Risk of metabolic syndrome in adults exposed to the great Chinese famine during the fetal life and early childhood

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1 (2012) 66, & 2012 Macmillan Publishers Limited All rights reserved /12 ORIGINAL ARTICLE Risk of metabolic syndrome in adults to the great Chinese famine during the fetal life and early childhood X Zheng 1, Y Wang 2, W Ren 1, R Luo 2, S Zhang 1, JH Zhang 3 and Q Zeng 4 1 Department of Endocrinology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; 2 The Public Health Center, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; 3 Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA and 4 Department of Statistics, Chongqing Medical University, Chongqing, China Background/Objectives: To determine whether exposure to the Chinese famine during fetal life and early childhood was associated with a greater risk of metabolic syndrome in later life. Subjects/Methods: We used data of adults from the 2008 annual physical examinations in Public Health Center of the First Affiliated Hospital of Chongqing Medical University in Chongqing. To minimize misclassification of the famine exposure periods, subjects born in 1959 and 1962 were excluded. Totally, 5040 participants were enrolled and categorized into control, fetally and postnatally group. We adopted the definition of metabolic syndrome recommended by the Chinese Diabetes Society in Results: Women in fetally and postnatally groups had significantly higher prevalences of metabolic syndrome than in control group (7.3% and 8.6% vs 4.0%, Po0.05, respectively). Women in fetally and postnatally groups had a significantly higher risk of metabolic syndrome, as compared with control women (odds ratio (OR) 1.87 (95% confidence interval (CI) , P ¼ 0.012), OR 1.50 (95% CI , P ¼ ), respectively). Similar association was not observed among men. The prevalences of metabolic syndrome among men in control, fetally and postnatally groups were 20.1%, 22.5% and 18.8%, respectively, but there was no significant difference of prevalences among the three groups. Conclusions: We found that exposure to the Chinese famine in early life period was associated with higher risk of metabolic syndrome in adulthood of women, but not men. This gender difference might be due to the mortality selection and son preference hypothesis. (2012) 66, ; doi: /ejcn ; published online 5 October 2011 Keywords: metabolic syndrome; famine; malnutrition; China Introduction Metabolic syndrome is a rising disease entity characterized by a clustering of metabolic conditions (Pan et al., 2008). Clinical manifestations of the syndrome include glucose intolerance, central obesity, dyslipidemia and hypertension (Magliano et al., 2006). Metabolic syndrome is a common cause of the development of atherosclerotic vascular disease and type 2 diabetes (Lorenzo et al., 2003; Gupta and Gupta, 2006; Rutter et al., 2006). Available studies on the Correspondence: Dr Y Wang, The Public Health Center, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China. wyh @yahoo.com.cn Received 11 October 2010; revised 11 August 2011; accepted 11 August 2011; published online 5 October 2011 pathogenesis of metabolic syndrome are discrepant. Insulin resistance was thought to underlie all the changes observed in metabolic syndrome (Lann and LeRoith, 2007). However, insulin resistance alone is insufficient to cause all of these abnormalities (Avogaro, 2006; Ferrannini, 2006; Onat et al., 2006). Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development (Heijmans et al., 2008; Nijland et al., 2008; Swanson et al., 2009; Langley-Evans and McMullen, 2010; Warner and Ozanne, 2010). David Barker s group proposed the fetal origins hypothesis that malnutrition at a very early age (in utero and in infancy) resulted in earlier and more severe adult chronic diseases (Barker, 2004, 2007; Barker et al., 2006). A useful approach to testing the

2 232 hypothesis in humans is to assess the impact of a natural disaster, when fetus and infant suffered from the adverse effects of food shortage and undernutrition (Roseboom et al., 2001; Painter et al., 2005). There are several representative studies on famine and long-term health consequences. Results from the Leningrad siege study (Stanner et al., 1997) showed that intrauterine malnutrition was not associated with glucose intolerance, dyslipidemia, hypertension or cardiovascular disease in adulthood. Findings from the Channel Island study (Ellison and Kelly, 2005) suggested that the levels of postnatal undernutrition at different stages of the life-course were a more important determinant of cardiovascular disease in later life than the levels of prenatal undernutrition. However, another study (Head and Ellison, 2009) did not find a relationship between undernutrition at different stages of the life course and cholesterol levels in later life. Analyses from the Dutch Famine (Ravelli et al., 1999) confirmed that famine exposure during gestation was associated with higher body mass index and waist circumference and a more atherogenic lipid profile, but a study (de Rooij et al., 2007) on fetal famine exposure and later metabolic syndrome did not observe significant associations. The great Chinese famine was one of the 20th century s great horrors. All provinces in China were affected owing to the bad weather, and Chongqing region was one of the most severely affected regions (Smil, 1999; Cai and Wang, 2005; Chen and Zhou, 2007). Most babies born during that period suffered from the adverse effects of food shortage and undernutrition. Studies on this famine found that early life exposure to the famine was also associated with the increased risk of overweight (Luo et al., 2006; Yang et al., 2008; Wang et al., 2010), hypertension (Huang et al., 2010) and hyperglycemia (Li et al., 2010) in adult life. People survived from this disaster are now middle aged and suffering the high prevalence of metabolic syndrome, and this provided the opportunity to assess whether there was an impact of early nutrition on the increased risk for metabolic syndrome in adulthood. The purpose of this study is to examine whether exposure to the Chinese famine during fetal life and early childhood is associated with higher risk of metabolic syndrome in later life. Subjects and methods Data source We used data from subjects for annual physical examinations from January to December 2008 in Public Health Center of the First Affiliated Hospital of Chongqing Medical University in Chongqing, China. The data were randomized by multistep cluster sampling methods. The variables selected for this study included age, gender and indexes of metabolic syndrome. All subjects were Chongqing urban residents who were voluntary to participate in the routine physical examinations every year. They were born around the great Chinese famine year ( ), aged from 44 to 51 years. Subjects were categorized into three groups according to their birth years. To minimize misclassification of the famine exposure periods, subjects born in 1959 and 1962 were excluded because the exact dates of the start and the end of the Chinese famine were not available. Subjects born in 1963 and 1964 (no intrauterine or postnatal exposure) were classified as control group; subjects born in 1960 and 1961 (entirely intrauterine exposure) were classified as fetally group; subjects born in 1957 and 1958 (entirely postnatal exposure) were classified as postnatally group. In our preliminary analysis, there was a significant difference between genders, so the data were further divided into subgroups by gender. Methods and instruments Serum samples were collected from vein at fasting during 8 to 10 o clock, four lipid indexes including total cholesterol, triglyceride, high-density lipoprotein cholesterol and lowdensity lipoprotein cholesterol were measured by enzymatic methods on Japanese Hitachi auto-analyzer (Hitachi Ltd, Tokyo, Japan). Fasting plasma glucose was measured by glucose oxidase method. Anthropometry indexes such as height and weight were measured to calculate body mass index, and the right upper brachial artery pressure was measured at sitting position. Definition of metabolic syndrome We adopted the definition of metabolic syndrome recommended by the Chinese Diabetes Society in Patients with three or more of the following disturbances were diagnosed with metabolic syndrome, they are: (1) body mass index X25.0 kg/m 2 ; (2) triglyceride X1.70 mmol/l or drug treatment for elevated triglyceride; (3) high-density lipoprotein cholesterol o0.90 mmol/l in men or o1.00 mmol/l in women or drug treatment for decreased high-density lipoprotein cholesterol; (4) systolic blood pressure X140 mm Hg or diastolic blood pressure X90 mm Hg or drug treatment for hypertension; (5) fasting plasma glucose X6.1 mmol/l or drug treatment for diabetes (also known as dysglycemia). Statistical analysis All statistical analyses were performed with SAS software (version 9.0; SAS Institute Inc., Cary, NC, USA). Continuous variables with normal distribution were expressed as mean±s.d. ( X±s.d.); logarithmic transformations were applied to variables with skewed distributions; categorical variables were described as a percentage (%). Multiple-group comparisons of means were performed with generalized linear models. The w 2 -test method was used for comparisons

3 among percentages. A survey logistic regression model was used to estimate the risk of metabolic syndrome in famine subjects compared with non- subjects. Multi-factor analysis of variance and survey logistic regression analysis were used to control for age. All of the statistical analyses were two-sided, and a P-value o0.05 was considered significant. Results A total of 5040 subjects were enrolled (Table 1), of whom 3116 (62%) were men and 1924 (38%) were women. There was no significant difference of gender composition among the three groups (P40.05). Compared with the control group, the fetally and postnatally groups had significantly higher systolic blood pressure and fasting plasma glucose both in men and women (Po0.01). Significantly higher body mass index, diastolic blood pressure, total cholesterol and low-density lipoprotein cholesterol were found in fetally and postnatally women, as compared with the control women (Po0.05), details in Table 2. In men, the prevalence of hypertension in postnatally group was significantly higher than in control group (32.1% vs 24.3%, Po0.01), and the prevalence of dysglycemia in fetally and postnatally groups was significantly higher than in control group (15.6% and 14.2% Table 1 Gender and birth year distribution Fetally Postnatally Total N Men, n (%) 1684 (63.0) 610 (59.7) 822 (61.2) 3116 (61.8) Women, n (%) 990 (37.0) 412 (40.3) 522 (38.8) 1924 (38.2) There was no difference of gender composition among the three groups. vs 10.7%, Po0.01). In women, the prevalence of obesity in postnatally group was significantly higher than in control group (25.5% vs 17.0%, Po0.01), and the prevalence of hypertriglyceridemia, hypertension and dysglycemia in fetally and postnatally groups was significantly higher than in control group (Po0.05). Details in Table 3. The prevalences of metabolic syndrome among men in control, fetally and postnatally groups were 20.1%, 22.5% and 18.8%, respectively. Men in fetally group seemed to have the highest prevalence of metabolic syndrome among the three groups, but there was no significant difference of prevalences among these groups (P40.05). The prevalences of metabolic syndrome among women, were much lower than men, in control, fetally and postnatally groups were 4.0%, 7.3% and 8.6%, respectively. Women in fetally and postnatally groups had significantly higher prevalences of metabolic syndrome than in control group (Po0.05). Table 3 The prevalence of components of metabolic syndrome according to the definition of CDS Fetally Postnatally Men Obesity, n (%) 713 (42.3) 257 (42.1) 319 (38.8) Hypertriglyceridemia, n (%) 755 (44.8) 264 (43.3) 388 (47.2) Low HDL-c, n (%) 215 (12.8) 75 (12.3) 85 (10.3) Hypertension, n (%) 409 (24.3) 157 (25.7) 264 (32.1)* Dysglycemia, n (%) 180 (10.7) 95 (15.6)* 117 (14.2)* Women Obesity, n (%) 168 (17.0) 76 (18.5) 133 (25.5)* Hypertriglyceridemia, n (%) 166 (16.8) 83 (20.2)* 125 (24.0)* Low HDL-c, n (%) 51 (5.2) 23 (5.6) 27 (5.2) Hypertension, n (%) 134(13.5) 68 (16.5)* 100 (19.2)* Dysglycemia, n (%) 33 (3.3) 23 (5.6)* 42 (8.1)* Abbreviations: CDS, Chinese Diabetes Society; HDL-c, high-density lipoprotein cholesterol. *Po0.05 compared with control cohort born in Table 2 Demographic and laboratory variables of the studied men and women Factors Men Women Fetally Postnatally Fetally Postnatally BMI (kg/m 2 ) 24.4± ± ± ± ±2.7* 23.2±2.9* SBP (mm Hg) 125.1± ±16.9* 127.6±18.2* 117.6± ±16.3* 123.1±18.3* DBP (mm Hg) 81.7± ± ± ± ±10.6* 77.0±11.5* TC (mmol/l) 5.2± ± ± ± ±0.8* 5.2±0.9* TG (mmol/l) 2.4± ± ± ± ± ±1.0 HDL-c(mmol/l) 1.2± ± ± ± ± ±0.3 LDL-c(mmol/l) 3.1± ± ± ± ±0.8* 3.1±0.8* FPG(mmol/l) 5.3± ±1.6* 5.5±1.5* 5.0± ±0.9* 5.2±1.2* Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride. *Po0.05 compared with control cohort born in

4 234 Table 4 Prevalence and ORs of metabolic syndrome among different birth cohorts Women in fetally group had a significantly higher risk of metabolic syndrome, as compared with control women (odds ratio (OR) 1.87 (95% confidence interval (CI) , P ¼ 0.012)). As compared with control women, the risk of metabolic syndrome among women who were postnatally to the famine was 1.50 (95% CI , P ¼ ). Similar association was not observed among men who were fetally or postnatally to the famine, as compared with control men (OR 1.15 (95% CI , P ¼ 0.213), OR 1.04 (95% CI , P ¼ 0.942), respectively), details in Table 4. Discussion (n ¼ 2674) Fetally (n ¼ 1022) Postnatally (n ¼ 1344) Men Prevalence, n (%) 338 (20.1) 137 (22.5) 166 (18.8) OR 1.0 (ref) % CI P Women Prevalence, n (%) 40 (4.0) 30 (7.3)* 45 (8.6)* OR 1.0 (ref) % CI P Abbreviations: CI, confidence interval; ORs, odds ratios. *Po0.05 compared with control cohort born in All ORs use non- cohort as reference cohort (ref). On the basis of previously reported association between preand postnatal exposure to the Chinese famine and various metabolic outcomes later, we hypothesized that the high prevalence of metabolic syndrome in urban residents of Chongqing may be related to their experience of the Chinese famine during early life. In this study, we found that women to the Chinese famine during fetal life and early childhood was associated with a higher risk of metabolic syndrome in later life. However, the same association was not found in men. Studies that stratified their samples by gender mostly found severe and more pronounced impacts of famine on women than on men. For example, adult women to the Dutch famine during early gestation were found to have a high prevalence of overweight, whereas the impact on men was negative (Ravelli et al., 1999). In particular, studies on exposure to the Chinese famine also found that malnutrition in early life had more harmful long-term impacts on women. Yang et al. (2008) found the higher risks of overweight and obesity in women were caused by malnutrition in fetal life, however, such differences were not found in men. In our previous study (Wang et al., 2010), we also found that the Chinese famine led to shorter and more overweight women in Chongqing population, but not in men. Why does the Chinese famine affect the men and women differently? There are several possible reasons. First, the mortality selection hypothesis might predict a positive link between early life exposure and later health outcomes (Mu and Zhang, 2011). In the event of a severe famine, male mortality was greater than the female mortality, in particular for infants. Because of this mortality selection, the observed men might be the healthier portion of the total population to the famine (Mu and Zhang, 2008). The existence of mortality selection might partly explain the finding that the famine exposure men did not have worse health outcomes in later life. Second, the son preference hypothesis might also likely result in better outcomes for men. In Chinese traditional values, sons are generally more productive and important and valuable than women. Parents often rely on sons. In a society with strong preference for sons and discrimination against girls often lead to unequal distribution of food. Consequently, famine- women might have more severe food shortage and malnutrition in their early life. So theoretically speaking, son preference might result in worse health outcomes for women in later life (Mu and Zhang, 2011). When compared the prevalence of components of metabolic syndrome, we found the effects of famine exposure on glucose metabolism and hypertension in both men and women. The mechanism of the associations between famine exposure and risk of hyperglycemia or hypertension in later life may be associated with insulin resistance (Fowden and Hill, 2001). Insulin resistance is a common pathogenesis of hypertension and hyperglycemia. Exposure to extreme starvation in animals led to poor development of pancreatic b-cell mass and function, and insulin resistance, which might persist in later life. A poor intrauterine environment may also reduce skeletal muscle development, which may subsequently lead to insulin resistance in peripheral tissues (Gluckman et al., 2008; Li et al., 2010). Several methodological issues must be raised. The prevalence of the metabolic syndrome is highly dependent on the definition used to diagnose the syndrome. de Rooij et al. (2007) assessed the prevalence of the metabolic syndrome according to the National Cholesterol Education Program definition in 783 members of the Dutch famine cohort. They found exposure to famine was not associated with a significantly greater prevalence of metabolic syndrome. This discrepancy might be due to the different definition of metabolic syndrome. We adopted the definition of metabolic syndrome recommended by the Chinese Diabetes Society in 2004, which might be more suitable for Chinese people. Another reason for the different results between the Dutch famine and the Chinese famine is the duration and severity of the disaster. As the largest famine of the twentieth

5 century, the Chinese famine lasted for 3 years and caused million excess deaths (Cai and Wang, 2005). Although the exact start and end dates of this famine were not clear and not the same across regions, by now it is generally accepted that the Chinese famine happened between the spring of 1959 and the end of The exact rations for children were not available. In 1959, grain output dropped sharply by 15%, and in the following 2 years, the output continued to decline, only reaching about 70% of the 1958 record level. The declining trend in grain production came to a halt in The estimated daily per capita availability of food energy during decreased considerably, falling well below average food energy requirements (about 2100 calories). The worst case occurred in 1960, with only 1500 calories (Jowett, 1991). However, the Dutch famine only lasted for 5 months, the limited period of famine did not last for the whole gestation, whereas the different metabolic syndrome components have different underlying origins and critical periods (de Rooij et al., 2007). Furthermore, most of the subjects selected in our study were urban residents. The effect of the famine on rural residents was still unknown. However, China has an effective urban bias of the food supply system, the urban population has quantitative food right protected by law, so, no matter how the outputs of the year, such a system allows city residents to get food on the priority right, while farmers only have control over the remaining foods (Sen, 1981). Almost all indices of famine conditions were more severe in the countryside than in city areas, we therefore infer that there might be higher prevalence of metabolic syndrome in rural adult residents to the Chinese famine in their early life. In conclusion, we found that exposure to the Chinese famine in early life period was associated with higher risk of metabolic syndrome in adulthood of women, but not men. This gender difference might be due to the mortality selection and son preference hypothesis. Conflict of interest The authors declare no conflict of interest. Acknowledgements In this study, we thank all participants: the data collection team of The First Affiliated Hospital, Chongqing Medical University, Chongqing, China. References Avogaro A (2006). Insulin resistance: trigger or concomitant factor in the metabolic syndrome. Panminerva Med 48, Barker DJ (2004). The developmental origins of adult disease. J Am Coll Nutr 23(6 Suppl), 588S 595S. Barker DJ (2007). The origins of the developmental origins theory. J Intern Med 261, Barker DJ, Bagby SP, Hanson MA (2006). Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nat Clin Pract Nephrol 2, Cai Y, Wang F (2005). 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