Objectives: Impaired fasting glucose (IFG) is a risk factor for the development of type 2 diabetes in adults. In obese children and adolescents, IFG and impaired glucose tolerance constitute distinct prediabetic stages, which do not necessarily coexist. Pathophysiological mechanisms leading to IFG in children have not been fully elucidated. Available data from cohorts of obese adolescents living in the US suggest a concurrent worsening of insulin sensitivity and β-cell function. If these results can be applied to European populations is currently unknown.
Methods: Here we combine our method for mathematical modelling of insulin secretion and disposal from 3h, 8 sample OGTT data in children and adolescents (Vogt et al., Am J Physiol Endocrinol Metab. 3111:E82-94, 2016) with a minimal model of glucose to estimate insulin sensitivity SI, β-cell responsiveness Phi, and insulin-independent glucose disposal (SG) in a population of n=284 (n=146 girls) obese children and adolescents (Øage 13.8 ± 3.0 years), ØBMI z-score 2.73 ±0.75. A subpopulation of n=34 children underwent a follow-up OGTT (median time to follow-up 1.92 years).
Results: Of the total study population, n=12 subjects were diagnosed with IFG. After adjustment for age, IFG subjects were characterized by a 12% lower β-cell responsiveness Phi (P<0.01), higher insulin sensitivity SI (+15%, P=0.05), and significantly decreased glucose effectiveness SG (-19%, P=0.04) compared to NFG subjects. In the follow-up cohort, all n=34 patients were NFG at baseline, and n=4 progressed from NFG to IFG. At baseline, SI did not differ between 'progressors' and stable subjects, but Phi was higher (60.8 pmol/min per mg/dl vs. 38.2 pmol/min per mg/dl) and SG was decreased in progressors compared to stable subjects (adjusted for age, each P<0.001). Progression from NFG to IFG was associated with a significant decline in β-cell responsiveness (-14.5 pmol/min per mg/dl), moderately decreasing insulin sensitivity (-4.2%), and significant worsening of SG (-17.5%; all p-values for intra- and inter-group comparisons <0.04, adjusted for age), whereas all three parameters remained unchanged in stable subjects.
Conclusions: Impaired fasting glucose is a prediabetic stage characterized by a defect in β-cell function and significantly impaired glucose effectiveness in our large cohort of obese children and adolescents living in Middle Europe. Our data demonstrates for the first time, that in children and adolescents progression from NFG to IFG is driven by declining β-cell function and a marked collateral decrease in insulin-independent glucose disposal, ultimately leading to disruption of fasting glucose homeostasis.
19 Sep 2019 - 21 Sep 2019