GABA requires GLP-1R to exert its pancreatic function during STZ challenge

in Journal of Endocrinology
Authors:
Weijuan Shao Divsion of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto, Canada

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Wenjuan Liu Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China

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Ping Liang Department of Biological Sciences, Brock University, St. Catherine, Canada

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Zhuolun Song Divsion of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto, Canada
Department of Physiology, University of Toronto, Toronto, Canada

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Odisho Israel Divsion of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada

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Gerald J Prud’homme Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Canada

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Qinghua Wang Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto, Canada
Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Canada

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Tianru Jin Divsion of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto, Canada
Department of Physiology, University of Toronto, Toronto, Canada

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Correspondence should be addressed to Q Wang or T Jin: qinghua.wang@utoronto.ca or tianru.jin@utoronto.ca

*(W Shao and W Liu contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-20-0109
Volume/Issue:
Volume 246: Issue 3
Article Type:
Research Article
Page Range:
207–222
Online Publication Date:
Sep 2020
Copyright:
© 2020 Society for Endocrinology 2020
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Gamma-aminobutyric acid (GABA) administration attenuates streptozotocin (STZ)-induced diabetes in rodent models with unclear underlying mechanisms. We found that GABA and Sitagliptin possess additive effect on pancreatic β-cells, which prompted us to ask the existence of common or unique targets of GLP-1 and GABA in pancreatic β-cells. Effect of GABA on expression of thioredoxin-interacting protein (TxNIP) was assessed in the INS-1 832/13 (INS-1) cell line, WT and GLP-1R–/– mouse islets. GABA was also orally administrated in STZ-challenged WT or GLP-1R–/– mice, followed by immunohistochemistry assessment of pancreatic islets. Effect of GABA on Wnt pathway effector β-catenin (β-cat) was examined in INS-1 cells, WT and GLP-1R–/– islets. We found that GABA shares a common feature with GLP-1 on inhibiting TxNIP, while this function was attenuated in GLP-1R–/– islets. In WT mice with STZ challenge, GABA alleviated several ‘diabetic syndromes’, associated with increased β-cell mass. These features were virtually absent in GLP-1R–/– mice. Knockdown TxNIP in INS-1 cells increased GLP-1R, Pdx1, Nkx6.1 and Mafa levels, associated with increased responses to GABA or GLP-1 on stimulating insulin secretion. Cleaved caspase-3 level can be induced by high-glucose, dexamethasone, or STZ in INS-1 cell, while GABA treatment blocked the induction. Finally, GABA treatment increased cellular cAMP level and β-cat S675 phosphorylation in WT but not GLP-1R–/– islets. We, hence, identified TxNIP as a common target of GABA and GLP-1 and suggest that, upon STZ or other stress challenge, the GLP-1R-cAMP-β-cat signaling cascade also mediates beneficial effects of GABA in pancreatic β-cell, involving TxNIP reduction.

Supplementary Materials

    • Supplementary Figure 1
    • Supplementary Figure 2
    • Supplementary Figure 3
    • Supporting Table 1: List of oligonucleotide primers utilized in this study
    • Supporting Table 2: List of antibodies utilized in this study
    • Supporting Table 3: Percentages of genes that remain responsiveness to GABA treatment in GLP-1R-/- mouse islets
    • Supporting Table 4: Fold increase on genes that are up or down regulated by GABA treatment in GLP-1R-/- mouse islets
    • Supporting Table 5. List of 45 genes that were activated by GABA treatment in both WT and GLP-1R-/- mouse pancreatic islets
    • Supporting Table 6. List of 53 genes that were repressed by GABA treatment in both WT and GLP-1R-/- mouse pancreatic islets
    • Supporting Table 7. Comparison of TxNIP mRNA and GLP-1R mRNA “signal” in WT and GLP-1R-/- mouse islets treated without or with GABA
    • Supporting Table 8. Comparison of a battery of pancreatic islet specific gene expression in WT and GLP-1R-/- mouse islets treated without or with GABA

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
16
Article Type:
Research Article
Received Date:
05 Jun 2020
Accepted Date:
15 Jun 2020
Print Publication Date:
01 Sep 2020
Online Publication Date:
Sep 2020
Keywords:
β-catenin; GABA; GLP-1R; pancreatic β-cells; TxNIP; and Wnt signaling

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