BACKGROUND: A marked elevation of serum leptin is observed soon after the start of peritoneal dialysis (PD), suggesting that leptin production may be stimulated by this treatment. Glucose metabolism is the major factor regulating leptin. The current study was designed to test if glucose-based PD fluids might regulate leptin production in vitro. METHODS: 3T3-L1 adipocytes were exposed to a 50:50 mixture of dialysis solutions and medium M199 containing 10% serum for <or=48 h. Leptin secretion in culture cell supernatants was measured by enzyme-linked immunosorbent assay and leptin mRNA content by northern blot analysis. RESULTS: The high glucose-based commercial dialysate PD4 produced a higher leptin secretion compared with an identical laboratory-manufactured dialysate (Lab-D), but with a physiological glucose concentration of 5 mM (P<0.05). Raising glucose concentration from 2.75 to 40 mM in Lab-D induced a dose-dependent increase in leptin secretion of <or=110+/-12% at 48 h (P<0.001) and leptin mRNA (P<0.05; glucose 2.75 vs 40 mM). Inhibition of UDP-N-acetylglucosamine biosynthesis, with 6-diazo-5-oxo-norleucine added to Lab-D, abolished most of the glucose-stimulated leptin release and downregulated leptin gene expression. Furthermore, glucose-free Lab-D supplemented with 1 mM glucosamine, an intermediate product in UDP-N-acetylglucosamine biosynthesis, increased leptin secretion by 28+/-11% over control (P<0.05), although without effect on leptin mRNA, after 48 h of culture. CONCLUSIONS: These results suggest that the PD-induced hyperleptinaemia could, in part, be mediated by the effect of glucose-based dialysis fluids on leptin production by adipocytes via activation of the hexosamine biosynthetic pathway.