Association of GLP1R polymorphisms with the incretin response: The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH)
Abstract
ABSTRACT PAPER 1 Objective: Polymorphisms in the gene encoding the glucagon-like peptide-1 receptor (GLP1R) are associated with type 2 diabetes, fasting glucose, and postprandial glucose, but their effects on incretin levels remain unclear. We evaluated the physiologic and hormonal effects of GLP1R genotypes before and after interventions that influence glucose physiology. Methods: We analyzed 5 type 2 diabetes-associated variants, rs761387, rs10305423, rs10305441, rs742762, and rs10305492 in GLP1R in 868 diabetes-free individuals and recorded biochemical data before and after a 5-mg glipizide challenge and a 75-g oral glucose tolerance test (OGTT) performed after administration of 500 mg of metformin twice daily over two days. We used an additive mixed-effects model to evaluate the association of these variants with glucose, insulin, and incretin levels over multiple timepoints. Incretin levels were measured in 143 of 868 participants. Results: The G-risk allele at rs761387 was associated with higher total GLP-1 (2.61 pmol/L, 95% CI 1.0.72–4.50, p=0.01) and total GLP-1 (2.61 pmol/L, 95% CI 0.04–5.18, p=0.04) per allele across multiple timepoints during the OGTT. After glipizide challenge, the G allele was associated with higher insulin levels per allele (2.01 IU/ml, 95% CI 0.26–3.76, p=0.02). The other variants were not associated with any of the outcomes tested. Conclusions: Genetic variation at GLP1R is associated with differences in GLP-1 levels following an oral glucose…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 1,000 participants or records.
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