The Ala/Val98 polymorphism of the hepatocyte nuclear factor-1 alpha 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

The third form of maturity-onset diabetes of the young is caused by mutatio ns in the hepatocyte nuclear factor-1 alpha 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 toler ance test (OGTT) in middle-aged glucose-tolerant Danish Caucasian subjects. The major objective of the present study was to replicate this finding amo ng glucose-tolerant first degree relatives of type 2 diabetic patients of t he 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 h eterozygous carriers of the Ala/Val variant were identified, whereas no sub jects had the variant in its homozygous form. Ala/Val carriers had a 20% re duction 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 d ifferences in serum insulin levels during the OGTT were observed between ca rriers 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-la gene is associated with a decreased serum C-peptide secretion during an OGTT. This finding con firms our previously reported observation of the functional importance of t he variant to insulin secretion during an OGTT among middle-aged healthy su bjects.