Background: Annona muricata has been used in folklore in the management of diabetes. A major strategy in decreasing postprandial hyperglycemia in diabetes involves the inhibition of carbohydrate-hydrolyzing enzymes-αamylase and α-glucosidase. Thus, this study evaluated the in vivo and in vitro inhibitory potentials of the different parts (fruit-pulp, leaf, stem-bark and root-bark) of Annona muricata. Methods: A total of 120 Wistar rats were treated with methanol extracts for 28 days after which blood and tissue samples were collected for α-amylase assay. In vitro inhibitory properties of methanol, ethyl acetate and dichloromethane extracts of the various parts of the plant on α-amylase and α-glucosidase activities were performed using standard procedures. The mode and mechanism of interactions between the enzymes and extracts (and isolated acetogenin) were determined using various kinetic interpolations and in silico experiments. Result: The fruit-pulp and root-bark methanolic extracts better-inhibited plasma and tissue amylase in vivo. The in vitro studies revealed that the stem-bark methanolic, fruit-pulp ethyl acetate, and leaf dichloromethane extracts, better inhibited α-amylase activity compared with the standard acarbose. Also, the leaf methanol, fruit-pulp ethyl acetate, and root-bark dichloromethane extract better inhibited α-glucosidase activity. These observations were corroborated with their higher Bmax and Vmax and lower Kd values. All the extracts exhibited an "uncompetitive" type of inhibition pattern. Also, the isolated acetogenin (15-acetyl guanacone) from the fruit-pulp showed a better binding affinity compared to the standard drug, Metformin. Conclusion: Better natural remedy for diabetics can be obtained from Annona muricata with minimal or no adverse side effects.

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