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

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 beta-cells, which prompted us to ask the existence of common or unique targets of GLP-1 and GABA in pancreatic beta-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 beta-catenin (beta-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 beta-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 beta-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-beta-cat signaling cascade also mediates beneficial effects of GABA in pancreatic beta-cell, involving TxNIP reduction.