Glucose metabolism in high-risk subjects for type 2 diabetes carrying the rs7903146 TCF7L2 gene variant

Context: The mechanisms responsible for contribution of variants in the gene TFC7L2 to the risk for type 2 diabetes (T2DM) remains far from being completely understood, and available studies have generated nonunivocal results. Objective: We investigated the postprandial glucose metabolism in subjects at risk for T2DM carrying the TCF7L2 risk allele. Design, Setting, and Participants: Twenty-three subjects carrying the risk-conferring TCF7L2 genotypes (11 TT and 12 CT at rs7901346) and 13 subjects with wild-type genotype (CC) underwent a standard mixed-meal test (MMT) in combination with stable isotope tracers. Outcome Measurements: We evaluated endogenous and exogenous glucose fluxes and hormonal responses. Results: Fasting plasma glucose, insulin, C-peptide, glycated hemoglobin, endogenous glucose production, and plasma glucose clearance were similar in the three groups, whereas plasma glucagon levels were lower in both CT and TT than in CC (64 ± 20, 63 ± 18 and 90 ± 29 pg/mL, respectively; both P = .01). In response to the MMT, TT subjects had lower plasma glucose levels than CC subjects [mean area under the time-concentration curve (AUC) 6.1 ± 3.9 vs 7.1 ± 12.0 mmol/L, P = .04] and lower insulin secretion rate (mean AUC 385 ± 95 vs 530 ± 159 pmol/m² · min, P = .02). Initial (0-60 min) rate of appearance (Ra) of oral glucose was lower in TT compared with CT/CC (AUC 2.7 ± 1.1 vs 3.8 ± 1.2 ?mol/kg · min, P = .02) with no difference among the three groups in endogenous glucose production. The AUC<inf>0-60min</inf> for Ra of exogenous glucose (Ra<inf>ex</inf>) was positively correlated with the plasma glucose AUC<inf>0-60min</inf>. Total Ra<inf>ex</inf> AUC<inf>0-120min</inf> was correlated with total AUC<inf>0-120min</inf> of plasma glucose (r = 0.45, P < .01). Plasma glucagon-like peptide-1 and glucose-dependent insulinotropic peptide levels in response to the MMT were not affected by genotype. Conclusions: In subjects at risk for T2DM, the TCF7L2 polymorphisms were associated with reduced Ra<inf>ex</inf> into systemic circulation, causing reduced postprandial blood glucose increase and, in turn, lower insulin secretion rate with no impairment in ?-cell function. The reduced Ra<inf>ex</inf> is likely due to greater glucose retention in the splanchnic area.