Dual Inhibition of PTP1B and DPP-IV by Metabolites from Artocarpus elasticus Leaves Enhances Insulin Signaling and Sensitivity

초록

BackgroundProtein tyrosine phosphatase 1B (PTP1B) and dipeptidyl peptidase-IV (DPP-IV) play key roles in the regulation of insulin sensitivity and insulin resistance, which are central to the pathogenesis of diabetes. Artocarpus elasticus has been traditionally used for diabetes treatment; however, specific bioactive compounds responsible for antidiabetic effects remain unclear.ObjectivesStudy aimed to isolate and characterize compounds from A. elasticus leaves and to evaluate their inhibitory activities against PTP1B and DPP-IV, enzyme inhibition mechanisms, binding affinities, molecular docking and effects on insulin signaling in adipocyte cells.MethodsDifferent techniques were used for isolation and characterization of compounds. Their inhibitory activities against PTP1B and DPP-IV, mode of inhibition and binding affinities were performed carefully. Compounds 1 and 5 were tested in 3T3-L1 adipocytes for insulin receptor substrate (IRS) phosphorylation and downstream signalling markers. Molecular docking of 1, 5, and 6 against PTP1B was also performed.ResultsAll compounds inhibited PTP1B (IC50 = 0.25 to 3.00 & micro;M), whereas 1-4 showed significant DPP-IV inhibition (IC50 = 1.01-15.75 & micro;M). Compound 1 showed potent dual inhibitory activity. Kinetic studies revealed mixed-type inhibition for 1-4 and competitive inhibition of PTP1B by 5 and 6. Binding affinity results correlated well with enzyme inhibitory potency. Cellular assays showed that 1 and 5 enhanced insulin signaling by modulating phosphorylated IRS, PI3K, and p-AKT expression. In docking analysis, 1, 5, and 6 showed strong binding affinity with PTP1B.ConclusionA. elasticus compounds 1 and 5, inhibit PTP1B and increase insulin signalling, making them promising antidiabetic therapeutic leads.

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