Introduction

Type-2 diabetes mellitus (T2DM) is being diagnosed at an increasingly younger age, signaling towards increasing early exposure to various risk factors. Low birth weight and overweight in both childhood and youth have long been identified as the developmental risk factors for adult T2DM. Nevertheless, the combined impact of these two factors on the risk of T2DM development in young adulthood has not been ascertained till date.

Aim

To determine the relative impact of low birthweight and overweight during childhood and young adulthood on the risk of T2DM in men.

Profile of the Study Subjects

• Male participants from the population-based BMI Epidemiology Study (BEST) Gothenburg born between1945 and 1961 (n=34,231).
• Data on birthweight and overweight status in childhood was available for all the study participants.

Methods

Study Design

• An observational study.

  Assessments

• Information on birthweight and height and weight measurements was retrieved from centrally archived school healthcare records.
• Information of T2DM diagnoses was retrieved from the medical records.

Exposures

Birthweight

• Childhood (pre-pubertal) overweight at 8 years of age (BMI >17.9 kg/m²)
• Young adult (post-pubertal) overweight at 20 years of age (BMI >25 kg/m²)

  Outcomes

• Diagnoses of T2DM

  Follow-up

• Participants were followed from age 30 years until censoring due to T2DM diagnosis, death, or the study end period.
• Based on the median age at T2DM diagnosis, the follow-up was segregated into early (≤59.4 years of age) and late (>59.4 years of age) T2DM.

Results

• Birthweight exhibited a clear inverse linear association with T2DM risk [Hazard ration (HR): 0.84, 95% confidence interval (CI) 0.81, 0.87]. On the contrary, both childhood BMI and young adult BMI showed significant direct associations with the risk of T2DM.
• A birthweight below the median (<3.6 kg) was significantly associated with an increased risk of both early and late T2DM vs. a birthweight above the median.
• Children overweight at 8 years of age (BMI >17.9 kg/m²) had an increased risk of early and late T2DM vs. those with normal weight at 8 years.
• Being overweight at 20 years of age (BMI >25 kg/m²) was associated with a dramatically increased risk of early (HR: 4.12, 95% CI 3.63, 4.66) and late (HR: 2.29, 95% CI 1.94, 2.70) T2DM vs. with normal weight at 20 years. (Table 1).

Table 1: Birthweight & developmental overweight & risk of early & late T2DM

    a Early type 2 diabetes (follow-up from 30 years until ≤59.4 years): n=34,231, 1367 cases

    b Late type 2 diabetes (follow-up starting at >59.4 years): n=27,260, 1366 cases

• No statistically significant interactions were observed between dichotomized birthweight and overweight at either 8 or 20 years of age for early or late T2DM, or between overweight at 8 and 20 years of age for early or late T2DM. Nevertheless, overweight in childhood and adulthood exhibited significant correlation with risk of T2DM (Spearman’s r=0.34).
• Keeping the group with birthweight above the median and normal weight at 20 years as the reference (ref), the groups with birthweight below the median and normal weight at 20 years, and the group with birthweight above the median and overweight at 20 years had higher risk of early and late T2DM (Table 2).
• Amongst the individuals with a birthweight above the median, the absolute risks for early T2DM were 2.6% and 11.1% for those with normal weight at 20 years and those overweight at 20 years, respectively.
• Amongst individuals with normal weight at 20 years, the absolute risk of late T2DM was 4.1% and 5.4% in the groups with birthweight above the median and below the median, respectively (Table 2).
• Participants in the group with birthweight below the median and overweight at 20 years had a substantially increased risk of both early T2DM (absolute risk: 14.9%) and late T2DM (8.9%). The risk of early T2DM was significantly higher than for the group with high birthweight and overweight at 20 years (Table 2).

Table 2: HRs for risk of T2DM for the combination of birthweight above or below the median & normal weight or overweight at age 20 years

a Early type 2 diabetes (follow-up from 30 years until ≤59.4 years): n=34,231, 1367 cases

b Late type 2 diabetes (follow-up starting at >59.4 years): n=27,260, 1366 cases

• The combination of birthweight below the median and young adult overweight displayed an additive risk for early T2DM (HR:6.07, 95% CI 5.08, 7.27), beyond the risk of birthweight below the median or young adult overweight separately.
• Amongst individuals with overweight in young adulthood, a birthweight below the median increased the risk of early T2DM by 39% (HR 1.39, 95% CI 1.11, 1.72) but not of late T2DM, as compared with birthweight above the median.

• Individuals with low birthweight and young adult normal weight and individuals with birthweight >2.5 kg and young adult overweight had a significantly increased risk of adult T2DM vs. the ref. However, the group with low birthweight and young adult overweight had a ten-fold higher risk of early T2DM (HR: 9.94, 95% CI 6.57, 15.05), again establishing an additive effect as compared to low birthweight or young adult overweight separately.
• The group with low birthweight and young adult overweight had a significantly higher absolute risk of early T2DM vs. the group with low birthweight and young adult normal weight (27% vs. 6%).
• In individuals with young adult overweight, those with a birthweight <2.5 kg had more than two-fold higher risk of early T2DM (HR: 2.38, 95% CI 1.56, 3.64), but had no significant risk of late T2DM (HR 1.28, 95% CI 0.52, 3.11), compared with those with a birthweight >2.5 kg.

  Conclusions

• The study demonstrated that low birthweight and young adult overweight were the main developmental determinants of the risk of adult T2DM.
• The combination of a low birthweight and overweight at age 20 years increased the risk for early T2DM excessively, beyond that associated with low birthweight or young adult overweight separately.
• Individuals with a low birthweight who avoided overweight in young adulthood, had a 21% absolute risk reduction for early T2DM.
• Efforts should be initiated right from childhood in low-birthweight individuals to prevent the subsequent development of young adult overweight to alleviate the risk of T2DM development.

Diabetologia. 2024 May;67(5):874-884.