GLP-1R Variants May Influence Early Metabolic Traits in Children

Research study background

Experts in our Department of Pediatric Endocrinology at Children’s Hospital Colorado and the Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center are conducting research on the link between specific variations in the glucagon-like-peptide-1 receptor (GLP-1R) gene and metabolic traits among children.

Previous studies in adults have identified that common GLP-1R polymorphisms — rs10305420, rs6923761 and rs1042044 — are independently associated with below average metabolic outcomes. This study is among the few to evaluate these GLP-1R variants with body mass index (BMI) trajectories in children and the first to focus on obesity and glucose-insulin homeostasis during adolescence. Using historical data collected from the LEAD Center’s Exploring Perinatal Outcomes among Children (EPOCH) study, researchers analyzed longitudinal BMI measurements and oral glucose tolerance test (OGTT) results from 464 pediatric participants genotyped for the three variants.

Approximately half of the participants were female and 54% of the cohort identified as non-Hispanic white. More than one third of participants had identical copies of the major alleles of at least one variant, with a greater number of non-Hispanic white youth carrying these variants compared to other racial and ethnic groups.

Among the three variants studied, rs10305420 and rs6923761 were found to be linked to BMI growth and glucose-insulin homeostasis early in life. Participants with identical copies of the major alleles for these variants had lower insulin sensitivity during adolescence. Those with identical copies of rs6923761 experienced above-average BMI growth that began in middle childhood (around 10 years of age) and continued through adolescence, which could increase the risk for obesity throughout their lifetime.

Participants with identical copies of the major alleles for rs10305420 were less sensitive to insulin and secreted more insulin when fasting. They also had higher — but not significantly different — glucose levels at 30 and 120 minutes post-OGTT. Given that the major alleles for s10305420 are associated with a greater risk of type 2 diabetes in adults, researchers noted the potential for observable differences in insulin and blood sugar during fasting and after eating.

Clinical implications

These results suggest that common polymorphisms of the GLP-1R gene are linked to differences in BMI growth, insulin sensitivity and insulin secretion that can be detected as early as middle childhood. Future studies are needed to further validate these findings and determine whether the identified variants are directly associated with these outcomes. If they are, genotyping for GLP-1R could provide an important opportunity for early interventions to combat obesity and type 2 diabetes.