PKCβ Inhibition Promotes TXNIP Degradation to Ameliorate Pancreatic β-Cell Dysfunction

Abstract

Introduction: Pancreatic β-cell dysfunction is largely regulated by TXNIP accumulation, we have previously disclosed the role of PKA in TXNIP degradation during β-cell dysfunction. However, whether other kinases (PKCs) still regulate TXNIP is unclear, which is beneficial to alleviate β-cell dysfunction. Methods: Thapsigargin (ER stress inducer) was used to induce β-cell dysfunction. PKC’s inhibitors were screened by Western blotting indicated by TXNIP. Also RT-qPCR and Co-immunoprecipitation were applied for evaluating the β-cell improvement ability of PKC’s inhibitors, and the insulin secretion ability was evaluated by glucose-stimulated insulin secretion assay. Results: PKC’s pan-inhibitor, Ro31-8220, decreased β-cell apoptosis and improved insulin secretion under ER stress or high glucose (HG) conditions. Further studies showed that Ro31-8220 reduced ER stress or HG-induced TXNIP levels. On the other side, PKCβ activation or overexpression could reverse the effect of Ro31-8220 on TXNIP. Also, PKCβ selective inhibitor, ruboxistaurin, induced TXNIP degradation as significantly as Ro31-8220 did. Conclusion: This study reveals the regulating mechanism of PKCβ inhibitor on TXNIP degradation to improve β-cell dysfunction. These data indicated PKCβ inhibitor is a promising agent for ameliorating β-cell dysfunction through TXNIP.