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 1025 Italian children with obesity, 2 GLP1R SNPs (rs6923761 and rs1042044) were analyzed individually and as haplotypes. Associations with fasting (FPG, HbA1c, HOMA-IR) and oral glucose tolerance test (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 analyzed using mixed-effects models. Results rs6923761 variant was associated with Matsuda index, IGI, AUCins, and AUCins/AUCglu ratio (P-all < .031). The haplotype A-C, tagging the rs6923761 variant, was associated with lower FPI, HOMA-IR, IGI, and AUCins (P < .02) as well as higher Matsuda index (P = .009). GLP-1 circulating concentrations varied over time, with lower levels observed at 120 minutes compared with baseline (P < .001). GLP1R haplotype A-C was associated with lower GLP-1 concentrations (P = .025). Conclusion 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.