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Treatment with glucokinase activator, YH-GKA, increases cell proliferation and decreases glucotoxic apoptosis in INS-1 cells.
- Source :
-
European Journal of Pharmaceutical Sciences . Jan2014, Vol. 51, p137-145. 9p. - Publication Year :
- 2014
-
Abstract
- 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 β-cells. YH-GKA treatment increased cell numbers at 3mM 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 GSK3β 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. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 09280987
- Volume :
- 51
- Database :
- Academic Search Index
- Journal :
- European Journal of Pharmaceutical Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 92028288
- Full Text :
- https://doi.org/10.1016/j.ejps.2013.09.005