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Joshua Columbus, YuTing Chiang, Weijuan Shao, Nina Zhang, Dingyan Wang, Herbert Y Gaisano, Qinghua Wang, David M Irwin, and Tianru Jin

Specific single-nucleotide polymorphisms in intronic regions of human TCF7L2 are associated with an elevated risk of developing type 2 diabetes. Whether Tcf7l2 is expressed in pancreatic islets of rodent species at a considerable level, however, remains controversial. We used RT-PCR and quantitative RT-PCR to examine Tcf7l2 expression in rodent gut, pancreas, isolated pancreatic islets, and cultured cell lines. The expression level of Tcf7l2 was relatively lower in the pancreas compared to the gut or the pancreatic β-cell line Ins-1. Immunostaining did not detect a Tcf7l2 signal in mouse pancreatic islets. Endogenous canonical Wnt activity was not appreciable in the pancreas of TOPGAL transgenic mice. Both Tcf7 and Tcf7l1, but not Lef1, were expressed in the pancreas. The expression of the three Tcf genes (Tcf7, Tcf7l1, and Tcf7l2) in the pancreas was reduced by treatment with insulin or high-fat diet feeding, in contrast to the stimulation of Tcf7l2 expression by insulin in the gut. We suggest that hyperinsulinemia represses Tcf gene expression in the pancreas. Whether and how this reduction alters the function of pancreatic β cells during hyperinsulinemia deserves further investigation.

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Weijuan Shao, Wenjuan Liu, Ping Liang, Zhuolun Song, Odisho Israel, Gerald J Prud’homme, Qinghua Wang, and Tianru Jin

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.