous glucose stimulation in the three study groups. The full lines are the best fits, and the dotted lines are their 95% CIs.