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The I27L Amino Acid Polymorphism of Hepatic Nuclear Factor-1 Is Associated with Insulin Resistance¹

Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, University of California School of Medicine, Los Angeles, California 90095; and Department of Internal Medicine and Graduate Institute of Clinical Medicine, National Taiwan University Hospital (L.-M.C.), Taipei 100, Taiwan

Address all correspondence and requests for reprints to: Ken C. Chiu, M.D., 675 Charles E. Young Drive South, 4629 MacDonald Research Laboratories, Los Angeles, California 90095-7097. E-mail: kchiu{at}mednet.ucla.edu

Mutations of the hepatic nuclear factor-1 (HNF-1) gene have been found in patients with maturity-onset diabetes of the young. We examined the relation between the I27L polymorphism of HNF-1 and insulin sensitivity and ß-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 ß-cell function. The mechanism of this association is unclear, but HNF-1 may play a role in regulating hepatic glucose metabolism.

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