A prevalent amino acid polymorphism at codon 98 in the hepatocyte nuclear factor-1alpha gene is associated with reduced serum C-peptide and insulin responses to an oral glucose challenge.
Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene cause the type 3 form of maturity-onset diabetes of the young (MODY3), which is characterized by a severe impairment of insulin secretion. In addition to disease-associated mutations, three common amino acid polymorphisms have been identified in the HNF-1alpha gene: Ile/Leu27, Ala/Val 98, and Ser/Asn487. We have addressed the question of whether these variants of the HNF-1alpha gene are associated with altered glucose-induced C-peptide and insulin responses or late-onset NIDDM. Among 245 NIDDM patients, the allelic frequency of the Val 98 variant was 3.7% (95% CI 2.0-5.4%) vs. 4.4% (2.6-6.2%) among 240 glucose tolerant control subjects (NS). Studies of genotype-phenotype interactions in 240 middle-aged control subjects showed, however, that heterozygous subjects (i.e., genotype Ala/Val 98) had an 18% decrease in 30-min serum C-peptide level (P = 0.004) as well as a 23% decrease in 30-min serum insulin level (P = 0.03) during an oral glucose tolerance test. One Val 98 homozygote subject had a more severe reduction in stimulated insulin and C-peptide levels. The impact of the homozygous carrier status was similar in a study of 377 healthy young subjects. In contrast, the Ile/Leu27 and Ser/Asn487 polymorphisms were not associated with altered C-peptide and insulin release or NIDDM. In conclusion, 8% of white subjects of Danish ancestry are heterozygous for the Ala/Val 98 polymorphism in the HNF-1alpha gene, which in middle-aged subjects is associated with a approximately 20% reduction in serum C-peptide and insulin responses 30 min after an oral glucose challenge. Val 98 homozygotes may exhibit a more severe defect in the early glucose-induced insulin response.
Urhammer
S A
SA
Steno Diabetes Center, Copenhagen, Denmark.
Fridberg
M
M
Hansen
T
T
Rasmussen
S K
SK
Møller
A M
AM
Clausen
J O
JO
Pedersen
O
O
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000409:Alanine / Q000235:genetics; D000596:Amino Acids / Q000235:genetics*; D001216:Asparagine / Q000235:genetics; D002096:C-Peptide / Q000097:blood*; D003062:Codon; D004268:DNA-Binding Proteins; D005260:Female; D005947:Glucose / Q000008:administration & dosage*; D005951:Glucose Tolerance Test; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007532:Isoleucine / Q000235:genetics; D007930:Leucine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D011110:Polymorphism, Genetic; D012694:Serine / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014633:Valine / Q000235:genetics
D000596:Amino Acids; D002096:C-Peptide; D003062:Codon; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D009687:Nuclear Proteins; D014157:Transcription Factors; D007532:Isoleucine; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D012694:Serine; D001216:Asparagine; D007930:Leucine; D014633:Valine; D005947:Glucose; D000409:Alanine