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

•5,6-dehydrokawain promotes glycaemic control in hyperglycaemic Drosophila.•5,6-dehydrokawain modulates AMPK signaling of Drosophila on high diet-induced T2D.•AMPK is a target for the metabolic effects 5,6-dehydrokawain.•AMPK modulates downstream target genes implicated in insulin sensitivity, gluconeogenesis, lipolysis and lipogenesis. 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. This research investigates the anti-diabetic properties of 56DHK and its roles in modulating AMPK signaling in a Drosophila model of diabetes. 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. 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. 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. [Display omitted]