Anti-diabetic effect of three new norditerpenoid alkaloids in vitro and potential mechanism via PI3K/Akt signaling pathway.

Abstract Diabetes is a metabolic disease with the characteristic of high blood glucose (hyperglycemia). In our previous study, we found that nigelladines A – C (compounds A – C ), three norditerpenoid alkaloids from the seeds of Nigella glandulifera Freyn (Ranunculaceae) exhibited protein of tyrosine phosphatase 1B (PTP1B) inhibitory activity in vitro . In the present study, we further investigated their anti-diabetes activities in L6 moytubes and illuminated the mechanisms of action of compounds A – C . Several parameters of glucose metabolism such as glucose consumption, glycogen content and hexokinase activity were increased by compounds A – C . The results suggested that compounds A–C improved glucose metabolism through promoting synthesis of glycogen. Expression of PTP1B protein was inhibited by compounds A – C in L6 moytubes. PI3K-dependent Akt phosphorylation was found to be activated by compounds A - C and completely blocked by wortmannin (a PI3K inhibitor). Moreover, the insulin-mediated induction of insulin receptor substrate-1 (IRS-1) and glycogen synthase kinase-3β (GSK-3β) were also suppressed by wortmannin. Western blot results indicated that compounds A – C -induced IRS-1/Akt activation was likely a consequence of PTP1B inhibition. Compounds A – C promoted glycogen synthesis through Akt-mediated GSK3 phosphorylation. Therefore, activation of PI3 K/Akt insulin signaling pathway and suppression of PTP1B is the molecular mechanism that contributes to the anti-diabetic effect of compounds A–C in cellular models. The three alkaloids potentially serve as lead compounds for the development of antidiabetic drugs.