Compound 19e, a Novel Glucokinase Activator, Protects against Cytokine-Induced Beta-Cell Apoptosis in INS-1 Cells
- Authors
- Oh, Yoon Sin; Seo, Eunhui; Park, Kaapjoo; Jun, Hee-Sook
- Issue Date
- Mar-2017
- Publisher
- FRONTIERS MEDIA SA
- Keywords
- compound 19e; glucokinase activator; beta-cell; apoptosis; cytokine; NAD-dependent protein; deacetylase sirtuin-1
- Citation
- FRONTIERS IN PHARMACOLOGY, v.8
- Journal Title
- FRONTIERS IN PHARMACOLOGY
- Volume
- 8
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/6302
- DOI
- 10.3389/fphar.2017.00169
- ISSN
- 1663-9812
- Abstract
- Previously, compound 19e, a novel heteroaryl-containing benzamide derivative, was identified as a potent glucokinase activator (GKA) and showed a glucose-lowering effect in diabetic mice. In this study, the anti-apoptotic actions of 19e were evaluated in INS-1 pancreatic beta-cells co-treated with TNF-alpha and IL-1 beta to induce cell death. Compound 19e protected INS-1 cells from cytokine-induced cell death, and the effect was similar to treatment with another GKA or exendin-4. Compound 19e reduced annexin-V stained cells and the expression of cleaved caspase-3 and poly (ADP-ribose) polymerase protein, as well as upregulated the expression of B-cell lymphoma-2 protein. Compound 19e inhibited apoptotic signaling via induction of the ATP content, and the effect was correlated with the downregulation of nuclear factor-kappa B p65 and inducible nitric oxide synthase. Further, 19e increased NAD-dependent protein deacetylase sirtuin-1 (SIRT1) deacetylase activity, and the anti-apoptotic effect of 19e was attenuated by SIRT1 inhibitor or SIRT1 siRNA treatment. Our results demonstrate that the novel GKA, 19e, prevents cytokine-induced beta-cell apoptosis via SIRT1 activation and has potential as a therapeutic drug for the preservation of pancreatic beta-cells.
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