Anti-diabetic potential of apigenin, luteolin, and baicalein via partially activating PI3K/Akt/Glut-4 signaling pathways in insulin-resistant HepG2 cells

 Food Science and Human Wellness, 12 (6), 1991-2000 (2023)

Dietary flavonoids are abundant in natural plants and possess multiple pharmacological and nutritional activities. In this study, apigenin, luteolin, and baicalein were chosen to evaluate their anti-diabetic effect in high-glucose and dexamethasone induced insulin-resistant (IR) HepG2 cells. All flavonoids improves the glucose consumption and glycogen synthesis abilities in IR-HepG2 cells via activating glucose transporter protein 4 (GLUT4) and phosphor-glycogen synthase kinase (GSK-3β). These flavonoids significantly inhibited the production of reactive oxygen species (ROS) and advanced glycation end-products (AGEs), which were closely related to the suppression of the phosphorylation form of NF-κB and P65. The expression levels of insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in IR-HepG2 cells were all partially activated by the flavonoids, with variable effects. Furthermore, the intracellular metabolic conditions of the flavonoids were also evaluated.

Apigenin alleviates diabetic endothelial dysfunction through activating AMPK/PI3K/Akt/eNOS and Nrf2/HO-1 signaling pathways

 Food Frontiers, 4(1) 420-431 (2023)

Apigenin (4′,5,7-trihydroxyflavone) is a natural flavone reported to present anti-diabetic and anti-oxidative bioactivities. The effect of apigenin to mitigate endothelial dysfunction in diabetes remains to be investigated. In the present study, the vaso-protective effect of apigenin as well as its underlying action mechanisms was investigated using in vitro- and in vivo-based assays. Aortas were detached from C57BL/6J mice for ex vivo treatment, and primary rat aortic endothelial cells (RAECs) were cultured and further stimulated using high glucose (HG) with or without apigenin. In-vivo diabetic model was established by feeding male C57BL/6J mice with a high-fat diet (60% kcal% fat) for a total of 14 weeks, whereas the treatment group was orally administered apigenin (25 mg/kg/day) during the last 4 weeks. Exposure to HG (30 mM, 48 h) impaired acetylcholine-induced endothelium-dependent relaxation (EDR) in mouse aortas and induced oxidative stress with the downregulation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/phosphatidyl inositol 3-kinase (PI3K)/protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathways in aortas and RAECs. These impairments were reversed by apigenin treatments. However, the vaso-protective effects of apigenin were abolished by Compound C (AMPK inhibitor) and wortmannin (PI3K inhibitor). Chronic oral administration with apigenin ameliorated EDR and reduced oxidative stress in the aortas of high-fat diet (HFD)-induced obese and diabetic mice. In conclusion, this study revealed that apigenin improved endothelial function and suppressed oxidative stress in the vasculature in diabetes through the activation of AMPK/PI3K/Akt/eNOS and Nrf2/HO-1 pathways, suggesting its therapeutic potential as a natural dietary flavonoid against vascular diseases associated with diabetes.