Mo1567 – Impact of Genetic Variation in Glp-1 (Glucagon-Like Peptide 1) and Cck (Cholecystokinin) Receptors and Tcf7L2 on Gastric Emptying and Glycemia During Enteral Dextrose Infusion

Background: Nutrient-mediated release of CCK and GLP-1 regulate gastric emptying (GE) via duodenogastric feedback mechanisms.GLP-1 also maintains postprandial glycemia.Some patients with functional upper GI symptoms have rapid GE of unexplained etiology.In addition, one-third of such patients have impaired glucose tolerance (IGT) during enteral dextrose infusion (i.e., unrelated to rapid GE, Am J Gastro 2014;109:1910).Hence, we hypothesized that genetically-mediated impaired release and/or actions of CCK and GLP-1 may explain rapid GE and/or hyperglycemia in these patients.Aims.To explore the associations between common single nucleotide polymorphisms (SNPs) of CCK, GLP-1, and TCF7L2 and rapid GE and separately IGT in healthy people and patients with functional upper GI symptoms.Methods: GE of solids (296kcal), plasma glucose, GLP-1, and CCK concentrations during dextrose infusion (75gm, 200 kcal over 2 hours via nasoduodenal feeding tube), and genetic variants were evaluated in healthy asymptomatic controls and pts with functional upper GI symptoms.Of 51 subjects who consented to assessment of SNPs, GE and enteral dextrose infusion were respectively evaluated in 46 (29 controls and 17 patients) and 42 subjects (28 controls and 14 patients).Rapid GE was defined as GE t 50 less than the 10th %tile value in controls.Selected functionally relevant SNPs for which the minor allele frequency (MAF) is >0.2 in Caucasians were studied ie, rs6923761 (GLP-1 receptor), which is associated with GLP-1-mediated insulin secretion, rs1042044 (GLP-1 receptor), which is linked to increased morning cortisol levels, rs7903146 (TCF7L2 gene), which is associated with reduced fasting gastric volume, faster GE of liquids, reduced insulin secretion, and increased risk of type 2 DM, and rs1800857 (CCK receptor), where the T allele is associated with slow GE.Fischer's exact test and Wilcoxon rank sum test evaluated associations between SNPs and variables using a dominant model.Results.Among 51 subjects, the minor allele frequency in this (prior) studies were comparable: rs1042044 -0.43 (0.4), rs6923761 -0.3 (0.37), rs7903146 -0.27 (0.28), and rs1800857 -0.11 (0.13).GE was normal in 39, rapid in 4, and slow in 3 subjects.Glucose tolerance was normal in 38 and impaired in 4 subjects.The T allele at rs7903146 (TCF7L2) was associated (p=0.14) with numerically faster GE (Table ).The associations between the SNPs and demographic variables, GE t half , glucose tolerance and plasma GLP1 levels during glucose infusion were not significant.Conclusions.Confirming prior observations (Clin Trans Sci 2011;4:183-187) in a different cohort, there was a trend toward an association between rapid GE and the minor allele at rs7903146 in the TCF7L2 gene.However, this and other SNPs were not associated with plasma glucose or GLP1 concentrations during enteral dextrose infusion. Comparison of Physiological Parameters versus SNPs