The aim of this study was to determine how birthweight together with overweight during development may contribute to the risk of adult type 2 diabetes. Using a well-powered, population-based cohort with growth data covering birth to young adulthood and an exceptionally long follow-up period, we found an inverse association between birthweight and the risk of type 2 diabetes in men. The combination of birthweight below the median and overweight at age 20 years was associated with a massive excess risk, especially for early type 2 diabetes, beyond that of the association between low birthweight or young adult overweight considered separately. Of note, individuals with a birthweight ≤2.5 kg and overweight at age 20 years had a 27% absolute risk of early type 2 diabetes, while for individuals with a birthweight ≤2.5 kg and normal weight at age 20 years the corresponding absolute risk was 6%. The absolute risk reduction from avoidance of overweight in young adulthood for an individual with a birthweight ≤2.5 kg is thus 21%. In contrast, we did not observe an independent contributing risk related to high BMI at age 8 years. Our findings establish low birthweight and overweight in young adulthood as the main developmental determinants of the risk of adult type 2 diabetes.

According to epidemiological studies, the risk accumulation for type 2 diabetes begins during early development. Previous observational studies have indicated an association between low birthweight and an increased risk of type 2 diabetes [10], and studies using the Mendelian randomisation approach have demonstrated a causal relationship between low birthweight and type 2 diabetes [11, 20]. In the present study, we found an inverse association between birthweight and the risk of adult type 2 diabetes, with a 16% reduction in the risk of type 2 diabetes per SD increase in birthweight. This finding is in line with existing evidence [10, 21], although for some populations a U-shaped association between birthweight and type 2 diabetes has been reported [10]. In addition to birthweight, we and others have demonstrated that a high childhood BMI is a weak determinant of risk of adult type 2 diabetes, and high BMI during puberty and in young adulthood are strong determinants of risk of adult type 2 diabetes [7, 8, 22]. Interestingly, in studies of both Finnish and Indian populations, individuals with impaired glucose tolerance or type 2 diabetes in adulthood had lower birthweight and lower BMI until 2 years of age, followed by a larger BMI increase until young adulthood [23, 24]. In analyses mutually adjusted for birthweight and overweight in childhood and young adulthood, we found that low birthweight and overweight in young adulthood, but not overweight in childhood, were associated with a considerable excess risk of type 2 diabetes. Of note, individuals with low birthweight followed by overweight in young adulthood had a risk of type 2 diabetes that was substantially higher than the risks for these two variables separately, indicating an additive risk of these two developmental determinants of type 2 diabetes.

While both a large BMI increase during puberty and overweight in late puberty/young adulthood have been demonstrated to associate strongly with the risk of type 2 diabetes [7, 8], the significant association between high pre-pubertal childhood BMI and type 2 diabetes in previous studies has been attenuated or lost after adjustment for BMI in adolescence or adulthood [7, 8, 25]. In a well-defined cohort of almost 2500 American individuals from the Bogalusa Heart Study, an increasing BMI trajectory during adolescence, but not during childhood, was associated with an increased risk of type 2 diabetes [9]. In a large Danish study including overweight status at 7 years, 13 years and young adult age, overweight at 7 years that had normalised at 13 years was not associated with an increased risk of type 2 diabetes, while overweight at all later ages was [8]. In the present study, consistent with these previous studies, the results for overweight in childhood were significant in separate analyses but, in analyses adjusted for birthweight and young adult overweight, the association between overweight in childhood and type 2 diabetes was attenuated and no longer statistically significant. However, a moderately increased risk related to excess BMI in childhood cannot be ruled out.

The proposed mechanisms for the association between low birthweight and increased risk of type 2 diabetes have primarily focused on the exposure to intrauterine growth restriction [26, 27]. This growth restriction, caused by deficiency of energy, primes the fetus to endure nutritional deprivation and, as a consequence, promotes fat storage and insulin resistance [28]. In the present study, a birthweight within the normal range (2.5–4.5 kg) was inversely associated with type 2 diabetes, indicating that this association is present over the entire range of birthweight and is not driven only by individuals with low birthweight. It is possible that babies within the normal birthweight range may also have been exposed to relative intrauterine growth restriction in which the genetic growth potential exceeded the energy supply. If so, an individual could still be primed towards a metabolic phenotype associated with a higher risk of type 2 diabetes, despite a birthweight in the normal or even upper normal range. During the pubertal period, the increased levels of sex hormones, growth hormone and insulin-like growth factor-1 are thought to cause the established physiological insulin resistance seen during puberty [29]. The natural progress of this insulin resistance is a decline and normalisation at the end of puberty, although in youth with obesity, this normalisation is often incomplete or absent, which may lead to more severe insulin resistance and later type 2 diabetes [29]. Furthermore, excess BMI acceleration during puberty is associated with increased visceral fat in young adulthood [30]. Visceral fat has a higher metabolic activity and contributes more to insulin resistance than subcutaneous fat [31]. Thus, the pubertal period involves several metabolic attributes with the potential to contribute to higher sensitivity to excess BMI acceleration, or sustained overweight, which are the foundations of overweight in young adulthood. It is plausible that the metabolic consequences of growth restriction during fetal life, when combined with a detrimental pubertal BMI trajectory, result in an additive excess risk of later type 2 diabetes, as suggested by the results in the present study.

The present study has several limitations. As conscription in the present cohort, born between 1945 and 1961, was mandatory only for men, and height and weight measurements at age 20 years were largely collected from conscription registers, BMI measurements for women in young adulthood were not available. Therefore, the present study was limited to men only. Furthermore, the cohort mainly consists of white individuals and therefore the results may have limited generalisability to other ethnicities. Information on gestational age was not available for the present cohort and, hence, premature individuals could not be identified [32]. Adjustment for other possible mediators, such as BMI in middle age, smoking, physical exercise level and dietary habits, would have been desirable, but this information was not available for this historical cohort. Another limitation could be that, in the model including birthweight, young adult overweight and risk of early type 2 diabetes, the hazard was not entirely proportional for young adult overweight.

In summary, we found that low birthweight and young adult overweight are the main developmental determinants of the risk of adult type 2 diabetes. The combination of a low birthweight and overweight at age 20 years was associated with a massive excess risk for early type 2 diabetes, beyond that associated with low birthweight or young adult overweight separately. Importantly, we observed a 21% absolute risk reduction for early type 2 diabetes if an individual with a low birthweight avoided overweight in young adulthood. We therefore propose that particular efforts should be directed at children with low birthweight to prevent the subsequent development of young adult overweight and the associated massive of risk of type 2 diabetes.