GLP-1R Gene Polymorphisms and Metabolic Traits During Childhood and Adolescence

Kylie K Harrall, Deborah H Glueck, Leslie A Lange, Elizabeth M Litkowski, Lauren A Vanderlinden, Iain R Konigsberg, Melanie G Cree, Wei Perng, Dana Dabelea
The Journal of Clinical Endocrinology & Metabolism, Volume 110, Issue 9, September 2025, Pages e3031–e3040
https://doi.org/10.1210/clinem/dgae880

Abstract

Context

This is the first study to examine the association between variants of the glucagon-like-peptide-1 receptor gene (GLP-1R) and metabolic characteristics among youth.

Objective

We explored separate associations of 3 GLP-1R polymorphisms (rs10305420, rs6923761, and rs1042044) with body mass index (BMI) trajectories and markers of glucose-insulin homeostasis.

Methods

Mixed models examined associations between GLP-1R polymorphisms and trajectories of BMI. Linear models examined associations of GLP-1R polymorphisms with glucose and insulin concentrations across oral glucose tolerance test (OGTT), insulin sensitivity (HOMA2-IR), insulin secretion (insulinogenic index and HOMA2-%B), and β-cell function (oral disposition index).

Results

Rs10305420 and rs6923761, but not rs1042044, were associated with growth and metabolic characteristics in early life. Rs6923761 genotype GG was associated with faster BMI growth velocity, when compared to carriers of the minor allele (difference in velocity [95% CI]: 0.16/year [0.07–0.24] at age 10), which led to significantly higher average BMI by age 16 (average difference [95% CI]: 1.29 [0.22–2.37]). Rs10305420 CC and rs6923761 GG genotypes had higher HOMA2-IR (β [95% CI]: 1.19% [1.06–1.32] and 1.13% [1.01–1.26], respectively) compared to minor allele carriers. Rs10305420 CC had higher HOMA2-%B (β [95% CI]: 1.09% [1.01–1.17]), and higher stimulated insulin secretion at 30 minutes (β [95% CI]: 27.62 μIU/mL [3.00–25.24]) and 120 minutes (β [95% CI]: 18.94 μIU/mL [1.04–36.84]), when compared to carriers of the minor allele.

Conclusion

GLP-1R polymorphisms are associated with faster BMI growth across development, and lower estimated insulin sensitivity and higher compensatory insulin secretion during adolescence. GLP-1R polymorphisms should be considered in future pediatric studies of genetic susceptibility for obesity and diabetes.

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