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

in Journal of Endocrinology
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  • 1 Divsion of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
  • 2 Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto, Canada
  • 3 Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
  • 4 Department of Biological Sciences, Brock University, St. Catherine, Canada
  • 5 Department of Physiology, University of Toronto, Toronto, Canada
  • 6 Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Canada

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)

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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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