Birthweight and early-onset type 2 diabetes in American Indians: differential effects in adolescents and young adults and additive effects of genotype, BMI and maternal diabetes.

The aim of this work was to estimate the impact of birthweight on early-onset (age <40 years) type 2 diabetes. A longitudinal study of American Indians, aged ≥5 years, was conducted from 1965 to 2007. Participants who had a recorded birthweight were followed until they developed diabetes or their last examination before the age of 40 years, whichever came first. Age- and sex-adjusted diabetes incidence rates were computed and Poisson regression was used to model the effect of birthweight on diabetes incidence, adjusted for sex, BMI, a type 2 diabetes susceptibility genetic risk score (GRS) and maternal covariates. Among 3039 participants, there were 652 incident diabetes cases over a median follow-up of 14.3 years. Diabetes incidence increased with age and was greater in the lowest and highest quintiles of birthweight. Adjusted for covariates, the effect of birthweight on diabetes varied over time, with a non-linear effect at 10-19 years (p < 0.001) and a negative linear effect at older age intervals (20-29 years, p < 0.001; 30-39 years, p = 0.003). Higher GRS, greater BMI and maternal diabetes had additive but not interactive effects on the association between birthweight and diabetes incidence. In this high-risk population, both low and high birthweights were associated with increased type 2 diabetes risk in adolescence (age 10-19 years) but only low birthweight was associated with increased risk in young adulthood (20-39 years). Higher type 2 diabetes GRS, greater BMI and maternal diabetes added to the risk of early-onset diabetes.