Comparison of the impact of the I27L polymorphism of the hepatocyte nuclear factor-1alpha on estimated and measured beta cell indices.
OBJECTIVE
We investigated the impact of the I27L polymorphism of the hepatocyte nuclear factor-1alpha gene on measured and estimated beta cell indices. We also examined the conservation of this amino acid among different species.


METHODS
Estimated first and second phase insulin responses (1stPH(S) and 2ndPH(S)) were estimated from oral glucose tolerance tests in 78 glucose tolerant subjects. Among these subjects, first and second phase insulin responses (1stIR and 2ndIR) were measured in 60 subjects. The I27L genotypes were determined from genomic DNA. We also reviewed the published peptide sequence data on this polymorphism.


RESULTS
The estimated beta cell indices correlated well with the measured indices. Although the impact of this polymorphism was noted in the measured indices (P<0.01 for 1stIR and P=0.04 for 2ndIR) from 60 subjects, the differences in the estimated indices were only noted in the extended sample set with 78 subjects (P=0.05 for 1stPH(S) and P=0.04 for 2ndPH(S)). This polymorphism occurs in the dimerization domain, which is completely conserved within human, rat, mouse and hamster. This amino acid is also conserved in chicken and zebrafish, but not in the frog. This conservation suggests a possible biological importance of this amino acid.


CONCLUSIONS
By increasing the sample size, we demonstrated the role of the I27L polymorphism in the pathogenesis of type 2 diabetes by using estimated beta cell indices. The conservation among species suggests a possible biological importance of this amino acid. Analysis of the published data confirms a modest role of this polymorphism in type 2 diabetes.
Chiu
Ken C
KC
Division of Endocrinology, Diabetes and Hypertension, University of California-Los Angeles School of Medicine, Los Angeles, CA, USA. kchiu@mednet.ucla.edu
Chuang
Lee-Ming
LM
Chu
Audrey
A
Yoon
Carol
C
Wang
Max
M
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*; D029961:Zebrafish Proteins
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; D029961:Zebrafish Proteins; C496491:hnf1a protein, zebrafish; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta