Ras homolog enriched in brain 1 regulates β cell mass and β cell function mTORC1/AMPK/Notch1 pathways.

Background: The identification of key regulators of β cell mass and function is crucial in developing effective therapeutic interventions for diabetes. Ras homolog enriched in brain 1 (Rheb1), an upstream binding protein of mTOR, is a potential therapeutic target for β cell in diabetes, while the underlying mechanisms remains unknown.

Aim: To assess the effect and potential mechanism of Rheb1 on β cell mass and function.

Methods: Islets samples were collected from mouse and human donors. Min6 transformed cell line and mouse models including pancreatic or β-cell specific knockout of Rheb1mice were established. Rapamycin (an mTORC1 inhibitor) and AICAR (an AMPK activator) was used to investigate mTORC1 or AMPK signaling in β cells. The effect of Rheb1 on β cell function mTORC1, AMPK or other pathways were assessed using western blotting and immunofluorescence,

Results: In this study, we demonstrate that Rheb1 is highly expressed in islets from young human donors (below the age of 18) compared to adults. Furthermore, our findings reveal that Rheb1 facilitates β-cell proliferation through both mTORC1 and AMPK signaling pathways, rather than solely relying on mTORC1. Specifically, we observed that either AICAR or rapamycin alone could partially inhibit Rheb1-induced β cell proliferation, while the combination of AICAR and rapamycin fully inhibits Rheb1-induced β cell proliferation in Min6 transformed cell line and mouse islets. In addition, our study highlights the role of Rheb1 in maintaining β cell identity through activation of mTORC1 and Notch1 signaling pathways. Moreover, we also found that Rheb1 could positively regulate HNF4α in β cells, which is a significant transcription factor for β-cell development and differentiation.

Conclusion: Overall, our findings reveal that Rheb1 regulates β cell proliferation and identity and β-cell development related significant marker, providing a promising novel therapeutic target for diabetes.