Abstract
BackgroundGlucagon-like peptide 1 (GLP-1) stimulates insulin secretion and reduces blood glucose in type 2 diabetes mellitus (T2DM). TCF7L2 rs7903146 polymorphism has been associated with decreased insulin secretion, reduced GLP-1 action, and possible impaired peripheral insulin sensitivity.ObjectivesTo evaluate the postprandial pancreatic hormone response in patients with T2DM carriers of the TCF7L2 variant rs7903146 (CT/TT) compared with noncarriers of this variant (CC) after treatment with the GLP-1 agonist exenatide.MethodsIntervention study. Patients with T2DM (n = 162) were genotyped for the TCF7L2 rs7903146 single nucleotide polymorphism (SNP). Individuals with CT/TT and CC genotypes were compared regarding basal serum levels of glucose, glycosylated hemoglobin A1C (HbA1c), HDL, uric acid, insulin, and C-peptide. A subset of 56 individuals was evaluated during a 500-calorie mixed-meal test with measurements of glucose, insulin, proinsulin, C-peptide and glucagon before and after treatment with exenatide for 8 weeks.ResultsPatients with genotypes CC and CT/TT presented similar glucose area under the curve (AUC) 0–180 min before treatment and a similar decrease after treatment (p < 0.001). Before exenatide, insulin levels at 30–120 min were higher in CT/TT versus CC subjects (p < 0.05). After treatment with exenatide, only CT/TT individuals demonstrated insulin reduction at 30–180 min during the meal test (p < 0.05). Patients with the CC genotype presented no differences in insulin concentrations before and after treatment. The areas under the glucagon curve between 0 and 180 min were similar before treatment and reduced after treatment in both groups (p < 0.001).ConclusionsThe presence of the TCF7L2 rs7903146 T allele in patients with T2DM was associated with increased secretion of insulin response to a mixed-meal test. Furthermore, after treatment with exenatide, only the carriers of the T allele showed significantly decreased postprandial plasma insulin peak levels comparing with non carriers.
Highlights
Modern genetic analysis is unquestionably one of the most powerful research tools in complex diseases such as diabetes
The presence of the TCF7L2 rs7903146 T allele in patients with type 2 diabetes mellitus (T2DM) was associated with increased secretion of insulin response to a mixed-meal test
After treatment with exenatide, only the carriers of the T allele showed significantly decreased postprandial plasma insulin peak levels comparing with non carriers
Summary
Modern genetic analysis is unquestionably one of the most powerful research tools in complex diseases such as diabetes. The canonical signaling pathway plays an important role in the modulation of cell proliferation and survival [25] In the intestine, this pathway regulates the expression of the proglucagon gene and consequent secretion of glucagon-like peptide 1 (GLP-1) by intestinal endocrine cells in response to meals [11]. The presence of polymorphic variants of TCF7L2 would determine a lower GLP-1 effect on target cells, which could be involved in the regulation of peripheral insulin sensitivity [21]. In addiction, it is questionable whether the presence of these variants would determine a functional defect in GLP-1 signaling in beta cells, as well as in liver and skeletal muscle tissues. TCF7L2 rs7903146 polymorphism has been associated with decreased insulin secretion, reduced GLP-1 action, and possible impaired peripheral insulin sensitivity
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