A Reduced Incretin Effect Mediated by the rs7903146 Variant in the TCF7L2 Gene Is an Early Marker of β-Cell Dysfunction in Obese Youth

Abstract

The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 (TCF7L2) gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, b-cell function relative to insulin sensitivity, the gastrointestinalinduced glucose disposal (GIGD) in obese youth with normal and impaired glucose tolerance. RESEARCH DESIGN AND METHODSThirty-nine obese adolescents without diabetes (median age 15 [25th, 75th percentile 14, 18] years; BMI 37 [33,43] kg/m 2 ) were genotyped for the rs7903146 variant of TCF7L2 and underwent a 3-h oral glucose tolerance test (OGTT) followed by an isoglycemic intravenous glucose infusion (iso-intravenous glucose tolerance test [IVGTT]) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100 * (AUC-SR OGTT 2 AUC-SR iso-IVGTT ) / AUC-SR OGTT , where AUC-SR 5 area under the curve of C-peptide secretion rate.Participants were grouped into tertiles according to the percentage incretin effect (high, moderate, and low) to describe their metabolic phenotype. RESULTSThe presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared with the wild-type genotype (0.3% [27.2, 14] vs. 37.8% [12.5, 52.4], P < 0.002). When the cohort was stratified by incretin effect, the high, moderate, and low incretin effect groups did not differ with respect to anthropometric features, while the low incretin effect group exhibited higher 1-h glucose (P 5 0.015) and a reduced disposition index, insulin sensitivity, and insulin clearance compared with the high incretin effect group. GIGD was reduced in the low incretin effect group (P 5 0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. CONCLUSIONSA reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese youth without diabetes, featuring a higher plasma glucose peak at 1 h; lower insulin secretion, sensitivity, and clearance; and GIGD.

No detectable effect of a type 2 diabetes-associated TCF7L2 genotype on the incretin effect

“…The findings in our study are in contrast with findings from other functional association studies in which the T allele of TCF7L2 rs7903146 was found to impair the incretin effect ( 17 , 24 ) or incretin-induced insulin secretion during a hyperglycemic clamp ( 18 , 19 ). In a study by Villareal et al including 18 individuals (8 with CT/TT) with normal or impaired glucose tolerance, carriers of the risk T allele were characterized by a diminished incretin effect (measured by OGTT/IIGI method) compared to homozygous C allele carriers ( 17 ).…”

“…In a study by Villareal et al including 18 individuals (8 with CT/TT) with normal or impaired glucose tolerance, carriers of the risk T allele were characterized by a diminished incretin effect (measured by OGTT/IIGI method) compared to homozygous C allele carriers (17). This finding has been reproduced by Galderisi et al, who found the OGTT/IIGI-derived incretin effect to be reduced in T allele carriers compared to C allele carriers in a group of 39 obese adolescents with normal or impaired glucose tolerance (24). Supporting this, Schäfer et al conducted a sophisticated study in which 73 individuals (38 with CT/TT) underwent a hyperglycemic clamp with a continuous intravenous GLP-1 infusion (1.5 pmol × kg -1 × min -1 ) (18).…”

“…TCF7L2 may also exert its effect via regulation of neighboring genomic regions ( 15 ). The TCF7L2 variant has been linked to impaired incretin-stimulated insulin secretion as well as changes in incretin metabolism in a number of studies ( 12 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ). Additionally, functional studies of rs7903146 suggest that TCF7L2 activity has effects related to gastric function, early onset of type 2 diabetes, hepatic lipid metabolism, pancreatic islet function, proinsulin conversion and insulin synthesis and secretion ( 10 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ).…”

“…Together, these findings point to a central role for TCF7L2 in the pathogenesis of some type 2 diabetes phenotypes. In T allele carriers with obesity and/or impaired glucose tolerance, the incretin effect is reduced compared to their C allele carrier counterparts ( 17 , 24 ). However, the specific contribution of the T allele to the reduced incretin effect observed in these studies is difficult to disentangle as both obesity and reduced glucose intolerance is associated with a reduced incretin effect ( 34 , 35 ).…”

“…However, the specific contribution of the T allele to the reduced incretin effect observed in these studies is difficult to disentangle as both obesity and reduced glucose intolerance is associated with a reduced incretin effect ( 34 , 35 ). Nevertheless, the well-described impaired incretin effect in patients with type 2 diabetes may to some extent be caused by this specific genetic variation in TCF7L2 ( 17 , 24 ). We, therefore, evaluated the impact of the T allele of TCF7L2 rs7903146 on the incretin effect in individuals with normal glucose tolerance and participants with type 2 diabetes separately to see if the findings from previous functional association studies applying the same methods as here were reproducible in these groups of participants.…”