Anthropometric and Behavioral Correlates of Insulin-like Growth Factor I and Insulin-like Growth Factor Binding Protein 3 in Middle-aged Japanese Men
Satoshi Teramukai1,
Thomas Rohan2,
Hiroyuki Eguchi3,
Takashi Oda4,
Koichi Shinchi4 and
Suminori Kono1
1 Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
2 Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, NY.
3 Self Defense Forces Fukuoka Hospital, Kasuga, Fukuoka, Japan.
4 Self Defense Forces Kumamoto Hospital, Kumamoto, Japan.
Received for publication November 27, 2001; accepted for publication May 8, 2002.
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ABSTRACT
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High levels of plasma insulin-like growth factor I (IGF-I) and low levels of insulin-like growth factor binding protein 3 (IGFBP-3) have been related to increased risk of several cancers. Little is known about the behavioral determinants of these biologic markers. The authors examined the relation of anthropometric and behavioral factors to plasma concentrations of IGF-I and IGFBP-3 in a cross-sectional study of 616 Japanese men aged 4555 years in 19951996. In univariate analyses, body mass index was strongly, positively associated with both IGF-I and IGFBP-3. The waist/hip ratio was also linearly related to IGF-I and IGFBP-3 up to the third quartile level. Height was weakly, positively associated with IGF-I and IGFBP-3. Smoking was inversely associated with IGF-I and IGFBP-3. Alcohol use was associated inversely with IGF-I and positively with IGFBP-3. Neither IGF-I nor IGFBP-3 was related to physical activity. Results of the multivariate analysis were essentially the same as those of the univariate analyses. The findings regarding body mass index are in contrast to those of previous studies showing null or inverse associations, and they suggest that the relation of body mass index to IGF-I or IGFBP-3 may vary among populations. The study also indicates that smoking and alcohol use might affect plasma IGF-I and IGFBP-3.
alcohol drinking; body constitution; body mass index; insulin-like growth factor I; insulin-like growth factor binding protein 3; smoking
Abbreviations:
Abbreviations: IGF-I, insulin-like growth factor I; IGFBP-3, insulin-like growth factor binding protein 3; MET, metabolic equivalent.
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INTRODUCTION
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High circulating levels of insulin-like growth factor I (IGF-I) and low levels of insulin-like growth factor binding protein 3 (IGFBP-3) have been shown to be associated with increased risk of breast cancer (1), prostate cancer (2), lung cancer (3), and colorectal cancer (46). IGF-I is a mitogen regulating human growth and development, and it has been implicated in human carcinogenesis not only by stimulating cell division and proliferation but also by inhibiting apoptosis (79). IGFBP-3 can oppose the actions of IGF-I by binding IGF-I, but it also has an IGF-independent inhibitory effect on cell growth (79).
Given the role of the IGF family in the development of cancer, it is of interest to study factors related to plasma levels of IGF-I and IGFBP-3. Several studies have addressed the relation of lifestyle factors to circulating levels of IGF-I (1017). The findings of these studies are, however, rather inconsistent regarding the associations for obesity (1017), smoking (1014), alcohol use (1113), and physical activity (10, 11, 14). The inconsistencies may be due to between-study differences in both the characteristics of the study subjects and the IGF assay methods. Furthermore, few of these studies have examined the correlates of IGFBP-3 (12, 14, 17). In the study reported here, we examined the relation of body mass index, waist/hip ratio, smoking, alcohol use, and physical activity to plasma levels of IGF-I and IGFBP-3 in a population of middle-aged Japanese men.
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MATERIALS AND METHODS
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Study subjects
The study subjects were male self-defense officials who received a preretirement health examination at the Self Defense Forces Fukuoka Hospital between January 1995 and December 1996 or at the Self Defense Forces Kumamoto Hospital between May and December of 1996. They were engaged in diverse jobs related to the national defense. Details of the health examination have been described elsewhere (18, 19). A sample of 7 ml of venous blood was taken after an overnight fast following the provision of written informed consent, and aliquots of plasma were frozen at 80°C until analysis. In the consecutive series of 803 men aged 4555 years, plasma samples were not available for 187 men either because the sample was not stored (n = 149) or because the sample had been used previously for the measurement of plasma folate in a study of colorectal adenomas (n = 38). Thus, 616 men were included in the present study.
Information on lifestyle factors was obtained using a self-administered questionnaire. The questions on smoking, alcohol use, and physical activity have been described in detail elsewhere (19). For physical activity, reported types of recreational exercise were classified into light, moderate, heavy, and very heavy activities, using the published metabolic equivalents (METs) for different physical activities (20), and the time spent in exercise was multiplied by the corresponding MET value (light = 2, moderate = 4, hard = 6, and very hard = 8) to yield a MET-hour score. Height and body weight were recorded, and body mass index (kg/m2) was calculated. Waist and hip circumferences were measured to obtain the waist/hip ratio.
Laboratory methods
Plasma IGF-I and IGFBP-3 levels were determined by an immunoradiometric assay at an external laboratory (CRC, Fukuoka, Japan) using commercial kits (Dai-ichi Radioisotope Laboratories, Tokyo, Japan). The methods described by Scott et al. (21) and Blum et al. (22) were modified for the assay of IGF-I (23) and IGFBP-3 (24), respectively. The intraassay coefficients of variation based on 10 measurements of two standard samples with mean IGF-I concentrations of 62 and 859 ng/ml were 3.9 and 1.2 percent, respectively. The corresponding values for mean IGFBP-3 concentrations of 0.50 and 1.73 µg/ml were 5.0 and 5.8 percent, respectively. The sensitivity of the assay for IGF-I was 10 ng/ml and that for IGFBP-3 was 0.25 µg/ml.
Statistical analysis
One-way analysis of variance was used to calculate the means of IGF-I and IGFBP-3 and their molar ratio according to categories of the covariates of interest. Trends in the associations of interest were evaluated by a linear regression model with ordinal scores (0, 1, and 2 or 0, 1, 2, and 3) assigned to the categories of respective covariates. Height, body mass index, waist/hip ratio, and exercise were categorized by quartiles. Multiple linear regression analysis was used to examine the independent association with each covariate on a continuous scale. Because of the slightly skewed nature of the IGF-I distribution, natural logarithms of IGF-I were used when performing the multiple linear regression. Reported p values were two tailed. All statistical analyses were done using SAS version 6.12 software (SAS Institute, Inc., Cary, North Carolina).
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RESULTS
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Approximately 98 percent of the study participants were aged 5054 years. The mean body mass index was 23.6 kg/m2, and the mean waist/hip ratio was 0.90. Plasma concentrations of IGF-I and IGFBP-3 were highly correlated with each other (Pearsons correlation coefficient = 0.59).
Both IGF-I and IGFBP-3 levels varied substantially according to the body mass index, waist/hip ratio, and smoking status (table 1). Plasma concentrations of IGF-I and IGFBP-3 were progressively higher with increasing levels of body mass index. As regards the waist/hip ratio, IGF-I and IGFBP-3 levels increased up to the third quartile but fell at the highest level. Height seemed to be positively associated with IGF-I and IGFBP-3 levels. As compared with lifelong nonsmokers and former smokers, current smokers showed lower levels of IGF-I and IGFBP-3, and the levels of IGF-I were much lower among heavy smokers. Alcohol intake tended to be associated inversely with IGF-I but positively with IGFBP-3. Neither IGF-I nor IGFBP-3 showed a material association with age or physical activity. As for the molar ratio of IGF-I to IGFBP-3, only alcohol use was a statistically significant correlate, having an inverse association with the ratio.
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TABLE 1. Mean insulin-like growth factor I and insulin-like growth factor binding protein 3 according to lifestyle variables, Japan, 19951996*
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In the multiple linear regression analysis, which simultaneously included the covariates except waist/hip ratio as well as indicator variables for hospital and rank in the Self Defense Forces as independent variables, body mass index also showed strong, positive associations with IGF-I (p = 0.0001) and IGFBP-3 (p = 0.0001) but not with the IGF-I/IGFBP-3 ratio (p = 0.30). Results for age, height, smoking, alcohol intake, and exercise were essentially the same as those in the univariate analyses (data not shown).
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DISCUSSION
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The present study has an advantage over previous studies in that the study subjects were relatively homogeneous with respect to age, ethnicity, and occupation. In adults, age has been shown consistently to be inversely associated with IGF-I levels (1017). Therefore, the limited age range in this study yielded a notable advantage in examining the effects of other variables on IGF-I levels, but it prevented examination of the relation between age and IGF-I itself. A weakness is that more than 20 percent of the men in the consecutive series were not included in the present analysis. However, they were excluded mostly because the plasma sample was not stored.
The present study demonstrated that body mass index was positively associated with plasma IGF-I and IGFBP-3 in rather lean subjects; the mean body mass index was 23.6 kg/m2, and three quarters were under the standard cutoff for overweight (i.e., 25.0 kg/m2). Previous studies in Western countries showed null or inverse associations between body mass index and plasma IGF-I in men (10, 11, 13), women (10, 11, 14), and both sexes combined (12, 15, 16). Some of these studies also addressed the association between body mass index and IGFBP-3 and found no association (12, 14). In these studies, the means of body mass index ranged from 24.9 to 26.2 kg/m2 in men (10, 11), from 23.6 to 25.0 kg/m2 in women (10, 11, 14), and from 27.2 to 27.7 kg/m2 in men and women combined (12, 15). Contrary to the studies in Western countries, a recent study in China (17) reported positive associations of body mass index with both IGF-I and IGFBP-3 in men with a mean body mass index of 22.3 kg/m2 in the univariate analysis. The present findings are consistent with those in China, and they suggest that the relation of body mass index to plasma IGF-I and IGFBP-3 may vary among populations with different ranges of body mass index. It should be noted that men at the highest category of waist/hip ratio had lower concentrations of IGF-I and IGFBP-3 than did those at the next lower category of waist/hip ratio in the present study.
The observed inverse association of smoking with IGF-I and IGFBP-3 is consistent with the findings in one study (10) but not with those of other studies (1114). One of the latter studies reported a positive association of smoking with IGF-I and an inverse association with IGFBP-3 (12). Regarding alcohol use, of the few studies to date, one reported a positive association with IGF-I (11), one showed some suggestion of an inverse association with IGF-I (13), and one showed no association with either IGF-I or IGFBP-3 (12). The present study uniquely showed an inverse association of alcohol intake with IGF-I and a positive one with IGFBP-3. The findings that physical activity was not associated with either IGF-I or IGFBP-3 are in agreement with those of two previous studies involving men and women (10, 11) but not with those of a recent study of women (14). The latter showed higher levels of both IGF-I and IGFBP-3 associated with regular exercise (14).
In summary, in a population of relatively thin, middle-aged Japanese men, we observed that plasma levels of IGF-I and IGFBP-3 varied with body mass index, smoking, and alcohol intake. However, findings of studies on this topic have not been consistent. Further, in light of the association between IGF and cancer, the findings of both the present study and some of the previous studies seem to run counter to expectation given the associations between the exposures of interest and cancer risk. This might suggest that these factors exert their effects independently of IGF, or it might reflect the limitations of cross-sectional data. Simultaneous study of these associations in diverse populations using standardized protocols may provide insight into the behavioral determinants of variation in IGF levels.
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ACKNOWLEDGMENTS
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Supported by Grants-in-Aid for Scientific Research (B) (12470098) from the Japan Society for the Promotion of Science and for Scientific Research on Priority Areas (12218226) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
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NOTES
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Reprint requests to Dr. Suminori Kono, Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan (e-mail: skono{at}phealth.med.kyushu-u.ac.jp). 
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