Pharmacological and mechanistic study of PS1, a Pdia4 inhibitor, in β-cell pathogenesis and diabetes in db/db mice

Pdia4 has been characterized as a key protein that positively regulates beta-cell failure and diabetes via ROS regulation. Here, we investigated the function and mechanism of PS1, a Pdia4 inhibitor, in beta-cells and diabetes. We found that PS1 had an IC50 of 4 mu M for Pdia4. Furthermore, PS1 alone and in combination with metformin significantly reversed diabetes in db/db mice, 6 to 7 mice per group, as evidenced by blood glucose, glycosylated hemoglobin A1c (Hb(A1c)), glucose tolerance test, diabetic incidence, survival and longevity (P < 0.05 or less). Accordingly, PS1 reduced cell death and dysfunction in the pancreatic beta-islets of db/db mice as exemplified by serum insulin, serum c-peptide, reactive oxygen species (ROS), islet atrophy, and homeostatic model assessment (HOMA) indices (P < 0.05 or less). Moreover, PS1 decreased cell death in the beta-islets of db/db mice. Mechanistic studies showed that PS1 significantly increased cell survival and insulin secretion in Min6 cells in response to high glucose (P < 0.05 or less). This increase could be attributed to a reduction in ROS production and the activity of electron transport chain complex 1 (ETC C1) and Nox in Min6 cells by PS1. Further, we found that PS1 inhibited the enzymatic activity of Pdia4 and mitigated the interaction between Pdia4 and Ndufs3 or p22 in Min6 cells (P < 0.01 or less). Taken together, this work demonstrates that PS1 negatively regulated beta-cell pathogenesis and diabetes via reduction of ROS production involving the Pdia4/Ndufs3 and Pdia4/p22 cascades.

Automated summary

In this study, the Pdia4 inhibitor PS1 was found to improve beta-cell function and reverse diabetes through the reduction of ROS production. PS1 also decreased cell death and dysfunction in the pancreatic beta-islets by inhibiting the enzymatic activity of Pdia4 and mitigating the interaction between Pdia4 and Ndufs3 or p22. This research is of great significance for understanding the pathogenesis of diabetes and identifying potential therapeutic targets.