ACE2 modulates glucose homeostasis through GABA signaling during metabolic stress

in Journal of Endocrinology
Authors:
Xiaoyi Ma Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Fei Gao Department of Orthopedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Qi Chen Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Xiuping Xuan Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Ying Wang Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Hongjun Deng Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Fengying Yang Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Li Yuan Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Correspondence should be addressed to L Yuan: yuanli18cn@126.com
DOI:
https://doi.org/10.1530/JOE-19-0471
Volume/Issue:
Volume 246: Issue 3
Article Type:
Research Article
Page Range:
223–236
Online Publication Date:
Sep 2020
Copyright:
© 2020 Society for Endocrinology 2020
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The angiotensin-converting enzyme 2 (ACE2)/angiotensin 1–7 (A1–7)/MAS axis and glutamate decarboxylase 67 (GAD67)/gamma-aminobutyric acid (GABA) signal both exist in the islet and play important roles in regulating blood glucose metabolism. It has been reported that the activation of ACE2 in the brain increases GABA expression to improve biological effects; however, it is unclear whether there is functional correlation between the ACE2/A1–7/MAS axis and GAD67/GABA signal in the islet. In this study, we showed that the ACE2/A1–7/MAS and GABA signaling systems decreased in the islet of different metabolic stress models. In ACE2-knockout mice, we found that GAD67 and GABA expression decreased significantly, which was reversed by exogenous administration of A1–7. Furthermore, A1–7 mediated PDX1 and AKT activation was inhibited by allylglycine (a specific GAD67 inhibitor) in MIN6 cells. Moreover, giving A1–7 and GABA could significantly reduce beta-cell dedifferentiation and improved glucose metabolism during metabolic stress in vivo and in vitro. In conclusion, our study reveals that the ACE2/A1–7/MAS axis improves beta-cell function through regulating GAD67/GABA signal in beta cells and that up-regulating the ACE2/A1–7/MAS axis and GABA signals delays the development of obesity-induced diabetes.

Supplementary Materials

    • Supplementary Figure 1. The expression of GABA receptors in islets of mouse models. (A) Experimental schedule for the metabolic stress models. (B) Real-time PCR analysis of Ace2 and GABA related genes in the pancreatic specimens. (C) IF staining of GBR positive beta cells in islets. Scale bars = 20 &#x03BC;m. (D) Experimental schedule for ACE2KO mice models. (E) Plasma A-7 levels in WT and ACE2KO models. (F) Real-time PCR analysis of Gad67 and GABA related receptors in the mouse pancreas of ACE2KO mice models. Data are mean &#x00B1; SEM (n=5-7 mice/group). One-way or two-way ANOVA was used for statistical analysis. *P < 0.05, **P < 0.01 and ****P < 0.0001.
    • Supplementary Figure 2. Effects of A1-7 and GABA on body weight and beta-cell proliferation. (A) Changes in body weight of each group. (B-C) Representative images of Ki67 positive beta cells (B) and ratio of ki67 positive beta cells (C). (D) TUNEL staining of pancreases. Scale bars = 50 &#x03BC;m. (E-F) Representative western blots of p-AKT expression in liver and eWAT specimens. Data are mean &#x00B1; SEM (n=5-8). One-way ANOVA was used for statistical analysis. *P < 0.05 vs SD group and #P < 0.05 vs HFD group. (eWAT, epididymal white adipose tissues)

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
14
Article Type:
Research Article
Received Date:
07 Jun 2020
Accepted Date:
01 Jul 2020
Print Publication Date:
01 Sep 2020
Online Publication Date:
Sep 2020
Keywords:
diabetes; glucose homeostasis; ACE2; GABA; paracrine

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