GLP-1 Receptor Activation Abrogates β-Cell Dysfunction by PKA Cα-Mediated Degradation of Thioredoxin Interacting Protein

Glucagon-like peptide 1 receptor (GLP-1R) agonist (Exendin-4) is a well-known agent used to improve beta-cell dysfunctions via protein kinase A (PKA), but the detailed downstream molecular mechanisms are still elusive. We have now found that PKA C alpha mediated- TXNIP phosphorylation and degradation played a vital role in the beta-cell protective role of exendin-4. After PKA activator (Exendin-4 or FSK) treatment, PKA C alpha could directly interact with TXNIP by bimolecular fluorescence complementation and Co-IP assays in INS-1 cells. And PKA C alpha overexpression decreased TXNIP level, whereas TXNIP level was largely increased in PKA C alpha-KO beta-cells by CRISPR-Cas9. Interestingly, TXNIP overexpression or PKA C alpha-KO has impaired beta-cell functions, including loss of insulin secretion and activation of inflammation. PKA C alpha directly phosphorylated TXNIP at Ser307 and Ser308 positions, leading to its degradation via activation of cellular proteasome pathway. Consistent with this observation, TXNIP (S307/308A) mutant resisted the degradation effects of PKA C alpha. However, exendin-4 neither affected TXNIP level in TXNIP (S307/308A) mutant overexpressed beta-cells nor in PKA C alpha-KO beta-cells. Moreover, exendin-4 treatment reduced the inflammation gene expression in TXNIP overexpressed beta-cells, but exendin-4 treatment has no effect on the inflammation gene expression in TXNIP (S307/308A) overexpressed beta-cells. In conclusion, our study reveals the integral role of PKA C alpha/TXNIP signaling in pancreatic beta-cells and suggests that PKA C alpha-mediated TXNIP degradation is vital in beta-cell protective effects of exendin-4.