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

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.

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S7663 Ruboxistaurin (LY333531) HCl Ruboxistaurin (LY333531) HCl is a β-specific protein kinase C inhibitor. It competitively and reversibly inhibits PKCβ1 and PKCβ2 with IC50 values of 4.7 and 5.9 nM respectively.

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PKC