<i>TCF7L2</i> Genetic Variation Augments Incretin Resistance and Influences Response to a Sulfonylurea and Metformin: The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH).

Abstract

The rs7903146 T allele in transcription factor 7 like 2 (<i>TCF7L2</i>) is strongly associated with type 2 diabetes (T2D), but the mechanisms for increased risk remain unclear. We evaluated the physiologic and hormonal effects of <i>TCF7L2</i> genotype before and after interventions that influence glucose physiology. We genotyped rs7903146 in 608 individuals without diabetes and recorded biochemical data before and after <i>1</i>) one dose of glipizide (5 mg) on visit 1 and <i>2</i>) a 75-g oral glucose tolerance test (OGTT) performed after administration of metformin 500 mg twice daily over 2 days. Incretin levels were measured in 150 of the 608 participants. TT risk-allele homozygotes had 1.6 mg/dL higher baseline fasting glucose levels and 2.5 pg/mL lower glucagon levels per T allele than carriers of other genotypes at baseline. In a subset of participants, the T allele was associated with higher basal glucagon-like peptide 1 (GLP-1) levels at visit 1 (β = 1.52, <i>P</i> = 0.02 and β = 0.96, <i>P</i> = 0.002 for total and active GLP-1, respectively), and across all points of the OGTT after metformin administration. Regarding drug response, the T allele was associated with a shorter time (β = -7.00, <i>P</i> = 0.03) and a steeper slope (β = 0.23, <i>P</i> = 0.04) to trough glucose levels after glipizide administration, and lower visit 2 fasting glucose level adjusted for visit 1 fasting glucose level (β = -1.02, <i>P</i> = 0.04) and a greater decline in glucose level between visits (β = -1.61, <i>P</i> = 0.047) after metformin administration. Our findings demonstrate that common variation at <i>TCF7L2</i> influences acute responses to both glipizide and metformin in people without diabetes and highlight altered incretin signaling as a potential mechanism by which <i>TCF7L2</i> variation increases T2D risk.