title: Diabetes-Associated Variation in TCF7L2 Is Not Associated With Hepatic or Extrahepatic Insulin Resistance.
abstract: A common genetic variation in TCF7L2 is associated with type 2 diabetes. However, the mechanism by which this occurs remains elusive. In addition to affecting insulin secretion, genetic variation at the TCF7L2 locus may alter insulin action or directly modify hepatic glucose metabolism. We sought to determine whether the diabetes-associated variant in this locus (the T allele of rs7903146) increases fasting endogenous glucose production (EGP), and impairs insulin-induced suppression of EGP and insulin-stimulated glucose disappearance. To address this, we studied individuals who were either homozygous for the diabetes-associated allele (TT) at rs7903146 or were homozygous for the protective allele (CC). Subjects were matched for other anthropometric characteristics and were studied using a euglycemic clamp. EGP and glucose uptake were measured using the tracer dilution technique, and the relative contribution of gluconeogenesis to EGP was quantitated using deuterated water corrected for transaldolase exchange. We report that the diabetes-associated variation in TCF7L2 did not associate with fasting EGP, insulin-induced suppression of EGP, and insulin-induced stimulation of glucose uptake. There was no association with the contribution of gluconeogenesis and glycogenolysis to EGP. These data indicate that genetic variation at TCF7L2 does not predispose an individual to type 2 diabetes by altering either hepatic or extrahepatic insulin action.
authors.affiliation: Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: Ron T
authors.initials: RT
authors.lastname: Varghese
authors.affiliation: Center for Neurosciences and Cell Biology, Department of Zoology, University of Coimbra, Coimbra, Portugal.
authors.forename: Ivan
authors.initials: I
authors.lastname: Viegas
authors.affiliation: Center for Neurosciences and Cell Biology, Department of Zoology, University of Coimbra, Coimbra, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barosa
authors.affiliation: Center for Neurosciences and Cell Biology, Department of Zoology, University of Coimbra, Coimbra, Portugal.
authors.forename: Catia
authors.initials: C
authors.lastname: Marques
authors.affiliation: Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: Meera
authors.initials: M
authors.lastname: Shah
authors.affiliation: Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rizza
authors.affiliation: Center for Neurosciences and Cell Biology, Department of Zoology, University of Coimbra, Coimbra, Portugal.
authors.forename: John G
authors.initials: JG
authors.lastname: Jones
authors.affiliation: Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN vella.adrian@mayo.edu.
authors.forename: Adrian
authors.initials: A
authors.lastname: Vella
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein
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