Gamma-Aminobutyric Acid Requires GLP-1 Receptor to Effectively Exert Its Pancreatic Function During Streptozotocin Challenge

Abstract

Background: Gamma-aminobutyric acid (GABA) administration attenuates streptozotocin (STZ) induced diabetes in rodent models, while the underlying mechanisms remain unclear. Since GABA and the incretin-based drug sitagliptin showed additive effect on pancreatic β-cells, we ask whether GLP-1 receptor (GLP-1R) is involved in mediating certain beneficial effects of GABA. Methods: Effect of GABA or GLP-1 on expression of the glucotoxicity meditator thioredoxin-interacting protein (TxNIP) was assessed in pancreatic INS-1 832/13 (INS-1) cell line, wild type (WT) and GLP-1R-/- mouse islets by qRT-PCR, Western blotting and luciferase reporter assay. GABA was orally administrated in WT or GLP-1R-/- mice received STZ injection, followed by immunohistochemistry assessment of pancreatic islets. Effect of GABA on Wnt pathway effector β-catenin was examined in INS-1 cells, WT and GLP-1R-/- mouse islets by Western blotting. Findings: We show here that GABA shares a common feature with GLP-1 on inhibiting TxNIP expression, while this function was attenuated in GLP-1R-/- islets. In WT mice with STZ challenge, GABA attenuated several “diabetic syndromes”, associated with increased β-cell mass. These features were virtually absent in GLP-1R-/- mice. Cleaved caspase-3 in pancreatic β-cells can be induced by high-glucose, dexamethasone, or STZ treatment in INS-1 cells; while GABA treatment blocked the induction. Finally, GABA treatment increased β-cat S675 phosphorylation in WT mouse islets but not in GLP-1R-/- mouse islets. Interpretation: These observations indicate that in β-cells upon STZ or other stress challenge, the GLP-1R-cAMP-β-catenin signaling cascade may also mediate the beneficial effects of GABA. Funding Statement: This study was supported by an Operating grant from the Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2015-64) to QW, GP, and TJ, and a pilot grant from Banting and Best Diabetes Centre (BBDC) to TJ. Declaration of Interests: There is no conflict interests for all authors. Ethics Approval Statement: All animal work was approved by the Institutional Animal Care and Use Committee of the University Health Network.