Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jun 15, 2025; 16(6): 104973
Published online Jun 15, 2025. 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
Yan Yang, Wan-Juan Song, Jing-Jing Zhang
Yan Yang, Jing-Jing Zhang, 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
Wan-Juan Song, Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
Co-corresponding authors: Wan-Juan Song and Jing-Jing Zhang.
Author contributions: All authors contributed to the study conception and design; Yang Y were responsible for conceptualization, methodology, literature search, data collection, investigation, visualization, and original draft writing sections; Song WJ and Zhang JJ were responsible for supervision, and reviewed the article and made helpful suggestions; Song WJ and Zhang JJ contribute equally to this study as co-corresponding authors; all authors read and approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 82430029, No. 82330025, No. 82370807, and No. 82070807; Leading Talents Program of Hunan Province, No. 2022RC3078; and Natural Science Foundation of Hunan Province, China, No. 2021JJ30976.
Institutional review board statement: The use of isolated human islets was approved by the Ethics Committee of the Central South University Second Xiangya Hospital (No. MSRC2016 LF).
Institutional animal care and use committee statement: All procedures for animal use were in accordance with the Animal Care and Use Committee of the Second Xiangya Hospital Animal Care and Central South University (20240083).
Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: sharing statement: All data supporting the findings of this study and unique biological materials used in this study are available from the corresponding authors upon reasonable request. Source data are provided with this paper.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jing-Jing Zhang, MD, PhD, 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, Renmin Middle Road, Changsha 410011, Hunan Province, China. doctorzhangjj@csu.edu.cn
Received: January 10, 2025
Revised: February 19, 2025
Accepted: April 3, 2025
Published online: June 15, 2025
Processing time: 157 Days and 1.7 Hours
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: Rheb1; β cells; Diabetes; mTOR; AMP-activated protein kinase; Hepatocyte nuclear factor4-alpha

Core Tip: Mechanisms underlying β cell dysfunction in diabetes remains unclear, our study explores the role of Ras homolog enriched in brain 1 (Rheb1) in regulating β-cell function and proliferation. The researchers found that Rheb1 is more highly expressed in islets from younger individuals (under 18) compared to adults. Rheb1 promotes β-cell proliferation through both the mTORC1 and AMP-activated protein kinase pathways, rather than relying solely on mTORC1. Moreover, Rheb1 also upregulated key transcription factor HNF4α in β cells. These findings suggest that Rheb1 plays a vital role in β-cell growth and function, making it a promising target for diabetes therapy.