Benincasa hispida (Thunb.) Cogn. (Cucurbitaceae) is an essential food plant in India possessing antihyperglycemic and antihyperlipidemic activities. The objective included comparative estimation of α-glucosidase and α-amylase enzyme inhibition potential of B. hispida fractions prepared by microwave-assisted extraction and prediction of metabolite interaction against non-insulin-dependent diabetes mellitus by metabolite profiling based network pharmacology analysis. A validated microwave-assisted extraction method was employed to obtain different fractions of B. hispida fruits. The invitro enzyme assay was done with p-nitrophenyl-α-D-glucopyranoside and acarbose as standard to evaluate antidiabetic potential. The phytomolecules present in the active fraction wereidentified by UHPLC-QToF-MS/MS analysis. Network pharmacology analysis gave possible gene and disease association, combination synergy network, and predicted probable mechanism of action. The highest enzyme inhibition potential (IC50) was shown by the ethyl acetate fraction (0.546 ± 0.17 mg/mL and 1.134 ± 0.42 mg/mL) compared to acarbose (0.298 ± 0.08 mg/mL and 0.532 ± 0.38 mg/mL), respectively, for α-glucosidase and α-amylase addressing the potential role in ameliorating non-insulin-dependent diabetes mellitus. Metabolite profiling resulted in the identification of 17 metabolites, and a synergy between the identified molecules suggested multimolecule action in the amelioration of non-insulin-dependent diabetes mellitus through insulin resistance pathway, AMPK signaling pathway, PPAR signaling pathway, and PI3K-Akt signaling pathway. Combination synergy of identified molecules was observed through a multitarget approach to manage non-insulin-dependent diabetes mellitus. Polyphenol-enriched fraction of B. hispida fruits and identified phytocompounds ameliorate non-insulin-dependent diabetes mellitus. Thus, enriched extract of B. hispida can be further investigated in order to develop high-quality, safe, and effective products for the management of non-insulin-dependent diabetes mellitus.
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