Fetal programming of early-onset type 2 diabetes: a Swedish nationwide cohort and sibling analysis

Incidence of early-onset (< 40 years) type 2 diabetes (T2D) is increasing. While multiple risk factors have been identified, particularly obesity and low socioeconomic status, early-life factors are hypothesised to play a role via fetal programming. We investigated sociodemographic and early-life factors in relation to early-onset T2D using a family-based design that accounts for shared genetic and environmental factors. We included 1,814,062 individuals born in Sweden 1983 to 2002 with follow-up data until 2020, and identified early-onset (age 19-39) T2D cases (n = 3505) through National Diabetes, Patient and Prescribed Drug Registers. Perinatal and sociodemographic factors were retrieved from registers. We used a cohort and sibling design, with multivariable-adjusted Cox proportional hazards regression. Sociodemographic factors associated with early-onset T2D included low parental education, single parenthood, younger parental age and non-Swedish origin. The latter association did not remain after mutual adjustment. Regarding perinatal factors, a higher incidence was noted in relation to lower birth weight (hazard ratio 2.38 [95% confidence interval: 1.98-2.87] and 1.43[1.33-1.54] for < 2500 g and 2500-3500 g, respectively, vs 3500-4500 g), small-for-gestational-age (SGA) (2.24[1.96-2.56]), large-for-gestational-age (LGA) (1.19[1.01-1.39]), and maternal obesity (2.34[2.04-2.69]), diabetes (1.59[1.36-1.85]), smoking (1.59[1.48-1.71]), and infection (1.21[1.03-1.41]) during pregnancy. In the sibling analysis, only low birth weight and SGA remained associated with early-onset T2D. Early-onset T2D is associated with sociodemographic and multiple perinatal factors; only growth restriction likely reflects fetal programming, while other perinatal-related associations might involve confounders. This study highlights the need for early-life, targeted strategies to prevent T2D and reduce health inequities.