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

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.

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.

rs6923761 variant was associated with Matsuda index, IGI, AUCins and AUCins/AUCglu ratio (p-all<0.031). The haplotype A-C, tagging the rs6923761 variant, was associated with lower FPI, HOMA-IR, IGI and AUCins (p < 0.02) as well as higher Matsuda index (p = 0.009). GLP-1 circulating concentrations varied over time, with lower levels observed at 120 min compared with baseline (p < 0.001). GLP1R haplotype A-C was associated with lower GLP-1 concentrations (p = 0.025).

GLP1R genetic variants, particularly rs6923761 and the A-C haplotype, are associated with distinct patterns of insulin secretion, insulin sensitivity, and circulating GLP-1 levels in children and adolescents with obesity. These findings provide new insights into the genetic architecture of incretin physiology.