Treatment with glucokinase activator, YH-GKA, increases cell proliferation and decreases glucotoxic apoptosis in INS-1 cells.
Eur J Pharm Sci
; 51: 137-45, 2014 Jan 23.
Article
em En
| MEDLINE
| ID: mdl-24056026
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 ß-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 GSK3ß 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.
Palavras-chave
Apoptosis; B-cell lymphoma; Bax; Bcl; Bcl-2-associated X protein; Beta-cell proliferation; CS; GKA; GSK; Glucokinase activator; Glucotoxicity; INS-1 cells; IRS-2; PARP; PGC-1α; TFAM; Type 2 diabetes; VDAC; citrate synthase; glucokinase activator; glycogen synthase kinase; insulin receptor substrate-2; mitochondrial transcription factor A; mitochondrial transmembrane potential; peroxisome proliferator-activated receptor gamma coactivator 1-alpha; poly (ADP-ribose) polymerase; voltage-dependent anion-selective channel protein; ΔΨm
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Benzamidas
/
Apoptose
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Proliferação de Células
/
Glucoquinase
Limite:
Animals
Idioma:
En
Revista:
Eur J Pharm Sci
Assunto da revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2014
Tipo de documento:
Article