Ethanolic extract obtained from Annona cherimola Miller (EEAc) and the flavonoid rutin (Rut) were evaluated in this study to determine their antihyperglycemic content, % HbA1c reduction, and antihyperlipidemic activities. Both treatments were evaluated separately and in combination with the oral antidiabetic drugs (OADs) acarbose (Aca), metformin (Met), glibenclamide (Gli), and canagliflozin (Cana) in acute and subchronic assays. The evaluation of the acute assay showed that EEAc and Rut administered separately significantly reduce hyperglycemia in a manner similar to OADs and help to reduce % HbA1c and hyperlipidemia in the subchronic assay. The combination of EEAc + Met showed the best activity by reducing the hyperglycemia content, % HbA1c, Chol, HDL-c, and LDL-c. Rutin in combination with OADs used in all treatments significantly reduced the hyperglycemia content that is reflected in the reduction in % HbA1c. In relation to the lipid profiles, all combinate treatments helped to avoid an increase in the measured parameters. The results show the importance of evaluating the activity of herbal remedies in combination with drugs to determine their activities and possible side effects. Moreover, the combination of rutin with antidiabetic drugs presented considerable activity, and this is the first step for the development of novel DM treatments.

Background: Annona cherimola Miller (A. cherimola) is traditionally used in Mexico to treat diabetes. Objectives: this study aimed to evaluate the antihyperglycemic activity of the aqueous leaf extracts (AEAcL) and stem (AEAcS) of A. cherimola alone and combined with oral antidiabetic drugs (OADs), as well as to determine their effect on % HbA1c, lipid parameters and toxicity. As well, the study aimed to isolate and identify some of its compounds to propose findings about its mode of action. Methods: Antihyperglycemic activity was evaluated using in vivo models with streptozotocin-induced experimental diabetes in Balb/c mice. Computer tools were used to obtain the pharmacokinetic and toxicological properties of the identified flavonoids; to obtain findings on their potential as α-glucosidase and SGLT1 inhibitors, in vivo and in silico studies were carried out using oral sucrose tolerance (OSTT) and glucose (OGTT) tests and molecular coupling studies. Results: ÇAEs and aSAAcS administered alone at 200 mg/kg showed a significant reduction in hyperglycemia. The best combination was AEAcL + Met (100/500 mg/kg), which significantly reduced hyperglycemic values and the % of HbA1c, TG, and LDL. The flavonoids isolated from AEAcL were identified as rutin, nicotiflorin, and narcissin. The molecular coupling assay and OSTT and OGTT tests showed that the flavonoids could inhibit α-glucosidase and SGLT1. Conclusions: AEAcL shows significant antihyperglycemic and antihyperlipidemic activity in murine models of diabetes, both alone (100 mg/kg) and in combination with metformin (100/500 mg/kg). Isolated flavonoids (rutin, nicotiflorin, and narcissine) appear to be partly responsible for these effects, although they have pharmacokinetic limitations. In silico and in vivo studies suggest a possible mechanism of action by inhibition of α-glucosidase and SGLT1.