Our findings indicate famine exposure in fetal stage is an independent predictor on type 2 diabetes incidence in later life, especially in women. Individuals lived in rural areas with famine exposure in fetal and childhood will increase the risk of type 2 diabetes.
Based on sensitive analysis, we elucidate that the severity of fetal exposure to famine determined heightened risk for subsequent type 2 diabetes, but no such association observed in adolescent exposure. Several observational studies investigated that prenatal exposure in famine was associated with prevalence of type 2 diabetes, with an increased risk of odd ratios from 1.22 to 2.20[10, 11]. A meta-analysis found that individuals exposed in fetal stage was a 36% higher risk of type 2 diabetes, but not in child exposed, as compared with those unexposed counterparts [4], with the pooled RRs(95%CIs) of 1.36 (1.12–1.65) and 1.40 (0.98–1.99), respectively. Moreover, a recent study including 88,830 participants with a median of 7.3 years follow up showed that, fetal exposure on the Chinese Famine was associated with a 25% increased risk of type 2 diabetes in adult [12]. The Chinese Famine affected almost everyone living in Qingdao, however, it did not include less severely affected regions as controls. Due to the severity differences across the regions during the Chinese Famine, the conclusions required further investigation based on national data.
Our study showed that the association between fetal exposure and diabetes incident was significantly stronger in women, but moderate in men. However, sex specific analysis found that the association during the time of birth were similar in men and women in the Dutch Study and in the Ukraine Study [13, 14]. Several studies also showed that biological difference of sex in hormones, body composition, glucose and fat metabolism, reproduction and some sex-dimorphic mechanisms in the risk development of type 2 diabetes. A recent meta-analysis including 18 cross-sectional or historical studies, indicated significant association between obesity risk and malnutrition exposed in early life and in women, but not in men [15]. The experimental studies also showed that the mechanisms of fetal programming on insulin resistance and insulin secretion contributed to sex differences in glucose tolerance [16, 17]. Inconsistent results were observed in the China health and retirement longitudinal study, suggesting that men were more vulnerable than women to adverse effects of famine exposure in fetal stage [18, 19]. Sex disparity on the association between famine effect and type 2 diabetes requires further investigations.
The underlying mechanism between famine exposure and type 2 diabetes was uncertain. The thrifty phenotype hypothesis indicates famine in early life, including reduced capacity for insulin secretion and insulin resistance, combined with effects of obesity, ageing and physical inactivity in adult, are the most important factors in subsequent type 2 diabetes [20]. For instance, the Dutch Winter Families study has shown that adults exposed to famine in their fetal period were more insulin resistant than those without. Another hypothesis shows that DNA methylation may be a common consequence of prenatal famine exposure and that these changes depend on the gestational timing of the exposure [21, 22]. A genome-wide mediation analysis showed that DNA methylation mediated the association of prenatal famine exposure with adult BMI and triglycerides but not with fasting glucose concentrations [22]. It suggested that epigenetic mechanisms play a role in mediating the association between prenatal famine exposure and later-life metabolic health.
The strengths of our study were longitudinal design including two large sizes of the random representative samples from general population. The individuals with known and newly diagnosed diabetes at baseline were excluded to eliminate the bias on the data analysis. All interviews were conducted face-to-face by professional health workers, and the anthropometric measurements were conducted on site. However, we also have some limitations in the current study. Due to extensive urban construction, housing demolition and relocation, some participants were failed to contact and lost to follow up during the recruitment. We compared the baseline anthropometric and laboratory measurements between follow-up and loss-to-follow-up participants. The mean waist circumference, diastolic blood pressure, total cholesterol, triglycerides, FPG and 2hPG were greater in lost-to-follow-up group than follow-up group (P < 0.05). But there were not significantly differences on age, BMI and systolic blood pressure across two groups. The Chinese Famine affected almost everyone living in Qingdao at that time period, therefore, the famine exposed age group cannot match to unexposed counterparts. A classification bias may exist referring to the incidence of diabetes increases with age. Therefore, we divided 3-year interval group to reduce age effect on diabetes incidence. The association between famine exposure and incidence risk was robust in a sensitivity analysis. The current findings were not generalized to other regions of China, further nationally representative study requires to investigate the association.
In conclusions, we elucidated the association between famine exposures and type 2 diabetes incidences based on population-based prospective study in Chinese. Fetal, but not adolescent famine exposure increased risk of diabetes process in adult. Appropriate nutrition and health lifestyle in early life may be beneficial to metabolic disorders intervention in later life.