Exendin-4 protects oxidative stress-induced β-cell apoptosis through reduced JNK and GSK3β activity.
Oxidative stress induced by chronic hyperglycemia in type 2 diabetes plays a crucial role in progressive loss of β-cell mass through β-cell apoptosis. Glucagon like peptide-1 (GLP-1) has effects on preservation of β-cell mass and its insulin secretory function. GLP-1 possibly increases islet cell mass through stimulated proliferation from β-cell and differentiation to β-cell from progenitor cells. Also, it probably has an antiapoptotic effect on β-cell, but detailed mechanisms are not proven. Therefore, we examined the protective mechanism of GLP-1 in β-cell after induction of oxidative stress. The cell apoptosis decreased to ~50% when cells were treated with 100 µM H(2)O(2) for up to 2 hr. After pretreatment of Ex-4, GLP-1 receptor agonist, flow cytometric analysis shows 41.7% reduction of β-cell apoptosis. This data suggested that pretreatment of Ex-4 protect from oxidative stress-induced apoptosis. Also, Ex-4 treatment decreased GSK3β activation, JNK phosphorylation and caspase-9, -3 activation and recovered the expression of insulin2 mRNA in β-cell lines and secretion of insulin in human islet. These results suggest that Ex-4 may protect β-cell apoptosis by blocking the JNK and GSK3β mediated apoptotic pathway.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Konyang University School of Medicine, Daejeon, Korea.
Ju-Young
JY
Kim
Dong-Mee
DM
Lim
Chan Il
CI
Moon
Kyung-Jin
KJ
Jo
Seong-Kyu
SK
Lee
Haing-Woon
HW
Baik
Ki-Ho
KH
Lee
Kang-Woo
KW
Lee
Keun-Young
KY
Park
Byung-Joon
BJ
Kim
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D000077270:Exenatide; D005434:Flow Cytometry; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D014688:Venoms / Q000494:pharmacology*
C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D006861:Hydrogen Peroxide; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D053453:Caspase 9