title: Glucose Metabolism in High-Risk Subjects for Type 2 Diabetes Carrying the rs7903146 TCF7L2 Gene Variant.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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 μmol/kg · min, P = .02) with no difference among the three groups in endogenous glucose production. The AUC0-60min for Ra of exogenous glucose (Raex) was positively correlated with the plasma glucose AUC0-60min. Total Raex AUC0-120min was correlated with total AUC0-120min 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 β-cell function. The reduced Raex is likely due to greater glucose retention in the splanchnic area.
authors.affiliation: Department of Clinical and Experimental Medicine (G.D., M.C., C.B., A.D., R.M., S.D.P.), University of Pisa, and Institute of Clinical Physiology (M.G., G.B., A.G.), 56124 Pisa, Italy; and Metabolic Unit (A.M.), Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Daniele
authors.affiliation: Department of Clinical and Experimental Medicine (G.D., M.C., C.B., A.D., R.M., S.D.P.), University of Pisa, and Institute of Clinical Physiology (M.G., G.B., A.G.), 56124 Pisa, Italy; and Metabolic Unit (A.M.), Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Gaggini
authors.affiliation: Department of Clinical and Experimental Medicine (G.D., M.C., C.B., A.D., R.M., S.D.P.), University of Pisa, and Institute of Clinical Physiology (M.G., G.B., A.G.), 56124 Pisa, Italy; and Metabolic Unit (A.M.), Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Comassi
authors.affiliation: Department of Clinical and Experimental Medicine (G.D., M.C., C.B., A.D., R.M., S.D.P.), University of Pisa, and Institute of Clinical Physiology (M.G., G.B., A.G.), 56124 Pisa, Italy; and Metabolic Unit (A.M.), Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bianchi
authors.affiliation: Department of Clinical and Experimental Medicine (G.D., M.C., C.B., A.D., R.M., S.D.P.), University of Pisa, and Institute of Clinical Physiology (M.G., G.B., A.G.), 56124 Pisa, Italy; and Metabolic Unit (A.M.), Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Basta
authors.affiliation: Department of Clinical and Experimental Medicine (G.D., M.C., C.B., A.D., R.M., S.D.P.), University of Pisa, and Institute of Clinical Physiology (M.G., G.B., A.G.), 56124 Pisa, Italy; and Metabolic Unit (A.M.), Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Dardano
authors.affiliation: Department of Clinical and Experimental Medicine (G.D., M.C., C.B., A.D., R.M., S.D.P.), University of Pisa, and Institute of Clinical Physiology (M.G., G.B., A.G.), 56124 Pisa, Italy; and Metabolic Unit (A.M.), Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Miccoli
authors.affiliation: Department of Clinical and Experimental Medicine (G.D., M.C., C.B., A.D., R.M., S.D.P.), University of Pisa, and Institute of Clinical Physiology (M.G., G.B., A.G.), 56124 Pisa, Italy; and Metabolic Unit (A.M.), Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.affiliation: Department of Clinical and Experimental Medicine (G.D., M.C., C.B., A.D., R.M., S.D.P.), University of Pisa, and Institute of Clinical Physiology (M.G., G.B., A.G.), 56124 Pisa, Italy; and Metabolic Unit (A.M.), Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.affiliation: Department of Clinical and Experimental Medicine (G.D., M.C., C.B., A.D., R.M., S.D.P.), University of Pisa, and Institute of Clinical Physiology (M.G., G.B., A.G.), 56124 Pisa, Italy; and Metabolic Unit (A.M.), Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Del Prato
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019518:Postprandial Period; D012306:Risk; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*
chemical_list: D001786:Blood Glucose; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D005947:Glucose