Treatment with glucokinase activator, YH-GKA, increases cell proliferation and decreases glucotoxic apoptosis in INS-1 cells
- Authors
- Oh, Yoon Sin; Lee, Youn-Jung; Park, Kaapjoo; Choi, Hyun Ho; Yoo, Sangjong; Jun, Hee-Sook
- Issue Date
- 23-Jan-2014
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- Glucokinase activator; Beta-cell proliferation; Glucotoxicity; INS-1 cells; Type 2 diabetes; Apoptosis
- Citation
- EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, v.51, pp.137 - 145
- Journal Title
- EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
- Volume
- 51
- Start Page
- 137
- End Page
- 145
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/12890
- DOI
- 10.1016/j.ejps.2013.09.005
- ISSN
- 0928-0987
- Abstract
- Glucokinase (GK), an enzyme that phosphorylates glucose to form glucose-6-phosphate, has a role in regulating insulin secretion and proliferation in beta cells. GK activators (GKAs) have been developed as new therapies for type 2 diabetes. In this study, we evaluated the proliferation and anti-apoptotic actions of YH-GKA, a novel and potent GKA, in INS-1 pancreatic beta-cells. YH-GKA treatment increased cell numbers at 3 mM glucose via upregulation of insulin receptor substrate-2 and subsequent activation of AKT/protein kinase B phosphorylation. YH-GKA also increased beta-catenin and cyclin D2 mRNA expression and inactivated GSK3 beta by increasing phosphorylation. These proliferative effects of YH-GKA were attenuated by IRS-2 downregulation. Moreover, YH-GKA reduced annexin-V-stained cells and expression levels of cleaved poly (ADP-ribose) polymerase and caspase-3 induced by glucotoxicity. YH-GKA inhibited apoptotic signaling via induction of ATP content, mitochondrial membrane potential, and citrate synthase activity and was correlated with changes of the mitochondrial function-related genes. YH-GKA also increased interaction between GK and voltage-dependent anion-selective channel protein. Our results suggest that the novel GKA, YH-GKA, promotes beta cell growth and prevents glucotoxic beta cell apoptosis. Therefore, YH-GKA may provide a therapy that compensates for beta cell loss in patients with type 2 diabetes. (C) 2013 Elsevier B.V. All rights reserved.
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