Angiotensin (1-7) reverses glucose-induced islet β cell dedifferentiation by Wnt/β-catenin/FoxO1 signalling pathway

Introduction: Recent studies have shown that a decline in isletβ cells quality is due to β-cell dedifferentiation, not only β-cell Apoptosis. Angiotensin (1-7) [Ang(1-7)] could attenuate high glucose-induced Apoptosis and dedifferentiation of pancreaticβ cells by combining with MAS receptors. However, the mechanism of such action has not been elucidated. Recent studies have revealed that Wnt/β-catenin and forkhead box transcription factor O1 (FoxO1) are associated with β-cell dedifferentiation. Our study aims to explore whether the effects of Ang(1-7)on islet b cell dedifferentiation are mediated through the Wnt/β-catenin/FoxO1 pathway.

Material and methods: Isletβ cells were divided into 6 groups: a control group, a high-glucose group, high glucose with Ang(1-7) group, high-glucose with Ang(1-7) and A779 group, high-glucose with angiotensin(1-7) and CHIR99021 group, and high-glucose with CHIR99021 group. A779 is a kind of MAS receptor antagonist that blocks the action of Ang(1-7), and CHIR99021 is a Wnt pathway activator. The morphology of pancreaticβ cells was observed in each group after 48 hours of intervention. β-cell Insulin secretory function and expressions of relevant factors were measured.

Results: Compared with the control group, the cell morphology became degraded in the high-glucose group and the capability of Insulin secretion was reduced. Meanwhile, the expressions of matureβ cells markers [pancreatic and duodenal homeobox 1 (Pdx1) and MAF BZIP transcription factor A (MafA)] were reduced, while the expressions of endocrine progenitor cells makers [octamer-binding transcription factor 4 (Oct4) and Nanog] were increased. The addition of CHIR99021 resulted in profound deep destruction ofβ cells compared with the high-glucose group. However, such changes were dramatically reversed following the treatment of Ang(1-7). The addition of A779 significantly inhibited the improvement caused by Ang(1-7).

Conclusion: Ang(1-7) can effectively reverseβ cell dedifferentiation through Wnt/β-catenin/FoxO1 pathway. It might be a new strategy for preventing and treating diabetes.

Wnt/β-catenin/FoxO1 pathway; angiotensin (1–7); dedifferentiation of islet β cells; diabetes; insulin secretion.