Xiuping Xuan1, Fei Gao2, Xiaoyi Ma1, Chenghu Huang1, Ying Wang1, Hongjun Deng1, Shiqi Wang1, Wencun Li1, Li Yuan3. 1. Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 2. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 3. Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: yuanli18cn@126.com.
Abstract
OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) has been identified in pancreatic islets and can preserve β cells. In this study, we aimed to examine the possible role of ACE2 and its end product, angiotensin 1-7 (A1-7), in reducing β cell dedifferentiation during metabolic stress. METHODS: First, a lineage-tracing experiment was performed to track β cells in mice fed a high-fat diet (HFD). Second, the ACE2/A1-7 axis was evaluated in the HFD mouse model. Intraperitoneal glucose tolerance tests (IPGTTs) and intraperitoneal insulin tolerance tests (IPITTs) were conducted. Phenotypic changes in β cells were detected by immunohistochemistry and quantitative real-time PCR. Pancreatic sections were immunostained for vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS). Finally, the effects of the ACE2/A1-7 axis were explored in isolated mouse islets exposed to different concentrations of glucose. Glucose-stimulated insulin release and levels of insulin mRNA and OCT4 mRNA were measured. RESULTS: Pancreatic β cell dedifferentiation occurred both in vitro and in vivo in response to metabolic stress and was accompanied by ACE2 reduction. HFD-induced insulin resistance and glucose intolerance were exacerbated in ACE2-knockout (ACE2KO) mice but were alleviated by exogenous A1-7 in C57BL/6J mice. Approximately 20% of β cells were dedifferentiated in ACE2KO mice fed a standard rodent chow diet (SD). A higher percentage of dedifferentiated β cells was detected in ACE2KO mice than in wild-type (WT) mice under HFD conditions. In contrast, the administration of A1-7 alleviated HFD-induced β cell dedifferentiation in C57BL/6J mice. Moreover, the exogenous injection of A1-7 improved microcirculation in islets and decreased the production of iNOS in islets of C57BL/6J mice fed an HFD. Additionally, ACE2 was found to be mainly expressed in α cells of mice, while Mas, the receptor of A1-7, was distributed in β cells. CONCLUSIONS: Overall, this study is the first to demonstrate that the ACE2/A1-7/Mas axis may be one of the intra-islet paracrine mechanisms of communication between α and β cells. Enhancing the ACE2/A1-7 axis exerts a protective effect by ameliorating β cell dedifferentiation, and this effect might be partially mediated through improvements in islet microcirculation and suppression of islet iNOS.
OBJECTIVE:Angiotensin-converting enzyme 2 (ACE2) has been identified in pancreatic islets and can preserve β cells. In this study, we aimed to examine the possible role of ACE2 and its end product, angiotensin 1-7 (A1-7), in reducing β cell dedifferentiation during metabolic stress. METHODS: First, a lineage-tracing experiment was performed to track β cells in mice fed a high-fat diet (HFD). Second, the ACE2/A1-7 axis was evaluated in the HFD mouse model. Intraperitoneal glucose tolerance tests (IPGTTs) and intraperitoneal insulin tolerance tests (IPITTs) were conducted. Phenotypic changes in β cells were detected by immunohistochemistry and quantitative real-time PCR. Pancreatic sections were immunostained for vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS). Finally, the effects of the ACE2/A1-7 axis were explored in isolated mouse islets exposed to different concentrations of glucose. Glucose-stimulated insulin release and levels of insulin mRNA and OCT4 mRNA were measured. RESULTS:Pancreatic β cell dedifferentiation occurred both in vitro and in vivo in response to metabolic stress and was accompanied by ACE2 reduction. HFD-induced insulin resistance and glucose intolerance were exacerbated in ACE2-knockout (ACE2KO) mice but were alleviated by exogenous A1-7 in C57BL/6J mice. Approximately 20% of β cells were dedifferentiated in ACE2KO mice fed a standard rodent chow diet (SD). A higher percentage of dedifferentiated β cells was detected in ACE2KO mice than in wild-type (WT) mice under HFD conditions. In contrast, the administration of A1-7 alleviated HFD-induced β cell dedifferentiation in C57BL/6J mice. Moreover, the exogenous injection of A1-7 improved microcirculation in islets and decreased the production of iNOS in islets of C57BL/6J mice fed an HFD. Additionally, ACE2 was found to be mainly expressed in α cells of mice, while Mas, the receptor of A1-7, was distributed in β cells. CONCLUSIONS: Overall, this study is the first to demonstrate that the ACE2/A1-7/Mas axis may be one of the intra-islet paracrine mechanisms of communication between α and β cells. Enhancing the ACE2/A1-7 axis exerts a protective effect by ameliorating β cell dedifferentiation, and this effect might be partially mediated through improvements in islet microcirculation and suppression of islet iNOS.
Authors: Melissa C White; Amanda J Miller; Justin Loloi; Sarah S Bingaman; Biyi Shen; Ming Wang; Yuval Silberman; Sarah H Lindsey; Amy C Arnold Journal: Biol Sex Differ Date: 2019-07-17 Impact factor: 5.027
Authors: Amany Magdy Beshbishy; Victor B Oti; Diaa E Hussein; Ibrahim F Rehan; Oluyomi S Adeyemi; Nallely Rivero-Perez; Adrian Zaragoza-Bastida; Muhammad Ajmal Shah; Khaled Abouelezz; Helal F Hetta; Natália Cruz-Martins; Gaber El-Saber Batiha Journal: Front Public Health Date: 2021-07-07