The effect of two frequent amino acid variants of the hepatocyte nuclear factor-1alpha 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 frequent amino acid polymorphisms, Ile/Leu27 and Ser/Asn487, of the hepatocyte nuclear factor-1alpha gene were associated with alterations in glucose-induced serum C-peptide and serum insulin responses among glucose-tolerant first-degree relatives of type 2 diabetic patients. The study comprised 2 independent Danish cohorts. Among 74 unrelated type 2 diabetic relatives, 12 homozygous carriers of the Ile/Leu27 polymorphism had a 32% decrease in the 30-min serum C-peptide level (P = 0.01), as well as a 39% decrease in the 30-min serum insulin level (P = 0.02) during an oral glucose tolerance test. Ten homozygous carriers of the Ile/Leu27 variant did, however, not differ from wild-type carriers, with respect to the acute circulating insulin and serum C-peptide responses during an i.v. glucose tolerance test in the same study cohort. In a larger (more than 3-fold) study group of 230 glucose tolerant offspring of 62 type 2 diabetic probands, 33 homozygous carriers of the Ile/Leu27 variant 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 i.v. glucose tolerance test. We therefore consider the former positive finding as a statistical type I error. There were no differences in the above mentioned variables between carriers of the Ser/Asn487 polymorphism and wild-type carriers within any of the 2 study populations. Nor did carriers of combined genotypes, i.e. carriers of both the Ile/Leu27 and the Ser/Asn487 variants, show any associations with the examined variables. In conclusion, the Ile/Leu27 and Ser/ Asn487 polymorphisms of the hepatocyte nuclear factor-1alpha gene have apparently no major impact on the pancreatic beta-cell function, after an oral and i.v. glucose challenge, in Caucasian first-degree relatives of type 2 diabetic patients.
Urhammer
S A
SA
Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark.
Møller
A M
AM
Nyholm
B
B
Ekstrøm
C T
CT
Eiberg
H
H
Clausen
J O
JO
Hansen
T
T
Pedersen
O
O
Schmitz
O
O
D000328:Adult; D019943:Amino Acid Substitution; D001216:Asparagine; D002096:C-Peptide / Q000378:metabolism; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; 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 / Q000097:blood; D007515:Islets of Langerhans / Q000502:physiology*; D007532:Isoleucine; D007930:Leucine; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D012694:Serine; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics*
D002096:C-Peptide; 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