Objective Circulating cytokines are frequently cited as contributors to insulin resistance in children with obesity. This study examined whether circulating adipocytokines, independent of adiposity, predicted pubertal changes in insulin sensitivity (SI), insulin secretion (AIR), and β-cell function in high-risk adolescents. Methods 158 Hispanic adolescents with overweight or obesity were followed for a median of 4 years. Adipocytokines were measured using Luminex technology. SI, AIR, and the disposition index were derived from an intravenous glucose tolerance test and minimal modeling. Total fat mass was measured by DXA and visceral adipose tissue (VAT) by MRI. Results Surprisingly, mean IL-8, IL-1β, IL-6, and TNF-α decreased between 5% and 6.5% per year from baseline (P-<-0.001). Despite the general temporal trends, gaining 1-SD of VAT was associated with a 2% and 5% increase in MCP-1 and IL-8 (P-<-0.05). In addition, a 1-SD higher MCP-1 or IL-6 concentration at baseline was associated with a 16% and 21% greater decline in SI during puberty vs. prepuberty (P-<-0.05). Conclusions Several adipocytokines decreased during adolescence and were weakly associated with VAT and lower SI during puberty. Circulating adipocytokines have relatively limited associations with pubertal changes in diabetes risk; however, the consistent findings with MCP-1 warrant further investigation.