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Background: Previous research demonstrated that the crude saponins of Platycodi radix improve glucose metabolism by enhancing insulin sensitivity in type 2 diabetic animals; however, which individual saponins are the most potent insulin sensitizers is unknown. Objectives: This study investigated which saponin(s) have anti-diabetic action in vitro and in vivo. Methods: The insulin-stimulated glucose uptake and PPAR-γ agonistic actions of six saponins from Platycodi radix were investigated in 3T3-L1 adipocytes, and glucose-stimulated insulin secretion was determined in Min6 cells. Four individual saponins (20 mg/kg body weight) were orally administered to low-dose streptozotocin-injected diabetic mice fed a high-fat diet for 8 weeks to evaluate glucose tolerance by oral glucose tolerance testing (OGTT), insulin sensitivity by insulin tolerance testing, and insulin signaling in the liver and adipose tissues. Results: Platyconic acid (PA) most effectively increased insulin-stimulated glucose uptake in 3T3-L1 adipocytes, possibly in part by working as a peroxisome proliferator-activated receptors (PPAR)-γ activator; however, none of the saponins improved glucose-stimulated insulin secretion in insulinoma cells. PA-treated diabetic mice exhibited the lowest peak serum glucose levels and highest serum insulin levels during the first part of OGTT. PA also improved insulin sensitivity: PA increased glycogen accumulation and decreased triacylglycerol storage in liver, which was associated with enhanced hepatic insulin signaling, while PA potentiated the expression of adiponectin and PPAR -γ in adipose tissue, and improved insulin signaling and increased GLUT4 translocation into the membranes. Conclusions: PA improves glucose homeostasis in type 2 diabetic mice, partly by enhancing hepatic and adipocyte insulin sensitivity, possibly by activating PPAR-γ. [ABSTRACT FROM AUTHOR]