Fig 7. The dopamine D₂-receptor-mediated control of the insulin/PI3K/AKT/FOXO1 signalling pathway activation.

Dopamine stimulates D₂-ARs on pancreatic β-cells and restricts the release of insulin in response to increased plasma glucose levels [61]. In contrast, blockade of D₂-dopaminergic receptors by sulpiride, increases insulin release [22], which in turn, stimulates insulin receptors (IR) in hepatocyte plasma membranes, an effect resulting in the phosphorylation of the Insulin Receptor Substrate (IRS) at different docking sites, where the phosphatidylinositol 3-kinase (PI3K) binds. Activated PI3K converts phosphatidylinositol biphosphate to phosphatidylinositol triphosphate, which subsequently activates protein kinase B (AKT). Upon activation AKT phosphorylates the transcription factor forkhead box O1 (FOXO1), which then translocates into the cytoplasm thus terminating CYP1A1, CYP1A2 and CYP1B1 gene transcription [22,75].