Associations among Lifestyle Status, Serum Adiponectin Level and Insulin Resistance

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1 ORIGINAL ARTICLE Associations among Lifestyle Status, Serum Adiponectin Level and Insulin Resistance Hirokazu YOKOYAMA, Hiroshi HIROSE, Hideki OHGO* and Ikuo SAITO Abstract Objective The aim of this study was to determine whether lifestyle status affects the insulin resistance index or serum adiponectin level, which may be responsible for the development of insulin resistance syndrome that sometimes indicates lifestyle-related diseases. Methods A cross-sectional study was performed. Patients Seven hundred thirty-eight males aged 30 to 65 years who had regular health checkups in our office were enrolled. Each subject s lifestyle status, level of serum adiponectin, and serum insulin level were assessed by a self-administered questionnaire based on Breslow s lifestyle index, enzyme-linked immunosorbent assay, and radioimmunoassay, respectively. Moreover, their insulin resistance indexes were assessed by the homeostasis model. Results One-way ANOVA demonstrated an inverse correlation between Breslow s index and the logarithmic insulin resistance index (p<0.0001), and a tendency of a correlation between Breslow s index and the logarithmic serum adiponectin level (p=0.0681). Multiple logistic regression analyses demonstrated that, among the seven lifestyle items in Breslow s index, body mass index of more than 26.1 kg/m 2 and insufficient exercise style had 8.9 times and 2.1 times the risks for insulin resistance and the former also had 3.2 times the risk for hypoadiponectinemia. Partial correlation coefficients of these correlations were (p<0.0001), (p=0.0013), and 0.165, (p<0.0001), respectively. Conclusion Unhealthy lifestyles may cause hypoadiponectinemia and insulin resistance followed by insulin resistance syndrome, i.e. lifestyle-related diseases. These findings present reasonable explanations for the relationships between lifestyles and lifestyle-related diseases. Improvement of unhealthy lifestyles, especially the control of body weight, may have beneficial effects against the development of lifestyle-related diseases. (Internal Medicine 43: , 2004) Key words: Breslow s lifestyle index, insulin resistance, the homeostasis model assessment, hypoadiponectinemia Introduction Continuation of unhealthy lifestyles may result in various morbid states designated as lifestyle-related diseases, such as diabetes mellitus, hypertension, hyperlipidemia, and fatty liver. It is notable that these disorders practically constitute insulin resistance syndrome caused by persistence of the insulin resistance state (1). However, it still remains unclear how unhealthy lifestyles lead to these morbid states. Recently, the novel polypeptide, adiponectin, was identified (2, 3). Since it increases insulin utility in various organs (4) and inhibits endogenous glucose production from the liver (5), it has been thought to exhibit beneficial effects against insulin resistance (6). Increasing evidence supports the notion that a decrease of its serum level, namely hypoadiponectinemia, is related to the development of insulin resistance (7 9). The relationship between hypoadiponectinemia and insulin resistance has also been shown in clinical cases (10, 11). Thus, hypoadiponectinemia is now implicated in the pathogenesis of the various disorders of insulin resistance syndrome (12). With this background, we postulated that unhealthy lifestyles would lead to the development of hypoadiponectinemia and insulin resistance, resulting in the progression of insulin resistance syndrome i.e. lifestyle-related diseases. The aims of this study were to examine whether subjects unhealthy lifestyles were related to their insulin resistance status and hypoadiponectinemia. Subjects lifestyle statuses were assessed by Breslow s lifestyle index, comprising seven self-administered questionnaire items about their life- From Health Center, Keio University and *Department of Internal Medicine, School of Medicine, Keio University, Tokyo Received for publication July 25, 2003; Accepted for publication December 5, 2003 Reprint requests should be addressed to Dr. Hirokazu Yokoyama, Health Center, Keio University, Yotsuya Office, 35 Shinanomachi, Shinjuku-ku, Tokyo

2 YOKOYAMA et al Table 1. Questionnaire for Estimation of Subjects Lifestyle Status Based on Breslow s Lifestyle Index 1) Do you eat breakfast almost everyday? 2) Do you participate in active sports at least three times in a week? 3) Do you sleep for 7 8 hours almost every day? 4) Do you limit ethanol intake to less than 200 g in a week? 5) Do you avoid eating between meals? 6) Do you avoid smoking? 7) Do you keep your body mass index (BMI) at 26.1 kg/m 2 or less? styles (13). Moreover, particular lifestyles that could account for the elevated insulin resistance or hypoadiponectinemia were identified among the seven lifestyles assigned in Breslow s index. Methods The Ethical Committee of the Health Center at Keio University approved all the present studies. Seven hundred thirty-eight males aged 30 to 65 years (mean +/ standard deviation was / 10.0 years) who visited our office for their regular health checkups were enrolled. All consented to the use of their data for this study. All of them were active employees of a Japanese corporation. The lifestyle status of each subject was assessed by self-administered questionnaires based on Breslow s lifestyle index (13) with some modification. Each subject answered yes or no to seven questions regarding breakfast, exercise, sleeping, control of body weight, drinking, snacks between meals, and smoking. The answers of yes and no indicated proper and improper as to each lifestyle, respectively (Table 1). The answer of yes was assigned 1 point, whereas that of no was 0 point. The sum of the assigned points was designated as the total score of the index in each subject. Body mass index (BMI; kg/m 2 ) was calculated from height and weight of each subject and the mean plus standard deviation in this population (26.1 kg/m 2 )was temporarily determined as the highest limit of its normal range. All subjects fasted at least for 10 hours. The serum adiponectin level was measured by an enzyme-linked immunosorbent assay (ELISA) as described previously (11). The measured values were log transformed and the mean minus the standard deviation in this population (0.522 g/ml) was temporarily used as the lowest limit of the normal range. The serum insulin level was measured by a radioimmunoassay (RIA) and the insulin resistance index was calculated according to the homeostasis model assessment (HOMA), namely, serum insulin level (mu/ml) plasma glucose level (mmol/l)/22.5 (HOMA-IR, 14). A HOMA-IR of more than 2.0 units was designated as insulin resistance. To obtain its normal distribution, values of the HOMA-IR were also handled after log-transformation when required. All statistical analyses were performed with the StatView program (ver 5.0, SAS Inc, Cary N C, USA). Values were Figure 1. Association between subjects lifestyle status and the insulin resistance levels. Subjects were divided into 7 groups according to their total scores of Breslow s index and the HOMA- IR level was examined in each group. As total scores of Breslow s index became lower, the logarithmic insulin resistance level became higher; The bar and error bar indicate mean and standard error, respectively in each group. ( =36.4, p< assesses by ANOVA, a; p<0.05 compared to groups 1, 2, and 3 assessed by Fisher s PSLD test). expressed as mean +/ standard error (SE) or standard deviation (SD), as required. Differences between multiple groups were examined using one-way ANOVA followed by Fisher s PSLD test as a post hoc test or multiple logistic regression analysis. P-values less than 0.05 were considered statistically significant. Results The association between subjects lifestyle statuses and insulin resistance levels were studied by one-way ANOVA. The subjects were divided into 7 groups according to their total scores of Breslow s index and the HOMA-IR level was examined in each group. Subjects whose total scores were 0 were not observed in this population. As shown in Fig. 1, as the total scores of Breslow s index decreased, the logarithmic insulin resistance level increased, indicating an inverse association between Breslow s index and HOMA-IR ( =36.4, p<0.0001). In the above-mentioned 7 groups, subjects serum adiponectin levels were also examined. One-way ANOVA demonstrated that the logarithmic serum adiponectin level had a tendency to decrease as the total scores of Breslow s index decreased ( =11.8, p=0.0681, Fig. 2). The serum adiponectin levels in groups 2 7 were significantly higher than that in group 1. Although the values were not statistically different among groups 2 7, their averages decreased as the total scores of Breslow s index decreased. Among the seven lifestyles assigned in Breslow s index, 454

3 Lifestyle, Hypoadiponectinemia, and Insulin Resistance particular lifestyles accounting for insulin resistance (HOMA-IR>2.0 unit) or hypoadiponectinemia (the logarithmic serum adiponectin level <0.522 g/ml) were specified. The present multiple logistic regression analyses showed that BMI more than 26.1 kg/m 2 and improper exercise style had 8.9 times (partial correlation coefficients (R)=0.336, p<0.0001) and 2.1 times (R=0.107, p=0.0013) the risks for insulin resistance, respectively (Table 2). Moreover, BMI of more than 26.1 kg/m 2 was shown to have 3.2 times the risk for hypoadiponectinemia (R=0.165, p<0.0001, Table 3). Discussion Figure 2. Association between subjects lifestyle status and the serum adiponectin level. In the above-mentioned 7 groups, serum adiponectin levels were examined. As the total scores of Breslow s index became lower, the serum adiponectin level had tendency to become lower; The bar and error bar indicate mean and standard error, respectively in each group. ( =11.8, p= assessed by ANOVA. a; p<0.05 compared to the other groups assessed by Fisher s PSLD test). Associations among lifestyle status, insulin resistance index, and serum adiponectin level were examined. The ultimate purpose of this study was to determine how unhealthy lifestyles cause insulin resistance syndrome, i.e. lifestylerelated diseases. In the present study, subjects lifestyles were assessed by Breslow s lifestyle index (13) a well-established questionnaire method to estimate total status of subjects lifestyles. Moreover, we estimated the serum adiponectin level by the Table 2. Association between Seven Lifestyle Items in Breslow s Index and Insulin Resistance Index Assessed by Multiple Logistic Regression Analysis HOMA-IR 2.0 (n=609) vs HOMA-IR >2.0 (n=129) Partial correlation coefficient Odds ratio (95%CI) P value Sleeping 7 8 hours almost every day (n 394) or not (n 344) Avoiding smoking (n 597) or not (n 141) Avoiding eating between meals (n 355) or not (n 383) Taking breakfast almost every day (n 614) or not (n 124) Participating in active sports 3 times/week (n 308) or not (n 430) Limiting ethanol consumption <200/week (n 615) or not (n 123) Maintaining BMI 26.1 kg/m 2 (n 639) or not (n 99) ( ) 0.9 ( ) 0.9 ( ) 1.3 ( ) 2.1 ( ) 0.8 ( ) 8.9( ) < HOMA-IR: the homeostasis model assessment-insulin resistance, CI: Confidence interval, BMI: Body mass index. Table 3. Association between Seven Lifestyle Items in Breslow s Index and Serum Adiponectin Level Assessed by Multiple Logistic Regression Analysis Log serum adiponectin level g/ dl (n 633) or not (n 105) Partial correlation coefficient Odds ratio (95%CI) P value Sleeping 7 8 hours almost every day (n 394) or not (n 344) Avoiding smoking (n 597) or not (n 141) Avoiding eating between meals (n 355) or not (n 383) Taking breakfast almost every day (n 614) or not (n 124) Participating in active sports 3 times/week (n 308) or not (n 430) Limiting ethanol consumption <200/week (n 615) or not (n 123) Maintaining BMI 26.1 kg/m 2 (n 639) or not (n 99) ( ) 1.1 ( ) 0.8 ( ) 1.6 ( ) 0.9 ( ) 0.8 ( ) 3.2 ( ) < CI: confidence interval, BMI: Body mass index. 455

4 YOKOYAMA et al ELISA. We have reported that the serum adiponectin levels estimated by this method are negatively correlated with BMI and HOMA-IR (11). The present ANOVA demonstrated an inverse correlation between the total score of Breslow s index and the insulin resistance index. This indicates that subjects with unhealthier lifestyles have a higher insulin resistance level. Since insulin resistance causes insulin resistance syndrome, i.e. lifestylerelated diseases (1), the present findings support the idea that unhealthy lifestyles cause lifestyle-related diseases. The present ANOVA also demonstrated a trend toward a positive correlation between lifestyle status and serum adiponectin level, suggesting that unhealthier lifestyles cause a lower serum adiponectin level. Since hypoadiponectinemia may cause the development of insulin resistance (7 11, 15), it was postulated that hypoadiponectinemia may, at least in part, account for the association between unhealthy lifestyles and insulin resistance states. However, the association between unhealthy lifestyles and hypoadiponectinemia did not reach statistical significance, suggesting that factors other than lifestyle, including genetic factors (16, 17) may act as determinants of hypoadiponectinemia in each subject. To determine how unhealthy lifestyles affect hypoadiponectinemia or insulin resistance, particular lifestyle factors that could explain the elevated insulin resistance or hypoadiponectinemia were specified among the seven lifestyle items assigned in Breslow s index. The present multiple logistic regression analysis demonstrated that excessive BMI and improper exercise style were significant risks for the elevation of HOMA-IR. Since the associations between insulin resistance and obesity (18) and between insulin resistance and improper exercise style (19) have been fully demonstrated, the findings were not surprising. Moreover, another multiple logistic regression analysis in the present study also demonstrated that hypoadiponectinemia was related to obesity as previously reported (11, 20 22). From these observations, it was postulated that obesity would be practically responsible for the sequential development of hypoadiponectinemia, insulin resistance, and insulin resistance syndrome, i.e. lifestyle-related diseases, among the seven lifestyle components defined in Breslow s lifestyle index. The monitoring of subjects insulin resistance levels is useful in detecting and managing their insulin resistance syndrome, i.e. lifestyle-related diseases. However, because of its expense, it is impractical to incorporate the measurement of insulin resistance for all subjects in regular health checkups. From the present findings, we believe that Breslow s index could be a useful and economical tool for screening subjects insulin resistance level to a certain extent. Since Breslow s lifestyle index was proposed in 1972, it may not be suitable to estimate complicated lifestyles of the modern generation. Thus, it is important to assess the relationship between various lifestyle factors other than the 7 components in Breslow s index and the insulin resistance index or the serum adiponectin level. However, in view of the present findings that the index was correlated with the HOMA-IR status as well as the level of serum adiponectin, we believe that Breslow s index is fully applicable even in contemporary medical settings. In conclusion, unhealthy lifestyles, especially improper body weight control are associated with hypoadiponectinemia and insulin resistance, which may be responsible for the development of insulin resistance syndrome. These findings provide a reasonable explanation for the sequential development of hypoadiponectinemia, insulin resistance, and insulin resistance syndrome, i.e. lifestyle-related diseases. Moreover, they suggest that improvement of unhealthy lifestyles, especially correction of excessive body weight, should have beneficial effects against the development of insulin resistance syndrome, i.e. lifestyle-related diseases. References 1) Ferrannini E. Syndrome X. Horm Res 39 Suppl 3: , ) Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem (Tokyo) 120: , ) Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cdna cloning and expression of a novel adipose specific collagen-like factor, apm1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 221: , ) Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. 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