In this nationwide, prospective, population-based case–control study we found that maternal obesity in early pregnancy significantly increased the risk of type 1 diabetes in the offspring of mothers without diabetes. Gestational weight gain did not seem to influence the risk. Maternal obesity also correlated with early onset (0–4 years) of type 1 diabetes in the offspring. The strongest risk factor for type 1 diabetes was, however, maternal diabetes, especially type 1 diabetes, but gestational diabetes also increased the risk.
Our results strengthen the findings of a recent cohort study from Sweden which showed that high first trimester maternal BMI in women without diabetes was associated with an increased risk of type 1 diabetes in their offspring [18]. As also shown in our case–control study, maternal type 1 diabetes and gestational diabetes were risk factors for type 1 diabetes in the offspring [18]. In addition, our study investigated whether age at diabetes onset had any correlation with maternal obesity. In 2009, Rasmussen et al showed that maternal obesity and gestational weight gain ≥15 kg increased the risk of islet autoimmunity two- to threefold in offspring with a high genetic susceptibility for type 1 diabetes [5]. Furthermore, a recent study of a non-obese diabetic mouse model showed that the offspring of obese mice, compared with those of non-obese mice, had a significantly increased risk of insulitis and inflammation in the pancreas, impaired glucose tolerance and lower serum insulin [24]. The fact that several other studies [14,15,16] have failed to show a correlation between obesity and type 1 diabetes in the offspring might be due to their small size.
Consistent with previous studies [18, 19], our results showed that maternal type 1 diabetes was a strong risk factor for type 1 diabetes in the offspring. We also found that gestational diabetes increased the risk of type 1 diabetes in the offspring, a result which is in line with some studies [18], but which was somewhat less anticipated. The increased risk with gestational diabetes mellitus could be explained by many different factors. The risk of gestational diabetes mellitus increases with higher maternal BMI. A meta-analysis of 20 studies showed that the increased risks (OR) of developing gestational diabetes mellitus were 2.14 (95% CI 1.82, 2.53) among overweight, 3.56 (95% CI 3.05, 4.21) among obese and 8.56 (95% CI 5.07, 16.04) among severely obese women compared with normal weight pregnant women [25]. The increased risk of type 1 diabetes in the offspring could therefore be attributed to elevated glucose levels or epigenetic effects, as described below. Women with gestational diabetes mellitus are at high risk of developing type 2 diabetes and this genetic trait may also be a risk factor for type 1 diabetes in the offspring [26]. The increased risk could also be related to the subset of gestational diabetes that is thought to be autoimmune [27].
Type 1 diabetes has a strong genetic component and studies have revealed a 40–50% risk for monozygotic twins [28]. About 60% of the genetic susceptibility is explained by HLA [29]. Our results indicate that the genetic susceptibility for type 1 diabetes, in this case maternal diabetes, is superior to the risk increase conveyed by maternal obesity. However, in the absence of genetic risk, maternal obesity presents as a tangible risk factor which also seems to influence the onset of the disease.
Both diabetes and obesity correlate with higher blood glucose levels. Maternal glucose freely crosses the placenta, but insulin does not. Fetuses of mothers who are either diabetic or obese are therefore subjected to higher circulating glucose levels, prompting increased fetal insulin secretion [11]. Studies have shown that active pancreatic beta cells are more susceptible to destruction [17, 30], indicating that the overstimulated fetal beta cells are more prone to processes causing type 1 diabetes, and this might also influence when the child develops the disease. Animal studies have also shown that the metabolic imprinting caused by the obese and diabetic intrauterine environment can be transmitted across generations. The epigenome is especially vulnerable to alterations during gestation because the DNA methylation patterning required for normal tissue development is established and the DNA synthesis rate is high [12].
To our knowledge this is the first study that has investigated the correlation between maternal BMI and age at onset of type 1 diabetes in the offspring. Studies have shown that the largest increase in type 1 diabetes is in the youngest age group (0–4 years) [31]. One explanation for this could be the influence of maternal obesity. It is known that the pace of disease progress, from trigger to clinical disease, can vary [32]. It could be that children of obese mothers progress faster or that children of underweight women are not exposed to a necessary trigger or accelerant. In view of the growing obesity epidemic, these results highlight the importance of preventive work to reduce overweight and obesity in reproductive age women as a means to decrease the incidence of type 1 diabetes.
Our study failed to confirm an association between gestational weight gain and type 1 diabetes in the offspring. This is in accordance with most studies [13] but not with that of Rasmussen et al [5]. The latter, however, investigated children with high susceptibility for type 1 diabetes, which might be a reason for the diverging results. Also, in this study we were only able to look at the total gestational weight gain, not the rate of gestational weight gain or whether a high weight gain early or late in pregnancy could be a risk factor for type 1 diabetes in the offspring.
In the univariate and unadjusted multivariate analyses, maternal age 30 years and above seemed to be a risk factor for childhood type 1 diabetes, just as some previous studies have shown [33]. However, this correlation disappeared in the adjusted model, in accordance with findings in other studies [14, 16]. Our finding that smoking may protect against type 1 diabetes is not a novel association. Several studies have reported this before, and it is possible that maternal smoking could somehow influence the immune system or DNA methylation in the offspring [13, 16, 33]. However, maternal smoking may also just be another confounding factor and our result should be interpreted with caution. The fact that certain risk factors seem to influence each other might help to explain the conflicting evidence from previous studies.
The major strengths of using data from national registries are the large quantity of prospectively collected data and the fact that population-based information is free from recall bias. It is also possible to investigate confounding factors and adjust the analysis. However, there may of course be other potential confounders, such as paternal diabetes, but unfortunately we do not have access to this information. Register data can involve misclassification problems caused by incorrect registration of diagnostic codes, and this might have affected the validity of the data used in our study. If so, the incorrect registration is random and not systematic. BMI was calculated from self-reported height, whereas weight was sometimes measured and sometimes self-reported. Self-reported data can bias the results, but as individuals tend to over-report their height and under-report their weight any potential bias would probably underestimate the risks associated with maternal obesity.
In conclusion, maternal obesity, in the absence of maternal diabetes, is a risk factor for the development of type 1 diabetes in the offspring and it also influences the age of diabetes onset in the affected child. As mentioned above, this emphasises the importance of preventive work to maintain normal weight among women of reproductive age as a means to potentially decrease the incidence of type 1 diabetes.