THE EFFECT OF 2 FREQUENT AMINO-ACID VARIANTS OF THE HEPATOCYTE NUCLEAR FACTOR-1-ALPHA GENE ON ESTIMATES OF THE PANCREATIC BETA-CELL FUNCTION IN CAUCASIAN GLUCOSE-TOLERANT FIRST-DEGREE RELATIVES OF TYPE-2 DIABETIC-PATIENTS

The objective of the present study was to investigate whether the freq uent amino acid polymorphisms, Ile/Leu27 and Ser/Asn487, of the hepato cyte nuclear factor-la gene were associated with alterations in glucos e-induced serum C-peptide and serum insulin responses among glucose-to lerant first-degree relatives of type 2 diabetic patients. The study c omprised 2 independent Danish cohorts. Among 74 unrelated type 2 diabe tic relatives, 12 homozygous carriers of the Ile/Leu27 polymorphism ha d a 32% decrease in the 30-min serum C-peptide level(P = 0.01), as wel l as a 39% decrease in the 30-min serum insulin level (P = 0.02) durin g an oral glucose tolerance test. Ten homozygous carriers of the Ile/L eu27 variant did, however, not differ from wildtype carriers, with res pect to the acute circulating insulin and serum C-peptide responses du ring an iv glucose tolerance test in the same study cohort. In a large r (more than 3-fold) study group of 230 glucose tolerant offspring of 62 type 2 diabetic probands, 33 homozygous carriers of the Ile/Leu27 v ariant did not differ, with respect to either serum insulin and serum C-peptide levels during an oral glucose tolerance test or acute serum insulin and serum C-peptide responses during an iv glucose tolerance t est;. We therefore consider the former positive finding as a statistic al type I error. There were no differences in the above mentioned vari ables between carriers of the Ser/Asn487 polymorphism and wild-type ca rriers within any of the 2 study populations. Nor did carriers of comb ined genotypes, i.e. carriers of both the Ile/Leu27 and the Ser/Asn487 variants, show any associations with the examined variables. In concl usion, the Ile/Leu27 and Ser/Asn487 polymorphisms of the hepatocyte nu clear factor-1 alpha gene have apparently no major impact on the pancr eatic p-cell function, after an oral and iv glucose challenge, in Cauc asian first-degree relatives of type 2 diabetic patients.