Exendin-4 Protects Oxidative Stress-Induced β-Cell Apoptosis through Reduced JNK and GSK3β Activity

Abstract

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 H2O2 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.

Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium

“…It will be interesting to decipher the specific signaling pathway by which exendin-4 attenuates the generation of ROS and protects mitochondria at cellular levels in the future. In line with our observations, GLP-1R stimulation with exendin-4 was shown to reduce the rate of apoptosis following oxidative stress in cells and the diabetic rat (17,38). Therefore, this evidence indicates that exendin-4 is essential for initiating a protective signal for the survival of cells and organs during oxidative stress or injuries.…”

The regulatory roles of NADPH oxidase, intra- and extra-cellular HSP70 in pancreatic islet function, dysfunction and diabetes

“…GSK-3β deficiency preserves β-cell mass in insulin-resistant mice, maintaining proliferation rates and reducing apoptosis [112], whereas the hyperactivity of this enzyme increases apoptosis [113]. JNK inhibition preserves the pancreatic islet mass, by allowing for elevated Akt phosphorylation and promoting a reduction of GSK-3β activity [114], due to increased GSK-3β phosphorylation (Ser 9 ) (see Figure 2), so protecting the β-cell against GSK-3β and JNK-mediated cell apoptosis [115]. In other cells, the connection between TLR, Akt and GSK-3β activity with cell survival has been described at the molecular level.…”

Blockage of both the extrinsic and intrinsic pathways of diazinon-induced apoptosis in PaTu cells by magnesium oxide and selenium nanoparticles

“…The amount of caspase activity present in the sample is proportional to the intensity of yellow color produced upon cleavage. 24 Briefly, the treated cells were lysed in the supplied lysis buffer and were incubated on ice for 10 minutes. The whole cell lysates were incubated in caspase buffer (100 mM HEPES, pH 7.4, 20% glycerol, 0.5 mM ethylenediaminetetraacetic acid [EDTA], 5 mM dithiothreitol) containing 100 mM of caspase-3 and -9-specific substrates (N-acetyl-Asp-Glu-ValAsp-p-nitroanilide [Ac-DEVD-ρNA] and N-acetyl-Leu-GluHis-Asp-p-nitroanilide [Ac-LEHD-ρNA], respectively) for 4 hours at 37°C.…”