Treatment with glucokinase activator, YH-GKA, increases cell proliferation and decreases glucotoxic apoptosis in INS-1 cells.
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 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 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.
Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon, Republic of Korea; Gachon Medical Research Institute, Gil Hospital, 1198, Guwol-dong, Namdong-Gu, Incheon, Republic of Korea.
Yoon Sin
YS
Oh
Youn-Jung
YJ
Lee
Kaapjoo
K
Park
Hyun Ho
HH
Choi
Sangjong
S
Yoo
Hee-Sook
HS
Jun
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D056742:Cyclin D2 / Q000378:metabolism; D005941:Glucokinase / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D051176:beta Catenin / Q000378:metabolism
D001549:Benzamides; C486197:Ccnd2 protein, rat; D056742:Cyclin D2; D055504:Insulin Receptor Substrate Proteins; C526299:Irs2 protein, rat; D011725:Pyridines; C581883:YH-GKA; D051176:beta Catenin; D000255:Adenosine Triphosphate; D002950:Citrate (si)-Synthase; D005941:Glucokinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3
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