In this study of a large sample of Chinese adults, we found a significant association between severe famine exposure during the fetal period and an increased risk of hyperglycemia in adulthood. This association was stronger in subjects with a Western dietary pattern or higher economic status in adulthood. No consistent association was observed between famine exposure during childhood and hyperglycemia.
Several mechanisms might explain the associations between fetal famine exposure and risk of diabetes in later life. Exposure to extreme starvation in rats led to poor development of pancreatic β-cell mass and function and insulin resistance, which might persist in later life (18
). A poor intrauterine environment may also reduce skeletal muscle development (19
), which may subsequently lead to insulin resistance in peripheral tissues (20
). It has also been suggested that stress suffering from fetal famine exposure could change the setpoint of the hypothalamic-pituitary-adrenal (HPA) axis, which could result in long-term changes in secretion of neuroendocrine mediators of the stress response, and predispose to cardiovascular and metabolic disease in later life (21
To our knowledge, thus far three studies have assessed the associations of exposure to famine with measures of glucose intolerance. These studies were performed in the Netherlands (the Dutch Famine Study) (4
), Russia (the Leningrad Siege Study) (6
), and China (our Chinese Famine Study). The Dutch Famine Study reported higher 2-h glucose and insulin levels among subjects who were exposed to famine during fetal life (4
), but this association was not observed in the Leningrad Siege Study (6
).The inconsistent results might be due to differences in postnatal environmental life exposures. Although the Dutch population rapidly developed into a wealthy and rich population after the famine, the Leningrad people remained relatively poor. In our study, we observed that fetal exposure to the severe Chinese famine increases the risk of hyperglycemia in adulthood, which was exacerbated by an unhealthy adult diet and higher economic status. Our results support the hypothesis that exposure to a nutritionally rich environment modifies the association between fetal famine exposure and disease in later life (1
The association between fetal famine exposure and hyperglycemia was stronger in participants with an affluent/Western dietary pattern. These subjects were, to a large extent, less poor and more highly educated (15
), and they have benefited most from dramatically enhanced economic opportunities and have broken away from traditional Chinese food patterns (15
). Their diet is characterized by a high intake of meat, eggs, dairy, sugary beverages, edible oils, and a low vegetable use (15
). Apparently, this nutrition “rich” environment did not match the fetal starvation environment that people of fetal exposed cohort experienced, which in turn increased the risk of hyperglycemia in later life (1
Our study used annual mean income as the cutoff to categorize economic status (2,000 Chinese yuan/person/year). Subjects in the lower economic group might consume mostly traditional plant foods with little meat. Therefore, the discrepancy between the nutritional environment in adulthood and fetal undernutrition conditions may be less evident for those with a higher economic status. In other words, there was probably greater “mismatch” between in utero and adulthood environments in the higher economic group, which triggered an increased prevalence of hyperglycemia in the fetal-exposed cohort.
Overweight may also represent a nutritional “rich” environment. Overweight subjects in the fetal-exposed cohort had the highest prevalence of hyperglycemia. Similar results were described in the Dutch Famine Study (4
), showing that 2-h glucose concentrations were especially high among people exposed to the famine during fetal life and who became obese in later life. However, the relative risk of hyperglycemia in overweight subjects was not different from that in normal weight subjects. This may be partly due to the increased prevalence of hyperglycemia in the nonexposed cohort in overweight subset. These results therefore indicate that both improving fetal nutritional environmental and controlling BMI in later life are important for prevention of a disturbed glucose metabolism.
Childhood nutritional status, particularly during infancy, is another key factor in influencing the propensity to develop disease in adulthood (23
). Animal studies have shown that postnatal caloric restriction might hamper β-cell development (24
) and might disturb glucose metabolism in later life in rats (25
). Our study found significantly increased FPG in the early childhood–exposed cohort in the severely affected famine areas, but no significant differences in FPG in the less severely affected famine areas. We also observed a higher risk of hyperglycemia among subjects exposed in late childhood in both severely and less severely affected famine areas. These results suggest that famine exposure during childhood may increase the risk of hyperglycemia in later life. However, we cannot exclude a potential cohort effect, such as aging (26
). Similar risks of hyperglycemia among subjects exposed during childhood in both famine-exposed areas and nonfamine-exposed areas suggest rather a cohort (older age) effect than a famine effect. However, since almost all rural regions in China were affected by the famine during 1959–1961, no valid nonfamine-exposed cohort comprising subjects born in the same time period was available. Thus, the association between childhood exposure to famine and risk of hyperglycemia needs to be studied in more detail.
Some limitations should be noticed. First, we assumed that the residents we investigated at the time of the survey were born in the same province and in a similar rural area. This may not be the case for all of our subjects. However, severe restrictions on migration and relocation in China made our sample quite stable. Migration with permanent resident permission still needed to be approved by authorities on a case-by-case basis in China. According to the 2000 China National Population Census, 2.68% of the rural population lived in provinces other than the provinces of their birthplaces (27
). Our study sample was based on the residence registration system; only subjects with permanent resident permission in local areas were involved in our study. Therefore, we do not expect that intraprovince migration leading to measurement error in the coding of birth place is a major concern in our results (12
). Second, subjects in our fetal-exposed cohort may have actually experienced severe famine during both the fetal period and the infancy period because the famine lasted approximately 3 years. It was therefore difficult to distinguish whether the fetal period or the infancy period was more important. However, the early childhood cohort also included subjects exposed to famine in infancy, which did not have a substantial influence on the risk of hyperglycemia. Thus, our results indicate that the fetal period should be considered as the primary critical period. Third, our subjects who experienced severe famine in the fetal period were in their early 40s in 2002, and the cases of type 2 diabetes were few. The small numbers may partly explain why we did not observed significant associations with the risk of type 2 diabetes. We used the excess death rate as an indirect measure of famine exposure. With this method, we could not distinguish death due to famine from death due to unfavorable weather conditions or infections. We also did not have reliable information about individual food availability during the famine period. Therefore, from our data, we cannot conclude that the higher risk of hyperglycemia among subjects exposed to famine is exclusively due to malnutrition in early life. However, nutrition deficiency was highly prevalent during the Chinese famine. China's grain output declined by 15% in 1959 and in the following 2 years, and its food supply plunged further to 70% of its 1958 level (8
). As almost all foods were delivered through communal kitchens at that time, no social groups were spared from the effects of the famine (9
). In addition, we did not have data on birth size and childhood growth. However, since the famine effect on glucose intolerance did not depend on birth size in the Dutch Famine Study (4
), we do not consider the lack of information about individual birth outcomes as a major limitation.
In conclusion, we found that exposure to severe famine in fetal life increased the risk of hyperglycemia in adulthood. The “mismatched nutrition postnatal environment” represented by a Western dietary pattern and improved economic status further increased susceptibility to hyperglycemia in those who experienced fetal exposure to famine. Together with previous studies, our study emphasizes that early life environment is critical for the risk of hyperglycemia in adult life.