Background: Biomarkers of metabolism and inflammation may predict children with increased diabetes risk. Objective: To study plasma adiponectin, leptin, IL-8, and hepatocyte growth factor (HGF) in childhood and their independent associations with insulin insensitivity, cross-sectional and in 6-yr prospective. Subjects: Danish 8- to 10-yr-olds and 14- to 16-yr-olds from the European Youth Heart Studies I and II. Methods: Cross-sectional (n = 386) and prospective (n = 246) linear regressions of baseline concentrations of plasma biomarkers and insulin insensitivity at baseline and 6 yr later. Adjustments were made at four progressive steps for sex, sexual maturity, body mass index (BMI), other biomarkers, physical activity, and school location as well as baseline insulin insensitivity in prospective analyses. Insulin insensitivity was measured using homeostasis model assessment standardized to the sample mean [homoestasis model assessment (HOMA) Z-scores]. Plasma biomarkers were quantified using solid-phase protein immunoassays. Overweight was defined as the highest BMI tertile. Results: Among overweight but not lean children at baseline, one SD difference in baseline plasma adiponectin was associated with -0.41 SD difference in HOMA Z-scores 6 yr later (p = 0.006). At baseline, one SD difference in plasma leptin was associated with 0.36 SD difference in HOMA Z-scores (p =< 0.0001) among 8- to 10-yr-olds, but a prospective association was not found. Conclusions: We found a direct relationship between childhood hypo-adiponectinaemia and insulin insensitivity in adolescence. This association was stronger for overweight than for normal weight children. Hyper-leptinaemia was associated with concurrent insulin insensitivity at baseline but not 6 yr later.