Background: Candidate genes have been associated with development of obesity and diabetes. In three Caucasian population studies, the transcription factor 7-like 2 (TCF7L2) gene polymorphism rs7903146 (TT genotype) was predictive of the development of type 2 diabetes mellitus (T2DM). It is unclear whether TCF7L2 gene polymorphisms are associated with alterations of gastric motor functions or satiation. Aim: To determine whether genetic variations of TCF7L2 gene rs7903146 are associated with gastric emptying (GE), gastric accommodation (GA), satiation, satiety or postprandial plasma glucagon-like peptide 1 (GLP1) levels in overweight and obese people. Methods: 271 overweight or obese participants, predominantly Caucasian, underwent, on separate days, validated measurements of intermediate phenotypes: GE of solids and liquids by scintigraphy, gastric volume (GV) by SPECT during fasting and after 200mL Ensure® (accommodation GV), satiation (maximal tolerated volume, MTV) by Ensure® (1 kcal/mL) ingested at 30mL/min, satiety by kcal intake during a buffet meal ingested 4h after intake of the Ensure® meal for the GV test, and fasting and postprandial plasma GLP-1measured by radioimmunoassay. Genotyping of TCF7L2 gene rs7903146 was by TaqMan® SNP Assay. From the 271 participants, we identified 22 individuals with TCF7L2 rs7903146 TT homozygotes and 44 ageand gender-matched CC homozygotes. We tested associations of TCF7L2 genotype with each intermediate phenotype using ANCOVA based on the general genetic model. Results: Data are shown in table. Early phase of GE solids was faster with TCF7L2 TT compared to CC: T1/2 (p=0.031), GE lag time (or time for 10% emptied, p=0.031), percentage GE at 60min (p=0.029). However, percentage emptied at 2-4h was not different in the TT and CC groups. Mean postprandial GLP-1 levels (a measure of AUC) were higher in TT homozygotes compared to CC homozygotes (p=0.026). There were no associations of the TCF7L2 gene with age, BMI, GE of liquids, accommodation GV, satiation (MTV and aggregate symptoms score 30min postMTV), and satiety (kcal ingested 4h later). Although not statistically significant, the mean MTV was 140kcal greater with TT than CC genotype. Conclusion: TCF7L2 homozygous T genotype (rs7903146) is associated with faster gastric emptying of solids in overweight and obese adults; these findings may explain the propensity to develop postprandial hyperglycemia or T2DM, and the non-significant increase in kcal intake may contribute to obesity. The higher postprandial GLP-1 levels in TT homozygotes reflect the faster emptying of the first 50% of the meal; the data are consistent with elevated GLP-1 slowing the emptying of the second half of the meal. Overall, these data suggest important contribution of gastric function to the metabolic effects of TCF7L2 mechanisms. Funding: NIH DK67071