title: The Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene contributes to the interindividual variation in serum C-peptide response during an oral glucose tolerance test: evidence from studies of 231 glucose-tolerant first degree relatives of type 2 diabetic probands.
abstract: The third form of maturity-onset diabetes of the young is caused by mutations in the hepatocyte nuclear factor-1alpha gene. Recently, we demonstrated an association between a prevalent polymorphism at codon 98, Ala/Val98, of this gene and a 20% decreased insulin release during an oral glucose tolerance test (OGTT) in middle-aged glucose-tolerant Danish Caucasian subjects. The major objective of the present study was to replicate this finding among glucose-tolerant first degree relatives of type 2 diabetic patients of the same ethnic origin. All participants, 231 glucose-tolerant offspring of 62 type 2 diabetic probands, underwent an OGTT with measurements of plasma glucose, serum insulin, and serum C peptide during the test. Thirty-three heterozygous carriers of the Ala/Val variant were identified, whereas no subjects had the variant in its homozygous form. Ala/Val carriers had a 20% reduction in serum C peptide at 30 min during the OGTT (1225+/-636 vs. 1507+/-624 pmol/L; P=0.02) compared to wild-type carriers. No significant differences in serum insulin levels during the OGTT were observed between carriers of the variant and Ala/Ala homozygotes. In conclusion, among Danish glucose-tolerant first degree relatives of type 2 diabetic patients the Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene is associated with a decreased serum C-peptide secretion during an OGTT. This finding confirms our previously reported observation of the functional importance of the variant to insulin secretion during an OGTT among middle-aged healthy subjects.
authors.affiliation: Steno Diabetes Center and Hagedorn Research Institute, Department of Medical Genetics, University of Copenhagen, Denmark.
authors.forename: S A
authors.initials: SA
authors.lastname: Urhammer
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: C T
authors.initials: CT
authors.lastname: Ekstrøm
authors.forename: H
authors.initials: H
authors.lastname: Eiberg
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D002096:C-Peptide / Q000097:blood*; D004268:DNA-Binding Proteins; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005947:Glucose / Q000502:physiology; D005951:Glucose Tolerance Test; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D011110:Polymorphism, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002096:C-Peptide; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D005947:Glucose