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

Abstract

Aims/hypothesis: The aim of this work was to estimate the impact of birthweight on early-onset (age <40 years) type 2 diabetes.

Methods: 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.

Results: 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.

Conclusions/interpretation: 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.

Keywords: Birthweight; Diabetes mellitus; Genetic susceptibility; Incidence study; Type 2.

Fig. 1

Crude cumulative incidence (incidence proportion from the first research examination) of type 2 diabetes by birthweight quintile. Cumulative incidence (unadjusted for covariates), where the period of risk began at the first research examination when the participant did not have diabetes, was computed independently in each group of participants defined by birthweight quintile

Fig. 2

Effect of birthweight on the risk of type 2 diabetes. (a–c) Risk of type 2 diabetes (adjusted for all participant and maternal characteristics except BMI of participant and maternal diabetes) at age 10–19 years (a; n=2912, p<0.001), 20–29 years (b; n=1989, p=0.027) and 30–39 years (c; n=1079, p=0.042). (d–f) Risk of type 2 diabetes (adjusted for all participant and maternal characteristics including BMI of participant and maternal diabetes) at age 10–19 years (d; n=2912, p<0.001), 20–29 years (e; n=1989, p<0.001) and 30–39 years (f; n=1079, p=0.003). The height of each bar represents the point estimate of the IRR and the error bars represent its 95% CI

Fig. 3

Joint effects of BMI, type 2 diabetes GRS and maternal diabetes with birthweight on the incidence rate (per 1000 person-years) of type 2 diabetes at age 10–19 years. (a) Offspring of a non-diabetic woman with a low (below the median) type 2 diabetes GRS. (b) Offspring of a non-diabetic woman with a high (at or above the median) type 2 diabetes GRS. (c) Offspring of a diabetic woman with a low type 2 diabetes GRS. (d) Offspring of a diabetic woman with a high type 2 diabetes GRS. py, person-years