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/m(2).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 mu mol/kg.min, P =.02) with no difference among the three groups in endogenous glucose production. The AUC(0-60min) for Ra of exogenous glucose (Ra-ex) was positively correlated with the plasma glucose AUC(0-60min). Total Raex AUC(0-120min) was correlated with total AUC(0-120min) 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 Raex into systemic circulation, causing reduced postprandial blood glucose increase and, in turn, lower insulin secretion rate with no impairment in beta-cell function. The reduced Ra-ex is likely due to greater glucose retention in the splanchnic area.