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The Ala/Val98 Polymorphism of the Hepatocyte Nuclear Factor-1 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 Probands¹

Steno Diabetes Center and Hagedorn Research Institute (S.A.U., T.H., C.T.E., O.P.), and University Institute of Medical Biochemistry and Genetics, Department of Medical Genetics, University of Copenhagen (H.E.), Copenhagen, Denmark

Address all correspondence and requests for reprints to: Søren Urhammer, M.D., Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Copenhagen, Denmark.

The third form of maturity-onset diabetes of the young is caused by mutations in the hepatocyte nuclear factor-1 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-1 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.

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