| Summary: | Here, we identified the mechanisms of action of antidiabetic activity of novel compounds isolated from <i>Cassia fistula</i> stem bark in STZ-diabetic animals. Novel triterpenoid compounds (C1, C2 and C3) were treated to STZ-administered diabetic animals at a concentration of 20mg/kg body weight orally for 60 days to assess their effects on plasma glucose, plasma insulin/C-peptide, serum lipid markers and the enzymes of carbohydrate metabolism, glucose oxidation and insulin signaling molecules. Oral administration of novel triterpenoid compounds to STZ-diabetic animals significantly decreased (<i>p</i> < 0.05) the plasma glucose concentration on the 7th, 15th, 30th, 45th and 60th daysin a duration-dependent manner (<i>p</i> < 0.05). Plasma insulin (<i>p</i> < 0.0001)/C-peptide (<i>p</i> < 0.0006), tissue glycogen (<i>p</i> < 0.0034), glycogen phosphorylase (<i>p</i> < 0.005), glucose 6-phosphatase (<i>p</i> < 0.0001) and lipid markers were significantly increased (<i>p</i> < 0.0001) in diabetic rats, whereas glucokinase (<i>p</i> < 0.0047), glycogen synthase (<i>p</i> < 0.003), glucose oxidation (<i>p</i> < 0.001), GLUT4 mRNA (<i>p</i> < 0.0463), GLUT4 protein (<i>p</i> < 0.0475) and the insulin-signaling molecules IR mRNA (<i>p</i> < 0.0195), IR protein (<i>p</i> < 0.0001), IRS-1 mRNA (<i>p</i> < 0.0478), p-IRS-1<sup>Tyr612</sup> (<i>p</i> < 0.0185), Akt mRNA (<i>p</i> < 0.0394), p–Akt<sup>Ser473</sup> (<i>p</i> < 0.0162), GLUT4 mRNA (<i>p</i> < 0.0463) and GLUT4 (<i>p</i> < 0.0475) were decreased in the gastrocnemius muscle. In silico analysis of C1–C3 with IRK and PPAR-γ protein coincided with in vivo findings. C1–C3 possessed promising antidiabetic activity by regulating insulin signaling mechanisms and carbohydrate metabolic enzymes.
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