title: Compound 19e, a Novel Glucokinase Activator, Protects against Cytokine-Induced Beta-Cell Apoptosis in INS-1 Cells.
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-α and IL-1β 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-κB 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.
authors.affiliation: College of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityIncheon, South Korea; Gachon Medical Research Institute, Gil HospitalIncheon, South Korea; Department of Food and Nutrition, Eulji UniversitySeongnam, South Korea.
authors.forename: Yoon Sin
authors.initials: YS
authors.lastname: Oh
authors.affiliation: College of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University Incheon, South Korea.
authors.forename: Eunhui
authors.initials: E
authors.lastname: Seo
authors.affiliation: Yuhan Research Institute Gyeonggi-do, South Korea.
authors.forename: Kaapjoo
authors.initials: K
authors.lastname: Park
authors.affiliation: College of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityIncheon, South Korea; Gachon Medical Research Institute, Gil HospitalIncheon, South Korea; College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon UniversityIncheon, South Korea.
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
keywords: NAD-dependent protein deacetylase sirtuin -1; apoptosis; beta-cell; compound 19e; cytokine; glucokinase activator