European Journal of Clinical (2012) 66, 231–236 & 2012 Macmillan Publishers Limited All rights reserved 0954-3007/12 www.nature.com/ejcn

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

X Zheng1, Y Wang2, W Ren1, R Luo2, S Zhang1, JH Zhang3 and Q Zeng4

1Department of , The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; 2The Center, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; 3Department of Physiology and Pharmacology, Loma Linda University School of , Loma Linda, CA, USA and 4Department 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 (1963–1964), fetally exposed (1960–1961) and postnatally exposed (1957–1958) group. We adopted the definition of metabolic syndrome recommended by the Chinese Diabetes Society in 2004. Results: Women in fetally and postnatally exposed 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 exposed groups had a significantly higher risk of metabolic syndrome, as compared with control women (odds ratio (OR) 1.87 (95% confidence interval (CI) 1.15–3.04, P ¼ 0.012), OR 1.50 (95% CI 1.20–1.87, P ¼ 0.0003), respectively). Similar association was not observed among men. The prevalences of metabolic syndrome among men in control, fetally and postnatally exposed 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. European Journal of Clinical Nutrition (2012) 66, 231–236; doi:10.1038/ejcn.2011.161; published online 5 October 2011

Keywords: metabolic syndrome; famine; ; China

Introduction pathogenesis of metabolic syndrome are discrepant. Insulin resistance was thought to underlie all the changes observed Metabolic syndrome is a rising disease entity characterized in metabolic syndrome (Lann and LeRoith, 2007). However, by a clustering of metabolic conditions (Pan et al., 2008). insulin resistance alone is insufficient to cause all of Clinical manifestations of the syndrome include glucose these abnormalities (Avogaro, 2006; Ferrannini, 2006; Onat intolerance, central obesity, dyslipidemia and hypertension et al., 2006). (Magliano et al., 2006). Metabolic syndrome is a common Extensive epidemiologic studies have suggested that adult cause of the development of atherosclerotic vascular disease disease risk is associated with adverse environmental condi- and (Lorenzo et al., 2003; Gupta and tions early in development (Heijmans et al., 2008; Nijland Gupta, 2006; Rutter et al., 2006). Available studies on the et al., 2008; Swanson et al., 2009; Langley-Evans and McMullen, 2010; Warner and Ozanne, 2010). David Barker’s Correspondence: Dr Y Wang, The Public Health Center, The First Affiliated group proposed the ‘fetal origins’ hypothesis that malnutri- Hospital, Chongqing Medical University, Chongqing, China. tion at a very early age (in utero and in infancy) resulted in E-mail: [email protected] Received 11 October 2010; revised 11 August 2011; accepted 11 August earlier and more severe adult chronic diseases (Barker, 2004, 2011; published online 5 October 2011 2007; Barker et al., 2006). A useful approach to testing the Famine and later metabolic syndrome X Zheng et al 232 hypothesis in humans is to assess the impact of a natural All subjects were Chongqing urban residents who were disaster, when fetus and infant suffered from the adverse voluntary to participate in the routine physical examina- effects of shortage and undernutrition (Roseboom et al., tions every year. They were born around the great Chinese 2001; Painter et al., 2005). famine year (1957–1964), aged from 44 to 51 years. Subjects There are several representative studies on famine and were categorized into three groups according to their birth long-term health consequences. Results from the 1941–1944 years. To minimize misclassification of the famine exposure Leningrad siege study (Stanner et al., 1997) showed that periods, subjects born in 1959 and 1962 were excluded intrauterine malnutrition was not associated with glucose because the exact dates of the start and the end of the intolerance, dyslipidemia, hypertension or cardiovascular Chinese famine were not available. Subjects born in 1963 disease in adulthood. Findings from the 1940–1945 Channel and 1964 (no intrauterine or postnatal exposure) were Island study (Ellison and Kelly, 2005) suggested that the classified as control group; subjects born in 1960 and 1961 levels of postnatal undernutrition at different stages of the (entirely intrauterine exposure) were classified as fetally life-course were a more important determinant of cardiovas- exposed group; subjects born in 1957 and 1958 (entirely cular disease in later life than the levels of prenatal under- postnatal exposure) were classified as postnatally exposed nutrition. However, another study (Head and Ellison, 2009) group. In our preliminary analysis, there was a significant did not find a relationship between undernutrition at difference between genders, so the data were further divided different stages of the life course and cholesterol levels in into subgroups by gender. later life. Analyses from the 1944–1945 Dutch Famine (Ravelli et al., 1999) confirmed that famine exposure during gestation was associated with higher and Methods and instruments waist circumference and a more atherogenic profile, but Serum samples were collected from vein at fasting during 8 a study (de Rooij et al., 2007) on fetal famine exposure and to 10 o’ clock, four lipid indexes including total cholesterol, later metabolic syndrome did not observe significant triglyceride, high-density lipoprotein cholesterol and low- associations. density lipoprotein cholesterol were measured by enzymatic The 1959–1961 great Chinese famine was one of the 20th methods on Japanese Hitachi auto-analyzer (Hitachi Ltd, century’s great horrors. All provinces in China were affected Tokyo, Japan). Fasting plasma glucose was measured by owing to the bad weather, and Chongqing region was one of glucose oxidase method. Anthropometry indexes such as the most severely affected regions (Smil, 1999; Cai and height and weight were measured to calculate body mass Wang, 2005; Chen and Zhou, 2007). Most babies born index, and the right upper brachial artery pressure was during that period suffered from the adverse effects of food measured at sitting position. 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 Definition of metabolic syndrome et al., 2008; Wang et al., 2010), hypertension (Huang et al., We adopted the definition of metabolic syndrome recom- 2010) and hyperglycemia (Li et al., 2010) in adult life. People mended by the Chinese Diabetes Society in 2004. Patients survived from this disaster are now middle aged and with three or more of the following disturbances were suffering the high prevalence of metabolic syndrome, and diagnosed with metabolic syndrome, they are: (1) body mass this provided the opportunity to assess whether there was an index X25.0 kg/m2; (2) triglyceride X1.70 mmol/l or drug impact of early nutrition on the increased risk for metabolic treatment for elevated triglyceride; (3) high-density lipopro- syndrome in adulthood. The purpose of this study is to tein cholesterol o0.90 mmol/l in men or o1.00 mmol/l in examine whether exposure to the Chinese famine during women or drug treatment for decreased high-density lipo- fetal life and early childhood is associated with higher risk of cholesterol; (4) systolic blood pressure X140 mm Hg metabolic syndrome in later life. 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).

Subjects and methods Statistical analysis Data source All statistical analyses were performed with SAS software We used data from subjects for annual physical examinations (version 9.0; SAS Institute Inc., Cary, NC, USA). Continuous from January to December 2008 in Public Health Center of variables with normal distribution were expressed as the First Affiliated Hospital of Chongqing Medical University mean±s.d. (X±s.d.); logarithmic transformations were in Chongqing, China. The data were randomized by applied to variables with skewed distributions; categorical multistep cluster sampling methods. The variables selected variables were described as a percentage (%). Multiple-group for this study included age, gender and indexes of metabolic comparisons of means were performed with generalized syndrome. linear models. The w2-test method was used for comparisons

European Journal of Clinical Nutrition Famine and later metabolic syndrome X Zheng et al 233 among percentages. A survey logistic regression model was vs 10.7%, Po0.01). In women, the prevalence of obesity in used to estimate the risk of metabolic syndrome in famine- postnatally exposed group was significantly higher than in exposed subjects compared with non-exposed subjects. control group (25.5% vs 17.0%, Po0.01), and the prevalence Multi-factor analysis of variance and survey logistic regres- of hypertriglyceridemia, hypertension and dysglycemia sion analysis were used to control for age. All of the statistical in fetally and postnatally exposed groups was signi- analyses were two-sided, and a P-value o0.05 was considered ficantly higher than in control group (Po0.05). Details in significant. Table 3. The prevalences of metabolic syndrome among men in control, fetally and postnatally exposed groups were 20.1%, Results 22.5% and 18.8%, respectively. Men in fetally exposed group seemed to have the highest prevalence of metabolic A total of 5040 subjects were enrolled (Table 1), of whom syndrome among the three groups, but there was no 3116 (62%) were men and 1924 (38%) were women. There significant difference of prevalences among these groups was no significant difference of gender composition among (P40.05). The prevalences of metabolic syndrome among the three groups (P40.05). Compared with the control women, were much lower than men, in control, fetally and group, the fetally and postnatally exposed groups had postnatally exposed groups were 4.0%, 7.3% and 8.6%, significantly higher systolic blood pressure and fasting respectively. Women in fetally and postnatally exposed plasma glucose both in men and women (Po0.01). groups had significantly higher prevalences of metabolic Significantly higher body mass index, diastolic blood syndrome than in control group (Po0.05). pressure, total cholesterol and low-density lipoprotein cholesterol were found in fetally and postnatally exposed Table 3 The prevalence of components of metabolic syndrome women, as compared with the control women (Po0.05), according to the definition of CDS details in Table 2. In men, the prevalence of hypertension in postnatally Control Fetally Postnatally (1963–1964) exposed exposed exposed group was significantly higher than in control (1960–1961) (1957–1958) group (32.1% vs 24.3%, Po0.01), and the prevalence of dysglycemia in fetally and postnatally exposed groups was Men significantly higher than in control group (15.6% and 14.2% 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)* Table 1 Gender and birth year distribution Women Control Fetally Postnatally Total Obesity, n (%) 168 (17.0) 76 (18.5) 133 (25.5)* (1963–1964) exposed exposed Hypertriglyceridemia, n (%) 166 (16.8) 83 (20.2)* 125 (24.0)* (1960–1961) (1957–1958) Low HDL-c, n (%) 51 (5.2) 23 (5.6) 27 (5.2) Hypertension, n (%) 134(13.5) 68 (16.5)* 100 (19.2)* N 2674 1022 1344 5040 Dysglycemia, n (%) 33 (3.3) 23 (5.6)* 42 (8.1)* 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) Abbreviations: CDS, Chinese Diabetes Society; HDL-c, high-density lipoprotein cholesterol. There was no difference of gender composition among the three groups. *Po0.05 compared with control cohort born in 1963–1964.

Table 2 Demographic and laboratory variables of the studied men and women

Factors Men Women

Control Fetally exposed Postnatally exposed Control Fetally exposed Postnatally exposed (1963–1964) (1960–1961) (1957–1958) (1963–1964) (1960–1961) (1957–1958)

BMI (kg/m2) 24.4±3.0 24.4±3.1 24.3±2.9 22.5±2.7 22.8±2.7* 23.2±2.9* SBP (mm Hg) 125.1±16.6 126.7±16.9* 127.6±18.2* 117.6±16.2 121.8±16.3* 123.1±18.3* DBP (mm Hg) 81.7±12.2 82.6±12.4 83.0±12.3 75.3±11.1 76.8±10.6* 77.0±11.5* TC (mmol/l) 5.2±0.9 5.2±0.9 5.2±0.9 4.9±0.8 5.0±0.8* 5.2±0.9* TG (mmol/l) 2.4±1.9 2.4±2.1 2.2±1.7 1.3±1.0 1.3±0.9 1.4±1.0 HDL-c(mmol/l) 1.2±0.3 1.2±0.3 1.2±0.3 1.5±0.3 1.5±0.3 1.5±0.3 LDL-c(mmol/l) 3.1±0.8 3.1±0.8 3.1±0.8 2.8±0.7 2.9±0.8* 3.1±0.8* FPG(mmol/l) 5.3±1.2 5.5±1.6* 5.5±1.5* 5.0±0.7 5.1±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 1963–1964.

European Journal of Clinical Nutrition Famine and later metabolic syndrome X Zheng et al 234 Table 4 Prevalence and ORs of metabolic syndrome among different previous study (Wang et al., 2010), we also found that the birth cohorts Chinese famine led to shorter and more overweight women Control Fetally Postnatally in Chongqing population, but not in men. (1963–1964) exposed exposed Why does the Chinese famine affect the men and women (n ¼ 2674) (1960–1961) (1957–1958) differently? There are several possible reasons. First, the (n ¼ 1022) (n ¼ 1344) mortality selection hypothesis might predict a positive link between early life exposure and later health outcomes Men Prevalence, n (%) 338 (20.1) 137 (22.5) 166 (18.8) (Mu and Zhang, 2011). In the event of a severe famine, OR 1.0 (ref) 1.15 1.04 male mortality was greater than the female mortality, in 95% CI 0.92–1.44 0.91–1.11 particular for infants. Because of this mortality selection, the P 0.213 0.942 observed men might be the healthier portion of the total Women population exposed to the famine (Mu and Zhang, 2008). Prevalence, n (%) 40 (4.0) 30 (7.3)* 45 (8.6)* The existence of mortality selection might partly explain the OR 1.0 (ref) 1.87 1.50 finding that the famine exposure men did not have worse 95% CI 1.15–3.04 1.20–1.87 health outcomes in later life. P 0.012 0.0003 Second, the son preference hypothesis might also likely Abbreviations: CI, confidence interval; ORs, odds ratios. result in better outcomes for men. In Chinese traditional *Po0.05 compared with control cohort born in 1963–1964. values, sons are generally more productive and important All ORs use non-exposed cohort as reference cohort (ref). and valuable than women. Parents often rely on sons. In a society with strong preference for sons and discrimination Women in fetally exposed group had a significantly higher against girls often lead to unequal distribution of food. risk of metabolic syndrome, as compared with control Consequently, famine-exposed women might have more women (odds ratio (OR) 1.87 (95% confidence interval (CI) severe food shortage and malnutrition in their early life. 1.15–3.04, P ¼ 0.012)). As compared with control women, So theoretically speaking, son preference might result in the risk of metabolic syndrome among women who worse health outcomes for women in later life (Mu and were postnatally exposed to the famine was 1.50 (95% Zhang, 2011). CI 1.20–1.87, P ¼ 0.0003). Similar association was not When compared the prevalence of components of meta- observed among men who were fetally or postnatally bolic syndrome, we found the effects of famine exposure on exposed to the famine, as compared with control men glucose and hypertension in both men and (OR 1.15 (95% CI 0.92–1.44, P ¼ 0.213), OR 1.04 (95% women. The mechanism of the associations between famine CI 0.91–1.11, P ¼ 0.942), respectively), details in Table 4. 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 Discussion hypertension and hyperglycemia. Exposure to extreme starvation in animals led to poor development of pancreatic On the basis of previously reported association between pre- b-cell mass and function, and insulin resistance, which and postnatal exposure to the Chinese famine and various might persist in later life. A poor intrauterine environment metabolic outcomes later, we hypothesized that the high may also reduce skeletal muscle development, which may prevalence of metabolic syndrome in urban residents of subsequently lead to insulin resistance in peripheral tissues Chongqing may be related to their experience of the Chinese (Gluckman et al., 2008; Li et al., 2010). famine during early life. In this study, we found that women Several methodological issues must be raised. The exposed to the Chinese famine during fetal life and early prevalence of the metabolic syndrome is highly dependent childhood was associated with a higher risk of metabolic on the definition used to diagnose the syndrome. de Rooij syndrome in later life. However, the same association was et al. (2007) assessed the prevalence of the metabolic not found in men. syndrome according to the National Cholesterol Education Studies that stratified their samples by gender mostly Program definition in 783 members of the Dutch famine found severe and more pronounced impacts of famine on cohort. They found exposure to famine was not associated women than on men. For example, adult women exposed to with a significantly greater prevalence of metabolic syn- the Dutch famine during early gestation were found to have drome. This discrepancy might be due to the different a high prevalence of overweight, whereas the impact on men definition of metabolic syndrome. We adopted the was negative (Ravelli et al., 1999). In particular, studies on definition of metabolic syndrome recommended by the exposure to the Chinese famine also found that malnutrition Chinese Diabetes Society in 2004, which might be more in early life had more harmful long-term impacts on women. suitable for Chinese people. Yang et al. (2008) found the higher risks of overweight and Another reason for the different results between the Dutch obesity in women were caused by malnutrition in fetal life, famine and the Chinese famine is the duration and severity however, such differences were not found in men. In our of the disaster. As the largest famine of the twentieth

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