ESPE Abstracts

Introduction: Childhood obesity shows increasing numbers worldwide and presents as a global health issue due to multiple metabolic comorbidities. About 1 % of adolescents with obesity develop type 2 diabetes (T2D), however little is known about the genetic and pathophysiological background in young age. Genome-wide association studies in adults revealed genes with increased diabetes risk, most of them regulating insulin secretion. The objective of this study was to assess the prevalence of impaired glucose regulation (IGR) in a large clinical cohort of children and adolescents with obesity and to characterize insulin sensitivity and insulin secretion using data from the oral glucose tolerance test (OGTT). We also wanted to investigate adolescents with insulin secretion disorders more closely and analysed possible candidate genes of diabetes in a subcohort.

Methods: We included children and adolescents with overweight or obesity who completed an OGTT (glucose + insulin) in outpatient clinic. We calculated Matsuda Index, the area under the curve (AUC (Ins/Glu)) and an oral Disposition Index (ISSI-2) to estimate insulin resistance and beta-cell function. We identified patients with IGR and low beta cell function (maximum insulin during OGTT <200 mU/l) and tested a subgroup using Next Generation Sequencing (NGS) to identify possible mutations in 103 candidate genes (MODY, neonatal diabetes, syndromic diabetes, T2D susceptibility genes).

Results: The total group consisted of 903 children and adolescents with overweight or obesity. 4.5 % showed impaired fasting glucose, 9.4 % impaired glucose tolerance (IGT), and 1.2 % T2D. Matsuda Index (as a surrogate parameter of insulin sensitivity) and Total AUC (Ins/Glu) (as a surrogate parameter of beta cell function) showed a hyperbolic relationship. Out of 39 patients with low beta-cell function we performed genetic testing in a subgroup of 12 patients. We found 5 monogenetic defects (ABCC8 (n=3), GCK (n=1), GLI2/PTF1A (n=1)).

Conclusion: Using surrogate parameters of beta-cell function and insulin resistance can help to identify patients with insulin secretion disorder in clinical routine. The prevalence of 40 % mutations of known diabetes genes in the subgroup with low beta-cell function suggests a minimum of about 1.7 % monogenic T2D in a cohort of adolescents with obesity. A successful molecular genetic diagnosis can help to improve the individual therapy and enables genetic consultation of the family.