Objectives: Compared to the US, prevalence rates of T2DM in obese children are significantly lower in European countries. Data from cohorts of obese children living in the US suggest a concurrent worsening of insulin sensitivity and ß-cell function over the spectrum of glucose tolerance. If these results can be applied to European populations is currently unknown.
Methods: A combination of our novel method for mathematical modelling of insulin secretion and disposal from 3h, 8 sample OGTT data in children and adolescents (Am J Physiol Endocrinol Metab. 3111:E82-94, 2016) with a minimal model of glucose was used to estimate insulin sensitivity SI and β-cell responsiveness Φ in a population of n=285 (n=147 girls) obese children and adolescents (Øage 13.9±3.0 years), ØBMI z-score 2.74±0.75. A subpopulation of n=35 subjects underwent follow-up OGTTs (median time to follow-up 1.92 years).
Results: Of the total study population, n=23 subjects were diagnosed with IGT. Regrouping into quartiles of 2 h-glucose (q1: 5695 mg/dl, q2: 96109 mg/dl, q3: 110122, q4 123190 mg/dl) revealed a significant decrease of SI between each quartile of 2 h-glucose (P<0.03), whereas Φ was significantly lower in q3 and q4 compared to q1 and q2 (P<0.001). IGT was associated with a 64% lower SI and 36% lower Φ compared to NGT subjects (each P<0.001). Adjusted for age and BMI z-score, only the difference in Φ remained statistically significant (P 0.004). In the follow-up cohort, n=4 subjects progressed from NGT to IGT, n=5 reverted from IGT to NGT, and n=23 remained NGT. At baseline, progressors and reverters were characterized by a 30% lower Φ compared to stable subjects. Furthermore, reverters had a 1.6 times lower SI than stable subjects (P<0.02). Progression from NGT to IGT was associated with a 41% decline in SI while Φ remained unchanged. Conversely, reversion to NGT was associated with a 49% improvement of SI and an unchanged Φ.
Conclusions: β-cell function and insulin sensitivity continuously decline over the spectrum of glucose tolerance in obese European children and adolescents. Progression from NGT to IGT is heralded by an impairment of β-cell responsiveness, but ultimately driven by significant worsening of insulin sensitivity. Improvement of insulin sensitivity in the context of stable β-cell function leads to reversion of IGT. Therefore, stability of β-cell function may provide a pathophysiological explanation for the lower prevalence of T2DM in obese European compared to obese US adolescents.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology