Harrall Kylie K, Glueck Deborah H, Lange Leslie A, Litkowski Elizabeth M, Vanderlinden Lauren A, Konigsberg Iain R, Cree Melanie G, Perng Wei, Dabelea Dana
Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Health Outcomes and Biomedical Informatics, University of Florida School of Medicine, Gainesville, FL 32611, USA.
J Clin Endocrinol Metab. 2025 Aug 7;110(9):e3031-e3040. doi: 10.1210/clinem/dgae880.
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.
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.
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).
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.
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.
这是第一项研究胰高血糖素样肽 -1 受体基因（GLP-1R）变体与青少年代谢特征之间关联的研究。
我们探讨了 3 种 GLP-1R 多态性（rs10305420、rs6923761 和 rs1042044）与体重指数（BMI）轨迹以及葡萄糖 - 胰岛素稳态标志物之间的独立关联。
混合模型用于检验 GLP-1R 多态性与 BMI 轨迹之间的关联。线性模型用于检验 GLP-1R 多态性与口服葡萄糖耐量试验（OGTT）期间的葡萄糖和胰岛素浓度、胰岛素敏感性（HOMA2-IR）、胰岛素分泌（胰岛素生成指数和 HOMA2-%B）以及β细胞功能（口服处置指数）之间的关联。
rs10305420 和 rs6923761，而非 rs1042044，与早期生活中的生长和代谢特征相关。与次要等位基因携带者相比，rs6923761 基因型 GG 与更快的 BMI 生长速度相关（10 岁时速度差异[95%CI]：0.16/年[0.07 - 0.24]），这导致 16 岁时平均 BMI 显著更高（平均差异[95%CI]：1.29[0.22 - 2.37]）。与次要等位基因携带者相比，rs10305420 CC 和 rs6923761 GG 基因型具有更高的 HOMA2-IR（β[95%CI]：分别为 1.19%[1.06 - 1.32]和 1.13%[1.01 - 1.26]）。与次要等位基因携带者相比，rs10305420 CC 具有更高的 HOMA2-%B（β[95%CI]：1.09%[1.01 - 1.17]），并且在 30 分钟（β[95%CI]：27.62 μIU/mL[3.00 - 25.24]）和 120 分钟（β[95%CI]：18.94 μIU/mL[1.04 - 36.84]）时具有更高的刺激胰岛素分泌。
GLP-1R 多态性与整个发育过程中更快的 BMI 生长相关，以及与青春期较低的估计胰岛素敏感性和较高的代偿性胰岛素分泌相关。在未来关于肥胖和糖尿病遗传易感性的儿科研究中应考虑 GLP-1R 多态性。
