In a pooled analysis of five cohorts from LMICs, lower birth weight was associated with higher adult glucose concentrations and an increased risk of glucose intolerance. Weight at 24 months and 48 months and CWG between birth and 48 months were unrelated to glucose concentrations and IFG/DM. In contrast, CWG between 48 months and adulthood was strongly and positively related to both outcomes. Adult waist circumference was positively associated with all early weights, as well as with adult glucose concentration and IFG/DM. After adjusting for adult waist circumference, birth weight, infant weight, and infant CWG were all inversely associated with glucose and prevalence of IFG/DM. Birth weight showed no association with insulin resistance (estimated in three cohorts, ), whereas greater CWG in any period was associated with higher insulin resistance. After adjusting for waist circumference, insulin resistance, as with glucose and IFG/DM, was inversely associated with birth weight (). SGA status did not modify the associations between CWG and outcomes.
The inverse associations of birth weight with adult glucose concentrations and risk of IFG/DM were consistent with previous studies and with a recent systematic review, mainly from high-income populations (1
). The size of the effect on IFG/DM (9% [95% CI 1–16] reduction in risk per SD increase in birth weight of ~500 g) was similar to that reported for DM alone in the systematic review (25 [19–30] reduction in risk per kilogram of birth weight). Our findings are compatible with the hypothesis that environmental factors that influence fetal growth (e.g., maternal size and nutritional status) have long-term effects on glucose homeostasis. Insulin resistance later in life was not related to birth weight unadjusted, but was inversely associated with birth weight after adjusting for adult adiposity.
Infant and childhood weight and weight gain
There were no associations of 24- or 48-month weight, or CWG through 48 months, with adult glucose or IFG/DM. In contrast, CWG between 48 months and adulthood was strongly associated with these outcomes. This suggests that infancy and early childhood may be an important window of opportunity to promote weight gain in LMIC populations to improve survival and adult human capital without exacerbating adult DM risk. However, the findings for insulin resistance suggest that this conclusion still needs to be treated with caution. Insulin resistance was positively related to infant weight and CWG, and it is possible that this will result in a higher risk of diabetes at older ages. The strong association between CWG from 48 months to adulthood is consistent with other studies (9
) and suggests that accelerated weight gain or upward crossing of weight percentiles during childhood should be avoided.
Interpretation of the findings after adjustment for adult adiposity
Infant weight, 48-month weight, and CWGs were correlated with adult weight and with adult BMI and waist circumference. Thus, weight at these ages, or some component(s) of it, makes a contribution to adult adiposity and a strong risk factor for diabetes. Without adjustment for adult waist circumference, we found no association of 24- and 48-month weight/CWG with adult glucose and IFG/DM. After adjusting for adult waist circumference, we found inverse associations of birth and/or 24-month weight, and CWG between birth and 24 months, with all three outcomes. Our interpretation is that for any given adult waist circumference, higher birth weight and/or infant weight and weight gain are associated with a lower adult insulin resistance and DM risk. This suggests that there is a component of early weight/weight gain that is not associated with larger adult waist circumference and that may be protective against later disease. An example may be lean tissue or muscle mass. Our data suggest that the positive associations of 24- and 48-month weight, and CWG at all ages, with adult insulin resistance are driven by the component(s) associated with larger adult waist circumference.
Strengths and limitations of the study
The major strength of this study was the prospective serial measurements of weight from a large number of individuals in LMICs. Our choice of time points was limited due to differing ages of follow-up in the five sites; measurements earlier in infancy and later in childhood would have been valuable. Interpolation was required in two cohorts to estimate 48-month weight; however, weight gain between the end of infancy and the onset of puberty tends to be linear.
Another limitation was loss to follow-up, especially in the older (India and Guatemala) cohorts. However, comparison of the analysis sample with the original full cohorts showed that their early weights were similar. Bias would be introduced only if the associations between early size and glucose tolerance differ between those who were and were not included in the analysis.
Additional limitations were heterogeneity in the age of the participants among the five cohorts and the methods used for measuring birth weight, gestational age, and plasma glucose concentrations. Even though three cohorts used one approach and two cohorts used another to measure birth weight, both methods are acceptable means of obtaining birth weight. Only one of the five cohorts determined gestational age in an alternative way to the other four cohorts, and again used a recognized method.
We had only single plasma glucose concentrations (no glucose tolerance test data). The site in Brazil collected nonfasting blood glucose but validated the equation to correct these values to a fasting state (18
). The differences in glucose measurements between whole blood and plasma are well defined (22
). The differences between laboratory and glucometer measurements are less well known, but laboratory and glucometer values in venous and capillary samples, and in whole blood and plasma, have been compared extensively in the literature, including direct comparisons of the methods used in our study (20
). Despite these differences in methodologies we are struck by the consistency of results across the five sites. This speaks to the robustness of our findings.
In conclusion, lower birth weight is a risk factor for glucose intolerance and has important implications for LMICs, where poor birth outcomes are common. Greater CWG between 48 months and adolescence/adulthood (15–32 years) is also a risk factor for glucose intolerance, providing more evidence that upward crossing of weight percentiles after 48 months should be avoided in LMICs. Our analysis showed no increased risk of IFG/DM associated with greater infant and early childhood weight gain, which suggests that it may be possible to promote weight gain at this stage of life to accrue benefits for survival, growth faltering, and human capital, without increasing adult diabetes risk. However, the cohorts are still young, and the associations of above-average weight gain in infancy with increased adult waist circumference and insulin resistance may predict a risk of diabetes in the future.