Objective: The present study was undertaken to assess the effect of Momordica charantia fruits on diabetes mellitus and its related complications.Methods: Crude powder, aqueous, 95% and 50% ethanol extract of Momordica charantia fruits were administered to normal rats post sucrose load and streptozotocin-induced (STZ-induced) diabetic rats in single-dose study. The aqueous extract was further fractionated into butanol and aqueous fractions which were evaluated for the antihyperglycemic activity at a single dose in STZ-induced diabetic rats. The multiple dose effect of aqueous fraction was studied in high-fructose diet fed (HFD) rats and STZ-induced diabetic rats. The effect of the same fraction on cellular glucose uptake and insulin-signaling was studied in rat skeletal muscle cells (L6).Results: The aqueous extract of Momordica charantia fruits showed significant lowering of postprandial hyperglycemia in normal rats and also lowered blood glucose level in STZ-induced diabetic rats. The butanol and aqueous fractions also significantly declined the blood glucose level of STZ-induced diabetic rats in single-dose administration with comparatively higher activity in aqueous fraction. In a multiple - dose study the aqueous fraction significantly improved fasting blood glucose, oral glucose tolerance, plasma insulin level, lipid profile, hepatic and renal parameters in both high-fructose diet fed and STZ-induced diabetic rats. In vitro study of L6 cells revealed that the aqueous fraction significantly increased glucose uptake by treated cells by upregulating the expression of IRS, AKT and GLUT4 at both mRNA and protein level.Conclusion: It can be concluded that the aqueous fraction of aqueous extract of Momordica charantia fruits is competent in the control of diabetes and its related complications.Â