GLP1R haplotypes are associated with insulin secretion and sensitivity in children and adolescents with obesity

BACKGROUND: Glucagon-like peptide-1 (GLP-1) plays a key role in regulating glucose homeostasis and body weight, and GLP-1 receptor agonists have been developed and used for treating both type 2 diabetes and obesity. We hypothesized that genetic variation in the GLP-1 receptor gene (GLP1R) might be associated with the action of GLP-1 itself and, consequently, insulin sensitivity and/or secretion and circulating GLP-1, in a cohort of children and adolescents with overweight and obesity. METHODS: In a cohort of 1,025 Italian children with obesity, two GLP1R SNPs (rs6923761 and rs1042044) were analysed individually and as haplotypes. Associations with fasting (FPG, HbA1c, HOMA-IR) and OGTT-derived metabolic traits (IGI, Matsuda index, oDI, AUCins) were assessed using multivariable linear regression. In 26 children, selected according to their haplotype setting, circulating GLP-1 levels were measured during OGTT at 0, 30 and 120 minutes and analysed using mixed-effects models. RESULTS: rs6923761 variant was associated with Matsuda index, IGI, AUCins and AUCins/AUCglu ratio (p-all