Combination of citrus peel-derived essential oils with acarbose to inhibit amylolytic enzymes – a potential type II diabetes treatment approach

Abstract

Type 2 diabetes (T2D) can be managed by inhibiting amylolytic enzymes, α-amylase and α-glucosidase, reducing the impact of dietary carbohydrates on blood glucose elevation. Acarbose, a current α-glucose inhibitor (AGI), has excessive α-amylase inhibition, resulting in side effects associated with large amounts of undigested starch being fermented in the colon. This study evaluated the AGI efficacy of citrus peel-derived essential oils, where they were first tested in silico against the target amylolytic enzymes, and then their AGI activity was tested in vitro. The synergistic effects of the essential oils with acarbose against amylolytic enzymes were also determined. In silico and in vitro data of the efficacy of the essential oils as AGIs correlated positively; lower Ki values correlated with more negative binding affinity. Furthermore, molecular dynamic simulations of the most potent compounds were evaluated and indicated relative flexibility and stability induced upon ligand interactions with the protein. The standard AGI drug, acarbose, had the lowest Ki (0.10 ± 0.01 mg/mL) and more negative binding affinity (−7.5 kcal/mol) than the essential oils for α-glucosidase; however, the essential oils only showed potent inhibition against α-glucosidase, with the most potent essential oils being valencene (Ki = 0.33 ± 0.04 mg/mL), carveol (Ki = 0.53 ± 0.02 mg/mL) and geraniol (Ki = 0.56 ± 0.02 mg/mL). The essential oils and acarbose displayed competitive inhibition of α-glucosidase. Furthermore, a combination of acarbose with carveol or geraniol at a ratio of 12.5 μg/mL: 2 mg/mL exhibited antagonistic (CI > 10) and synergistic (CI < 0.7) effects on α-amylase and α-glucosidase inhibition, respectively. Carveol or geraniol can be considered as potentially therapeutic in managing T2D, as it may display lowered AGI-associated side effects.

HIGHLIGHTS • Terpenes were identified from Citrus peel-derived essential oils. • Some individual essential oils tolerably inhibited amylolytic enzymes. • Synergism of essential oils with acarbose against amylolytic enzymes was established. • Essential oils inhibited glucose release with reduced starch residues.