Association between allelic variants in the glucagon-like peptide 1 and cholecystokinin receptor genes with gastric emptying and glucose tolerance

Neurogastroenterol Motil. 2020 Jan;32(1):e13724. doi: 10.1111/nmo.13724. Epub 2019 Nov 5.

Abstract

Background: Nutrient-mediated release of cholecystokinin and glucagon-like peptide-1 (GLP-1) regulates gastric emptying (GE) via duodenogastric feedback mechanisms; GLP-1 also regulates postprandial insulin secretion. Some patients with functional upper gastrointestinal symptoms have impaired glucose tolerance during enteral dextrose infusion. Our hypothesis was that variants in CCK, GLP-1, and TCF7L2 (transcription factor 7-like 2 locus), which is associated with greatest genetic risk for development of type 2 diabetes mellitus, are associated with GE and independently with glucose tolerance. Our aims were to evaluate the associations between these GE, glucose tolerance, and these single nucleotide polymorphisms (SNPs).

Methods: Genetic variants, scintigraphic GE of solids, plasma glucose, insulin, and GLP-1 during enteral dextrose infusion (75gm over 2 hours) were measured. GE and enteral dextrose infusion were, respectively, evaluated in 44 (27 controls and 17 patients with functional dyspepsia or nausea) and 42 (28 controls, 14 patients) participants; of these, 51 participants consented to assessment of SNPs. Four functional SNPs were studied: rs6923761 and rs1042044 at GLP-1 receptor, rs7903146 (TCF7L2), and rs1800857 (CCK receptor).

Key results: Gastric emptying was normal in 38, rapid in 4, and delayed in two participants; 38 had normal, and four had impaired glucose tolerance. The T allele at rs7903146 (TCF7L2) was non-significantly associated (P = .14) with faster GE. The associations between SNPs and demographic variables, GE thalf , glucose tolerance and plasma GLP1 levels were not significant.

Conclusions & inferences: There is a trend toward an association between faster GE and the diabetes-associated allele at rs7903146 in TCF7L2. However, these SNPs were not associated with plasma glucose or GLP1 concentrations during enteral dextrose infusion.

Keywords: dumping; functional dyspepsia; glucose tolerance; insulin secretion.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Female
  • Gastric Emptying / genetics*
  • Gastrointestinal Diseases / genetics
  • Glucagon-Like Peptide 1 / genetics*
  • Glucose Intolerance / genetics*
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Receptors, Cholecystokinin / genetics*
  • Transcription Factor 7-Like 2 Protein / genetics*

Substances

  • Receptors, Cholecystokinin
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • Glucagon-Like Peptide 1