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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

	Abstract

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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.

	Introduction

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TYPE 2 DIABETES is a heterogeneous disorder with a complex pattern of inheritance and is characterized by both ß-cell dysfunction and insulin resistance. Although pancreatic ß-cells are the only cells in the body that secrete insulin, insulin resistance could occur in various tissues, including liver and muscle (1). The causes of ß-cell failure and insulin resistance in the common form of type 2 diabetes are largely unknown, but identification of the genes responsible will provide insights into basic mechanisms and etiologies. Although maturity-onset diabetes of the young (MODY), characterized by early onset (before age 25 yr) and autosomal dominant inheritance (2), only accounts for a very small subset of type 2 diabetes, it demonstrates major progress in identification of the gene for type 2 diabetes.

Hepatic nuclear factor-1 (HNF-1) is a liver-enriched transcription factor that plays a role in the regulation of several liver-specific genes. It binds to the promoters of a variety of developmentally regulated genes expressed exclusively in the liver, including albumin, 1-antitrypsin, and fibrinogen (3). Mice without HNF-1 fail to thrive and develop a progressive wasting syndrome with marked hepatomegaly after weaning (4). They have massive urinary glucose loss, which is attributed to the proximal renal tubular dysfunction but not to the effect of the HNF-1 on glucose metabolism.

The role of HNF-1 in glucose homeostasis was not appreciated until the discovery of mutations in HNF-1 (5) in patients with MODY. Although numerous mutations (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17) have been identified in MODY patients, it is generally believed that mutations in the HNF-1 gene are not a major cause of the common form of type 2 diabetes (7, 11, 18, 19, 20, 21). Nonetheless, three amino acid polymorphisms (I27L, A98V, and S487N) in HNF-1 have been described in patients with the common form of type 2 diabetes and nondiabetic subjects (7, 11, 19, 20, 21, 22). Although no biological consequences have been reported for S487N, the A98V polymorphism was shown to contribute to the interindividual variation in serum C peptide response (23) and to be associated with a 20% decrease in the insulin response (24) during an oral glucose tolerance test (OGTT) in nondiabetic subjects. The biological significance of the I27L polymorphism is less certain. Urhammer et al. (25) reported that the I27L polymorphism was associated with a 30% decrease in insulin secretion at 30 min after an oral glucose load in relatives of type 2 diabetic patients, but the results could not be replicated in another group of subjects (25).

It has been hypothesized that the ß-cell defect in patients with the common form of type 2 diabetes will be much more subtle than that in patients with MODY (26), and the defect may be neither necessary nor sufficient for the development of diabetes (27). Furthermore, various genome-wide searches for type 2 diabetes genes indicated a linkage between the MODY3 region and type 2 diabetes (28, 29). Therefore, we examined the impact of the I27L polymorphism on insulin secretion and insulin sensitivity using the hyperglycemic clamp technique.

	Subjects and Methods

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Study subjects

Biologically unrelated subjects were invited to undergo a screening OGTT with 75 g glucose and a brief physical examination as previously described (30, 31). To minimize the effects of these possible confounding factors and optimize the chance of detecting a modest effect of a genetic influence, only healthy subjects who received no medical treatment were enrolled. Only those subjects with a fasting plasma glucose level less than 6.1 mmol/L, a 2-h postchallenge plasma glucose level less than 7.8 mmol/L, and all interval plasma glucose levels less than 11.1 mmol/L were invited back for the assessment of insulin sensitivity and ß-cell function using the hyperglycemic clamp technique (32). As hypertension is also known to be associated with insulin resistance (33), hypertensive subjects were not included. Hypertension was defined by either diastolic blood pressure of 90 mm Hg or more or systolic blood pressure of 140 mm Hg or more. The blood pressure was the average of three measurements as described previously (31). Thus, this study included 52 subjects (31 women and 21 men), aged 26 ± 1 yr (mean ± SE), with a body mass index of 24.50 ± 0.63 kg/m² and a waist/hip ratio of 0.79 ± 0.01. Twenty-six subjects were Caucasian, 12 were Asian American, 9 were Mexican American, and 5 were African American. The study was approved by the institutional review board, and written informed consent was obtained from each participant before entering the study.

Hyperglycemic clamp

Subjects were admitted to the General Clinical Research Center the night before the clamp study. To minimize the effect of smoking, smokers (n = 5) were asked to refrain from smoking for at least 12 h before the clamp. Among 31 female subjects, 7 of them used birth control pills. After a 12-h overnight fast, participants received a bolus of glucose based on their body surface area (11.4 g/m²) at time zero. A continuous infusion of 30% glucose solution was commenced at 15 min at a variable rate, which was adjusted every 5 min to maintain a plasma glucose level around 10 mmol/L. The first phase insulin response was the sum of plasma insulin levels during the first 10 min (2.5, 5, 7.5, and 10 min), and the second phase insulin response was the average of plasma insulin levels at 130, 140, 150, 160, 170, and 180 min. The insulin sensitivity index was calculated by dividing the average glucose infusion rate during the last 60 min of the clamp by the average plasma insulin level. Fasting plasma glucose and insulin levels were the average of 3 samples before glucose loading (OGTT and hyperglycemic clamp). Plasma glucose, insulin, and lipid were assayed as previously described (30).

DNA extraction and genotyping

Genomic DNA was extracted from peripheral leukocytes as previously described (34). The I27L polymorphism was genotyped using a PCR-restriction fragment length polymorphism (20).

Statistical analysis

Data are presented as the arithmetic mean ± SE unless otherwise specified. The SYSTAT 8.0 for Windows package from SPSS, Inc. (Chicago, IL) was used for statistical analysis. Differences in continuous variables among the three genotypic groups were tested with one-way ANOVA, and categorical variables were evaluated by the ² test. Continuous variables, which failed the normality test (age, body mass index, waist/hip ratio, plasma insulin levels, insulin area under curve, insulin sensitivity index, and first and second phase insulin responses), were logarithmically transformed before analysis. A stepwise regression strategy (35) was employed to examine the effect of covariates on the parameter of interest (insulin sensitivity index and first and second phase insulin responses). The continuous covariates were age, body mass index, waist/hip ratio, and systolic and diastolic blood pressures. The categorical covariates were gender and ethnicity. Backward stepwise option with -to-enter of 0.10 and -to-remove of 0.10 was employed to exclude covariates that had much less or no influence on the parameter under analysis, one at a time starting from the one with the least impact, which was based on the P value (the highest P value). Stepwise regression analysis was stopped when all P values of all covariates examined were less than 0.10. P < 0.05 (two-tailed) was considered significant.

	Results

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Genotyping showed that 19 subjects had the LL, 24 IL, and 9 II genotypes. The allelic frequencies were 59.6% for the L allele and 40.4% for the I allele. The observed genotypic frequencies were in compliance with the Hardy-Weinberg equilibrium. Table 1 showed the characteristics of subjects by genotypes. There was no difference in age, body mass index, waist/hip ratio, blood pressure, or the distribution of gender and ethnicity (Table 1). During the OGTT (Fig. 1), the plasma glucose level at 90 min differed among the three genotypes (P = 0.026), but there was no difference in the glucose area under the curve among the three groups. The plasma insulin levels for the LL group were higher at 30 and 60 min than those of the IL and II groups (P = 0.038 and P = 0.015, respectively). Furthermore, the insulin area under curve of the LL group was significantly higher than that of the IL or II group (P = 0.009). These observations suggested that the LL group was more insulin resistant than the IL or II group.

View larger version (16K): [in this window] [in a new window]   Figure 1. Plasma glucose and insulin levels during the oral glucose tolerance test by the I27L genotypes. The data presented are the arithmetic mean ± SE for plasma glucose and the geometric mean ± SE for plasma insulin. The plasma glucose levels were different at 90 min (a, P = 0.026). The plasma insulin levels were different at 30 (b, P = 0.038) and 60 (c, P = 0.015) min. The insulin areas under the curve were different (P = 0.009).

As shown in Table 2, stepwise regression analysis showed that insulin sensitivity index was a determinant of ß-cell function (r² = 0.343 and P < 0.001 for the first phase insulin response; r² = 0.451 and P < 0.001 for the second phase insulin response), whereas other covariates had no influence on ß-cell function. After adjusting for the insulin sensitivity index, the I27L genotype had no impact on either the first phase (P = 0.301) or the second phase insulin response (P = 0.268), suggesting that this polymorphism does not play a role in regulating ß-cell function. In glucose-tolerant subjects, the insulin sensitivity index and ß-cell function are reciprocally interrelated to maintain plasma glucose within a relatively narrow physiological range. The trend of ß-cell function observed (Table 1) could well be the result of compensatory ß-cell response to the prevailing insulin sensitivity. However, the trend, especially the first phase insulin response (Fig. 2), remained even after adjustment for the insulin sensitivity index.

View larger version (28K): [in this window] [in a new window]   Figure 2. Adjusted first phase insulin response, second phase insulin response, and insulin sensitivity index. They were logarithmically transformed before analysis and expressed as the geometric mean ± SE. First and second phase insulin responses were adjusted for insulin sensitivity index. The insulin sensitivity index was adjusted for age, gender, waist to hip ratio, and ethnicity.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our data show that the I27L polymorphism of HNF-1 was significantly associated with insulin resistance, but not ß-cell function. This finding was rather unexpected, because mutations in the HNF-1 gene lead to ß-cell dysfunction in MODY3 patients (36). Furthermore, the HNF-1 knockout mice are characterized by defective insulin secretion (37). Nonetheless, our observations of no impact on ß-cell function are consistent with the observation by Urhammer et al. (25). They studied the effect of the I27L polymorphism on 99 Caucasian glucose-tolerant subjects and found no apparent major impact on pancreatic ß-cell function.

However, the molecular mechanism of the association between the I27L polymorphism and insulin resistance is not clear. In contrast to ß-cell dysfunction in the MODY3 patients with mutated HNF-1 (10, 36, 38, 39) and in the HNF-1 knockout mice (37), insulin resistance has not been reported. HNF-1 had been showed to be expressed in liver, kidney, and intestine (4), but its role in other tissues, such as muscle and adipose tissue, has not been examined systemically. Therefore, it is not known whether HNF-1 could play a role in regulating peripheral insulin action. It is possible that HNF-1 could affect hepatic insulin sensitivity through regulating the enzymes involved in hepatic glucose metabolism or its response to insulin. For example, HNF-1 has been shown to act as an accessory factor to enhance the inhibitory action of insulin on glucose-6-phosphatase gene transcription (40). In addition, it has been speculated that HNF-1 knockout mice had a constitutively active gluconeogenic pathway (4). Unfortunately, the method used in the current study measured whole body insulin sensitivity and did not provide separate estimates of the peripheral and hepatic components. Direct measurement of hepatic insulin sensitivity is needed to confirm this postulate.

The data were examined further to exclude that the observed difference in insulin sensitivity was a result of interaction with other confounding factors, such as the use of birth control pills, smoking, and ethnicity. First, there was no difference in the use of birth control pills among the three groups (three in LL, three in IL, and one in II groups), and those who took birth control pills were excluded from analysis (n = 7). The I27L polymorphism was an independent determinant of the insulin sensitivity index after adjusting for age, gender, waist/hip ratio, and ethnicity, with a P value of 0.001 (n = 45). To minimize the effect of smoking, smokers (n = 5) were asked to refrain from smoking for 12 h before the hyperglycemic clamp. No difference was noted in the distribution of smokers among the three groups (two in LL, three in IL and zero in II groups). In addition, we analyzed a subset of the sample group (n = 47) in which smokers were excluded, and we found that the I27L had an independent impact on the insulin sensitivity index (P = 0.001) after adjusting for age, gender, waist/hip ratio, and ethnicity. Finally, similar results were obtained in the Caucasians when analyzed separately. Therefore, we concluded that the observed difference in insulin sensitivity among the three groups was not affected by these potential covariates.

In this study we observed that the LL group was most insulin resistant, with the lowest adjusted insulin sensitivity index (3.778 µmol/L/m²·min/pmol/L) compared to the IL and II groups (6.762 and 6.268 µmol/L/m²·min/pmol/L, respectively). This association suggests that this polymorphism may play a role in the pathogenesis of type 2 diabetes. Insulin resistance has been shown to be a major pathophysiological feature that precedes and predicts the development of the disease (41, 42). Nonetheless, there are several reports examining the role of the I27L polymorphism in type 2 diabetes (7, 11, 19, 20, 21, 22, 43), and none of them concluded that the I27L polymorphism plays a role in glucose homeostasis. Among them, Urhammer et al (20) examined a larger sample size. Although they observed a marginal P value (P = 0.07), they rejected a role for the I27L polymorphism in type 2 diabetes. A marginal significant difference in the allelic frequency between diabetic and control groups (20) suggested that the I27L polymorphism could be a risk factor for type 2 diabetes if a much larger sample size was available.

In summary, we have shown that the I27L polymorphism of HNF-1 is associated with insulin resistance. It is possible that the I27L polymorphism per se may affect hepatic glucose metabolism, or it may be a genetic marker for another mutated gene in this region. Functional study of I27L and examination of the role of HNF-1 in hepatic glucose metabolism are required to resolve these issues.

	Acknowledgments

 
We thank the staff, especially Marcia Malmet and Barbara Carter, at the General Clinical Research Center of the University of California-Los Angeles for their continuous support. We also thank Jennifer L. McGullam and Jennifer E. McCarthy for their laboratory assistance, and Deborah Tan for secretary assistance.

	Footnotes

 
¹ This work was supported in part by USPHS Grant MO1-RR-00865 (University of California-Los Angeles General Clinical Research Center), NIH/NIDDK Grant RO1-DK-52337-01 (to K.C.C.), the Diabetes Action Research and Education Foundation (to K.C.C.), and the American Diabetes Association (to K.C.C.).

Received June 30, 1999.

Revised November 2, 1999.

Revised February 14, 2000.

Accepted February 27, 2000.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chiu, K. C. Articles by Saad, M. F. Search for Related Content PubMed PubMed Citation Articles by Chiu, K. C. Articles by Saad, M. F.