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

Yan Yang; Wan-Juan Song; Jing-Jing Zhang

doi:10.4239/wjd.v16.i6.104973

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

World J Diabetes. 2025 Jun 15;16(6):104973. doi: 10.4239/wjd.v16.i6.104973.

Authors

Yan Yang¹, Wan-Juan Song², Jing-Jing Zhang³

Affiliations

¹ National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China.
² Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China.
³ National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China. doctorzhangjj@csu.edu.cn.

Abstract

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 via mTORC1, AMPK or other pathways were assessed using western blotting and immunofluorescence, etc.

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.

Keywords: AMP-activated protein kinase; Diabetes; Hepatocyte nuclear factor4-alpha; Rheb1; mTOR; β cells.