5,6-dehydrokawain improves glycaemic control by modulating AMPK target genes in Drosophila with a high-sucrose diet-induced hyperglycaemia

Background: Type 2 diabetes (T2D) is among the leading causes of mortality and morbidity globally. Patients living with T2D are best managed with anti-diabetic agents concurrently with a lifestyle adjustment. AMP-activated protein kinase (AMPK) has been implicated in multiple pathways associated with obesity and diabetes, which makes it a target for drug discovery. 56DHK is naturally found in the rhizomes of Alpinia mutica. The anti-diabetic effects of 56DHK and its molecular mechanism have not been elucidated. Aim: This research investigates the anti-diabetic properties of 56DHK and its roles in modulating AMPK signaling in a Drosophila model of diabetes. Methods: Adult flies were fed with a high-sucrose diet and subsequently fed with a normal diet supplemented with varying concentrations of 56DHK (50, 100, and 200 µg/g). In the end, the flies were analysed for haemolymph levels of carbohydrates, triglycerides (TAG), and antioxidants status. Expressions of AMPK, insulin receptor substrate (IRS), Acetyl-CoA carboxylase (ACC), and phosphoenolpyruvate carboxykinase (PEPCK) were further analysed using qRT-PCR. Results: Dietary exposure to 56DHK decreased glucose, trehalose, TAG, glycogen, and T-AOC levels, most prominently at 100 and 200 µg/g as compared to that of metformin. Also, increased catalase activity at 100 and 200 µg/g as compared to that of metformin. Expression levels of AMPK and IRS were upregulated, while ACC and PEPCK were downregulated after 56DHK treatment. Conclusion: Findings from both biochemical and gene expression analysis suggest 56DHK ameliorate hyperglycaemia in a Drosophila model of diabetes. The overall data suggested that 56DHK could serve as a promising lead for the development of an effective anti-diabetic agent.