Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Correspondence: Anastasia Iliadou, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 171 77 Stockholm, Sweden. E-mail: Anastasia.iliadou{at}meb.ki.se
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Abstract |
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Method A cohort of 11 162 same-sexed Swedish twins born between 1906 and 1958 was used in order to investigate the risk of developing Type 2 diabetes between and within twin pairs by utilizing random effects linear models.
Results Between pairs there was a significant increase in risk of developing Type 2 diabetes for a 1-kg increase in their mean birthweight (odds ratio [OR] = 2.13; P < 0.01), adjusted for age, sex, body mass index (BMI), and smoking status. The corresponding risk within pair was 2.03 (P = 0.07) for monozygotic twins and 1.15 (P = 0.71) for dizygotic twins. The test of the heterogeneity of the within and between effects showed no significant difference between the estimates.
Conclusions The study suggests that reduced fetal growth increase the risk of Type 2 diabetes due to an in utero programming effect possibly caused by intrauterine malnutrition. However, it does not exclude the possibility of a common genetic mechanism.
Accepted 14 January 2004
Low birthweight has been associated with adult disorders such as Type 2 diabetes, hypertension, and coronary heart disease in many studies.13 The thrifty phenotype hypothesis proposes that the association between poor fetal and infant growth and the subsequent development of Type 2 diabetes and the metabolic syndrome is caused by poor nutrition in early life.4 Genetic factors are not part of this hypothesis, even though studies suggest that they are important factors in the variation of both birthweight and Type 2 diabetes.57
Even though associations between birthweight and risks of cardiovascular diseases have been shown in many studies,13 it is still disputed whether these associations are caused by intrauterine malnutrition per se or whether they are mediated by genetic and/or shared environmental effects.8,9 Twin studies can shed light on this matter. Differences in birthweight within twin pairs reflect differences in fetal growth. Studying birthweight within same-sex twin pairs discordant for disease allows matching for maternal factors influencing birthweight (i.e. maternal height, maternal nutrition status, and maternal diseases) and environmental factors shared by the twins. Studies within monozygotic twin pairs also allow perfect matching for genetic factors. Twin studies on the relationship between birthweight and blood pressure,1018 acute myocardial infarction,19 and angina pectoris20 have suggested that previously reported associations may be influenced by genetic and/or early environmental factors.
Previous twin studies of the association between birthweight and Type 2 diabetes and impaired glucose tolerance are based on small numbers and results are inconsistent. In a small study of 18 monozygotic (MZ) and 27 dizygotic (DZ) twin pairs discordant for Type 2 diabetes, a significant within-pair birthweight difference in both MZ and DZ twin pairs was reported: within each type of pair, diabetes occurred more often among the twins with the lowest birthweight.21 Bo et al.22 found a significant association of within-pair birthweight differences and metabolic abnormalities in 13 MZ pairs discordant for impaired glucose tolerance and hyperinsulinaemia. Within-pair differences were higher in twins with abnormal oral glucose tolerance tests compared with normal twins. They concluded that low birthweight may not be relevant per se, but rather the gap between the hypothetical programmed birthweight and the final effective birthweight.22 In contrast, Baird et al.10 found no statistically significant associations between birthweight and either blood pressure or glucose tolerance in a cohort of twins. Further they did not find any correlations between within-pair differences in birthweight and glucose tolerance or body mass index (BMI) in MZ or DZ twin pairs. Thus, whether there is a causal effect of birthweight on Type 2 diabetes or whether genetic or shared environmental effects mediate this association is far from clear.
In the present study we will investigate the association between low birthweight and diabetes in a cohort of adult Swedish twins. We will use random effects linear models to investigate the between and within pairs differences in exposure on Type 2 diabetes.
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Methods |
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Zygosity was based on responses to questions regarding childhood resemblance and has been validated using 13 DNA markers in a sub-sample of 199 twin pairs. The self-reported zygosity classification was proven to be correct in 99% of the pairs.23
Self-reported birthweight measures from the open-ended questions in the interview were used. We examined the validity of self-reported birthweight by comparing the self-reported measures with participants' birth certificates. The Pearson correlation coefficient between birthweight in birth certificates and self-reported birthweight was r = 0.82.
We also used self-reported information about diabetes in the present study. A flow chart in Figure 1 shows how the coding of Type 2 diabetes was done according to the twins' response on questions about their diabetes. If they did not know about past treatment or did not want to answer, or there was insufficient information to decide what kind of diabetes they had, they were coded as missing.
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The cohort used for the analysis comprised 11 162 same-sexed twins (4796 MZ and 6366 DZ twins; of these there were 3003 complete pairs and 5156 single twins), with complete information about self-reported birthweight and covariates used in the analysis.
Statistical analysis
Random effects linear models assuming a log-linear distribution were fitted to data in order to obtain the estimates of between- and within-pair differences in birthweight.24 Odds ratios (OR) were calculated from the regression coefficients by exponentiation, to evaluate the association between Type 2 diabetes and birthweight. Potential confounders included in the analysis were age, sex, BMI, and smoking status. Likelihood ratio tests for heterogeneity of the between- and within-pair effects were calculated by comparing the likelihood of the original model and of a model in which these effects are constrained to be identical.
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Results |
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Table 2 shows the results from the random-effects log-linear regression models for the association between Type 2 diabetes and birthweight fitted in the whole sample of twins and separately by zygosity. The Table presents the regression coefficients for the between- and within-pair effects with their 95% CI, followed by the OR estimates derived from the regression coefficient by exponentiation. The regression coefficients are presented for comparisons with other studies and OR are presented because they are easier to interpret with a binary outcome such as Type 2 diabetes. The OR for the between-pair effect estimates the risk of developing Type 2 diabetes in a pair for a 1-kg decrease in their mean birthweight, and the OR for the within-pair effect estimates the risk of developing Type 2 diabetes in a pair in relation to a 1-kg difference in their birthweight.
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Discussion |
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The results provide some evidence to support the thrifty phenotype hypothesis, which proposes that impaired glucose intolerance and other metabolic disorders originate through adaptations in the malnourished fetus. Maternal factors could be more important than individual fetal/placental influences in determining the risk for Type 2 diabetes. This is consistent with other twin studies on the association between low birthweight and Type 2 diabetes.21,22 Poulsen et al.21 studied within-pair differences in twins discordant for Type 2 diabetes and impaired glucose tolerance and concluded that the association between low birthweight and Type 2 diabetes in twins is partly independent of genotype and may be due to intrauterine malnutrition. Bo et al.22 also looked at the association between low birthweight and impaired glucose tolerance within discordant twin pairs and suggested that the association is due to environmental intrauterine factors. They also concluded that the birthweight difference within pairs and not the birthweight per se is responsible for the metabolic abnormalities in adult life.22
The thrifty phenotype hypothesis further proposes that as long as the child continues to be poorly nourished during childhood and adult life, these adaptations are beneficial. However, a sedentary lifestyle, changes in food intake (high calorie food), and the subsequent development of obesity ultimately lead to impaired glucose intolerance, insulin resistance syndrome, and Type 2 diabetes.4 In the current study the frequency of Type 2 diabetes was higher among overweight individuals. However, there was no significant interaction between birthweight and adult BMI, although birthweight and BMI independently predicted Type 2 diabetes in twins. Thus, the association between birthweight and Type 2 diabetes goes beyond the influence of low birthweight on adult BMI.
Twin studies looking at within pair differences in birthweight have shown a lack of association between low birthweight and cardiovascular disorders such as blood pressure,10,11,1418 myocardial infarction,19 and angina pectoris,20 suggesting that the association may be mediated by familial (genetic and/or shared environmental) effects. In the current study the within-pair effect for MZ twins was of the same magnitude as the between-pair effect. However, the wide CI including zero on the within-pair effect indicates that the effect could be due to chance. Hence, this does not exclude the possibility that the association could be due to a common genetic mechanism causing both low birthweight and Type 2 diabetes. However, to be consistent with a genetic mechanism, there should be no effect within MZ twins but a negative effect within DZ twins, which was not observed in the current study.14
Animal experiments have shown that growth-restricted offspring of protein malnourished rats undergo a greater age-dependent loss of glucose tolerance, which is associated with insulin resistance.25 The association with other cardiovascular outcomes, on the other hand, might be due to a common genetic aetiology. Women with pre-eclampsia have children with lower birthweight and are also more likely to transfer susceptibility genes for hypertension to their offspring, which subsequently might lead to other cardiovascular diseases.26,27 We can only speculate that the association between reduced fetal growth and Type 2 diabetes may be of a different origin than the association between fetal growth and other cardiovascular outcomes.
One limitation of the current study is that both birthweight and diabetes were self-reported. However, the validity of self-reported birthweight in this cohort of twins has been examined and correlated reasonably well with birthweight derived from medical birth records (r = 0.82). The agreement between questionnaire data and medical records has been shown to be good for well-known chronic diseases, such as diabetes and cardiovascular diseases in a study of middle-aged and elderly Finnish men and women.28 Another limitation was the lack of information on gestational age. Although the within-pair effect controls for differences in gestational age in a pair, we cannot exclude that the association between low birthweight and Type 2 diabetes is important only for premature children. However, the effect of gestational age on the association between low birthweight and Type 2 diabetes is unclear.2931
Twin studies may not necessarily be generalizable to singletons, due to their appreciably impaired growth in utero and the rapid catch-up growth they undergo in childhood. However, there is no evidence that twins have increased overall cardiovascular mortality compared with the general population.32,33
In conclusion, our findings partly support the hypothesis that the association between low birthweight and Type 2 diabetes could be due to poor nutrition in fetal life and infancy that leads to insulin resistance and subsequently Type 2 diabetes in adult life. However, given the wide CI for the within-pair effect, a purely genetic explanation for the programming phenomenon cannot be excluded.
KEY MESSAGES
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Acknowledgments |
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References |
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