The I27L amino acid polymorphism of hepatic nuclear factor-1alpha is associated with insulin resistance.
Mutations of the hepatic nuclear factor-1alpha (HNF-1alpha) gene have been found in patients with maturity-onset diabetes of the young. We examined the relation between the I27L polymorphism of HNF-1alpha and insulin sensitivity and beta-cell function assessed by a hyperglycemic clamp. This study included 52 healthy glucose-tolerant and normotensive subjects (age, 19-40 yr; body mass index, 17.58-35.61 kg/m2; waist/hip ratio, 0.65-1.03). We identified 19 LL subjects, 24 IL, and 9 II subjects. No difference was noted in the demographic features among the three genotypes. The LL group had the highest postchallenge insulin levels at 30 and 90 min (P = 0.038 and P = 0.015, respectively) and also the highest insulin area under curve (P = 0.009) among the three genotypes. The LL group was more insulin resistant than the IL and II groups (P = 0.042 for insulin sensitivity index). After adjusting for age, gender, obesity, and ethnicity, the I27L polymorphism was an independent determinant of the insulin sensitivity index (P = 0.001). However, it had no impact on either the first or second phase insulin response. Therefore, we conclude that the I27L polymorphism is associated with insulin resistance, but not beta-cell function. The mechanism of this association is unclear, but HNF-1alpha may play a role in regulating hepatic glucose metabolism.
Chiu
K C
KC
Department of Medicine, University of California School of Medicine, Los Angeles 90095, USA. kchiu@mednet.ucla.edu
Chuang
L M
LM
Ryu
J M
JM
Tsai
G P
GP
Saad
M F
MF
D000328:Adult; D019943:Amino Acid Substitution; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D001824:Body Constitution; D015992:Body Mass Index; D004268:DNA-Binding Proteins; D005006:Ethnicity; D005260:Female; D015309:Glucose Clamp Technique; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D008055:Lipids / Q000097:blood; D008297:Male; D009687:Nuclear Proteins; D011110:Polymorphism, Genetic; D014157:Transcription Factors / Q000235:genetics*
D001786:Blood Glucose; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D008055:Lipids; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta