Abstract
BACKGROUND: Early-life exposure to improved nutrition is associated with decreased risk of diabetes but increased risk of obesity. Leptin positively correlates with adiposity and has glucose-lowering effects, thus it may mediate the association of early-life nutrition and long-term glycemic status. OBJECTIVES: We aimed to investigate the role of leptin in the differential association between early-life nutrition and the risks of obesity and diabetes. METHODS: We analyzed data from a Guatemalan cohort who were randomly assigned at the village level to receive nutritional supplements as children. We conducted mediation analysis to examine the role of leptin in the associations of early-life nutrition and adult cardiometabolic outcomes. RESULTS: Among 1112 study participants aged (mean ± SD) 44.1 ± 4.2 y, 60.6% were women. Cardiometabolic conditions were common: 40.2% of women and 19.4% of men were obese, and 53.1% of women and 41.0% of men were hyperglycemic or diabetic. Median (IQR) leptin concentration was 15.2 ng/mL (10.2-17.3 ng/mL) in women and 2.7 ng/mL (1.3-5.3 ng/mL) in men. Leptin was positively correlated with BMI (Spearman's ρ was 0.6 in women, 0.7 in men). Women exposed to improved nutrition in early life had 2.8-ng/mL (95% CI: 0.3, 5.3 ng/mL) higher leptin and tended to have lower fasting glucose (-0.8 mmol/L; -1.8, 0.2 mmol/L, nonsignificant) than unexposed women. There were no significant differences in leptin (-0.7 ng/mL; -2.1, 0.8 ng/mL) or fasting glucose (0.2 mmol/L; -0.5, 0.9 mmol/L) in men exposed to improved nutrition in early life compared with unexposed men. Leptin mediated 34.9% of the pathway between early-life nutrition and fasting glucose in women. The mediation in women was driven by improved pancreatic β-cell function. We did not observe the mediation effect in men. CONCLUSIONS: Leptin mediated the glucose-lowering effect of early-life nutrition in women but not in men.