The I27L amino acid polymorphism of hepatic nuclear factor-1alpha is associated with insulin resistance

J Clin Endocrinol Metab. 2000 Jun;85(6):2178-83. doi: 10.1210/jcem.85.6.6618.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Amino Acid Substitution*
  • Blood Glucose / metabolism
  • Blood Pressure
  • Body Constitution
  • Body Mass Index
  • DNA-Binding Proteins*
  • Ethnic Groups
  • Female
  • Glucose Clamp Technique
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Humans
  • Insulin / blood*
  • Insulin / metabolism
  • Insulin Resistance / genetics*
  • Insulin Secretion
  • Lipids / blood
  • Male
  • Nuclear Proteins*
  • Polymorphism, Genetic*
  • Transcription Factors / genetics*


  • Blood Glucose
  • DNA-Binding Proteins
  • HNF1A protein, human
  • HNF1B protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Insulin
  • Lipids
  • Nuclear Proteins
  • Transcription Factors
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta