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

• Published in: Diabetes (New York, N.Y.) Vol. 46; no. 5; pp. 912 - 916
• Main Authors: Urhammer, S. A., Fridberg, M., Hansen, T., Rasmussen, S. K., Moller, A. M., Clausen, J. O., Pedersen, O.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.05.1997
• Subjects: Administration, Oral; Adult; Aged; Alanine - genetics; Amino Acids - genetics; Asparagine - genetics; C-Peptide - blood; Codon; DNA-Binding Proteins; Female; Glucose - administration & dosage; Glucose Tolerance Test; Hepatocyte Nuclear Factor 1; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 1-beta; Humans; Insulin - metabolism; Insulin Secretion; Isoleucine - genetics; Leucine - genetics; Male; Middle Aged; Nuclear Proteins; Polymorphism, Genetic; Serine - genetics; Transcription Factors - genetics; Valine - genetics
• ISSN: 0012-1797; 1939-327X; 0012-1797
• DOI: 10.2337/diabetes.46.5.912

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. S A Urhammer , M Fridberg , T Hansen , S K Rasmussen , A M Møller , J O Clausen and O Pedersen Steno Diabetes Center, Copenhagen, Denmark. Abstract 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.