The thrifty phenotype hypothesis was postulated to explain the associations between poor fetal and infant condition and increased risk of type 2 diabetes (T2D) due to the influences of malnutrition in early life that leads to irreversible changes in glucose-insulin metabolism [1
]. A general approach used to validate this hypothesis in human beings involves assessing the influence of a natural disaster, such as a famine, especially when it is consistent with the gestation or early-childhood periods, so that the prevalence of disease in these subjects during adulthoods can be observed. The first evidence of a direct link between malnutrition during gestation with decreased glucose tolerance in humans was found due to the Dutch famine in 1998 [2
]. However, due to the ethical issues, the related research that verifies this hypothesis in humans is scarce.
The Chinese Great Famine began in 1959 and ended in 1961, being one of the largest disasters of human history. Almost all people living in mainland China were impacted, and the total death toll caused by the Chinese famine was approximately 15–30 million [3
]. The influence of early-life malnutrition on adulthood health has already been reported in different countries [6
], and an increasing number of studies of Chinese populations have searched for the relationships between early-life exposure to famine and chronic diseases in later life. However, the results have been inconsistent [10
]. The evidence for the effects of exposure to poor conditions in early life among people in Northeastern China is inadequate, especially for a follow-up time of about 50 years after exposure. Due to a decline in the secretion of insulin, insulin resistance, and an increase in body mass index (BMI), the prevalence of hyperglycemia and T2D increases with age [13
]. This study was designed to determine the risk for hyperglycemia and diabetes 50 years after fetal and early-childhood exposure to the Chinese famine in a northeastern population.
From a sample of Northeastern Chinese adults in our study, we found a conspicuous association between famine exposure during the early-childhood period and an increased risk of hyperglycemia in adult women. Compared with the unexposed cohort, fetal undernutrition was associated with significant increases in the prevalence of diabetes. This association was more pronounced in women, even after adjusting for the confounding factors. No consistent association was observed in men. The fetal exposure overweight women had a significantly higher risk of diabetes than the unexposed cohort. Previous studies showed that nutrition during infancy may significantly impact health in later life and in the risk of diseases [6
]. Childhood nutritional condition, especially during the first few months of postnatal life, is a crucial factor in the propensity to develop disease in adulthood [25
]. Our study found a significantly increased risk of hyperglycemia in the early-childhood exposure cohort only in women, which indicates that malnutrition is an extremely important risk factor for adulthood hyperglycemia for women during infancy.
Our findings are consistent with previous studies that suggested that early life malnutrition is associated with type 2 diabetes risk in later life [26
]. In our study, the risks of diabetes in the early-childhood exposure and fetal exposure cohorts were all significant. After adjusting for the confounding factors in model 2 (Table 3
), only the fetal exposure cohort showed differences from the unexposed cohort. The results of stratified analysis by sex showed that early childhood and fetal exposure to famine resulted in an excess risk for diabetes in women. The experimental studies showed that the mechanisms of fetal programming on insulin resistance and insulin secretion may be sex-specific, which may be related to the interpretation of sex differences in glucose tolerance [29
The association between prenatal undernutrition and glucose tolerance in adulthood might be explained by several mechanisms. Animal experiments found that pancreatic development was impacted by poor conditions during gestation, which led to the functional impairment of β-cells and a subsequent insulin deficiency [30
]. The majority of human experiments indicated that insulin resistance may play a key role in the occurrence of diabetes [31
] and this possible explanation was supported by a Dutch cohort [33
]. A large amount of evidence demonstrated that skeletal muscle is an essential site for the programming of insulin resistance. Muscle is a crucial site of glucose absorption and a low ponderal index was found to be related to the metabolic changes of adult skeletal muscle. Another possible cause is that individuals who endure survival stress due to poor nutrition might alter the set point of their hypothalamic–pituitary–adrenal (HPA) axis, which may result in the long term alteration of the secretion of the neuroendocrine mediators of the stress response, and subsequently suffer from cardiovascular and metabolic disease in adulthood [34
Being overweight may partly represent a nutritional “rich” environment. In our study, overweight women in the fetal exposure cohort had a high risk of diabetes. Similar results were found in other studies [6
]. The rich nutrition status mismatch with the extremely poor fetal environment condition might increase the risk of diabetes in later life. According to our study, the associations between fetal exposure to famine and risk of diabetes were stronger among women who became overweight in later life.
The Great Chinese Famine between 1959 and 1961 was a three-year period of extreme food shortage. The role of undernutrition during early life for future health in adults has been previously evaluated in China [27
], but Northeastern China, having a distinct biogeoclimate and lifestyle, has been seldomly investigated. Our study, with population specificity, is representative of the inhabitants of Jilin Province in Northeastern China. Animal experiments demonstrated the effects of prenatal undernutrition on glucose tolerance that increased with age. Rats malnourished during gestation showed a decrease in glucose tolerance between 3 and both 12 and 15 months of age [26
]. This study, using a unique population more than 50 years after the Great Chinese Famine in Jilin region, consequently, was significant and needed.
This study was part of the Jilin Provincial Chronic Disease Survey, which was a large-scale, cross-sectional epidemiology study. The community-dwelling residents were recruited using a multistage stratified cluster sampling method. Therefore, we believe that the study subjects are representative of the residents of Jilin Province. Moreover, due to the exclusion of subjects born in the transitional period, there was no late gestational overlap with famine in the unexposed group. Our study has several limitations. The first limitation was that we did not have data for birth weight, which is the most commonly used index for fetal undernutrition [37
]. Secondly, we also did not have data about the exact severity of mother and infant malnutrition. Thirdly, as the Chinese famine lasted for three years (1959–1961), individuals who were exposed to famine during the fetal period might also have been exposed during infancy period. Despite these limitations, our study was conducted at an appropriate time after the famine period, and the follow-up was long enough after the famine to establish relationships to outcomes that are directly related to adult diabetes.
People generally believe that malnutrition only occurs in developing countries and regions, but according to the Global Nutrition Report in 2016 [38
], nearly half of the countries in the world were suffering from poor nutrition and obesity, and malnutrition in early life was a major global public health issue. Moreover, malnutrition in children was widespread in China, especially in seriously impoverished area. Studies [39
] showed that poor economic conditions and low levels of nutritional awareness are the important causes of poor nutrition in early life. Therefore, we hope that this study about the significance of early-life nutrition will help draw more attention to this problem. The government must formulate policies to strengthen pregnancy and early-childhood nutritional surveillance and improve nutritional status. The government also should conduct educational interventions to raise the public awareness of rational nutrition. For countries and regions still suffering from famine, including nutritional food supplementation projects for pregnant women and infants is essential.