title: TCF7L2 Genotype and α-Cell Function in Humans Without Diabetes.
abstract: The diabetes-associated allele in TCF7L2 increases the rate of conversion to diabetes; however, the mechanism by which this occurs remains elusive. We hypothesized that the diabetes-associated allele in this locus (rs7903146) impairs insulin secretion and that this defect would be exacerbated by acute free fatty acid (FFA)-induced insulin resistance. We studied 120 individuals of whom one-half were homozygous for the diabetes-associated allele TT at rs7903146 and one-half were homozygous for the protective allele CC. After a screening examination during which glucose tolerance status was determined, subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, FFA was elevated by infusion of Intralipid plus heparin. On the other study day, subjects received the same amount of glycerol as present in the Intralipid infusion. β-Cell responsivity indices were estimated with the oral C-peptide minimal model. We report that β-cell responsivity was slightly impaired in the TT genotype group. Moreover, the hyperbolic relationship between insulin secretion and β-cell responsivity differed significantly between genotypes. Subjects also exhibited impaired suppression of glucagon after an oral challenge. These data imply that a genetic variant harbored within the TCF7L2 locus impairs glucose tolerance through effects on glucagon as well as on insulin secretion.
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition Research, Mayo Clinic, Rochester, MN.
authors.forename: Meera
authors.initials: M
authors.lastname: Shah
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition Research, Mayo Clinic, Rochester, MN.
authors.forename: Ron T
authors.initials: RT
authors.lastname: Varghese
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition Research, Mayo Clinic, Rochester, MN.
authors.forename: John M
authors.initials: JM
authors.lastname: Miles
authors.affiliation: Department of Information Engineering, Università degli Studi di Padova, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Piccinini
authors.affiliation: Department of Information Engineering, Università degli Studi di Padova, Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dalla Man
authors.affiliation: Department of Information Engineering, Università degli Studi di Padova, Padova, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN.
authors.forename: Kent R
authors.initials: KR
authors.lastname: Bailey
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition Research, Mayo Clinic, Rochester, MN.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rizza
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition Research, Mayo Clinic, Rochester, MN vella.adrian@mayo.edu.
authors.forename: Adrian
authors.initials: A
authors.lastname: Vella
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000235:genetics*; D004655:Emulsions / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000502:physiology*; D005951:Glucose Tolerance Test; D005990:Glycerol / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010743:Phospholipids / Q000494:pharmacology; D013024:Soybean Oil / Q000494:pharmacology; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*
chemical_list: D004655:Emulsions; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D010743:Phospholipids; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C545823:soybean oil, phospholipid emulsion; D013024:Soybean Oil; D005934:Glucagon; D005990:Glycerol