The I27L Amino Acid Polymorphism of Hepatic Nuclear Factor-1 Is Associated with Insulin Resistance

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Abstract
Mutations of the hepatic nuclear factor-1a (HNF-1a) gene have been found in patients with maturity-onset diabetes of the young. We examined the relation between the I27L polymorphism of HNF-1a and insulin sensitivity and b-cell function assessed by a hyperglyce- mic clamp. This study included 52 healthy glucose-tolerant and nor- motensive 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 postchal- lenge insulin levels at 30 and 90 min (P 5 0.038 and P 5 0.015, respectively) and also the highest insulin area under curve (P 5 0.009) among the three genotypes. The LL group was more insulin resistant than the IL and II groups (P 5 0.042 for insulin sensitivity index). After adjusting for age, gender, obesity, and ethnicity, the I27L poly- morphism was an independent determinant of the insulin sensitivity index (P 5 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 b-cell function. The mechanism of this association is unclear, but HNF-1a may play a role in regulating hepatic glucose metabolism. (J Clin Endocrinol Metab 85: 2178 -2183, 2000)

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