Abstract
Type 2 diabetes is a heterogeneous disorder that develops as a result of relatively inappropriate insulin secretion and insulin resistance. Increased levels of free fatty acids (FFAs) are one of the important factors for the pathogenesis of type 2 diabetes and contribute to defective β-cell proliferation and increased β-cell apoptosis. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have been shown to possess an antiapoptotic effect, by increasing β-cell mass and improving β-cell function. However, their effects on β-cells in vitro against lipotoxicity have not been elucidated completely. In this study, we investigated whether the GLP-1 receptor agonist exendin-4 displays prosurvival effects in pancreatic β-cells exposed to chronic elevated FFAs. Results showed that exendin-4 inhibited apoptosis induced by palmitate in MIN6 cells. After 24 h of incubation, exendin-4 caused rapid activation of extracellular signal-related kinase 1/2 (ERK1/2) under lipotoxic conditions. The ERK1/2 inhibitor PD98059 blocked the antilipotoxic effect of exendin-4 on MIN6 cells. Exendin-4 also inhibited the mitochondrial pathway of apoptosis. This inhibition is associated with upregulation of BCL-2. Our findings suggested that exendin-4 may exert cytoprotective effects through activation of ERK1/2 and inhibition of the mitochondrial apoptosis pathway.
Highlights
Type 2 diabetes is a heterogeneous disorder characterized by peripheral insulin resistance, defects in insulin secretion, and β-cell apoptosis
All these results strongly suggested that exendin-4 protected MIN6 cells against lipotoxicity, at least in part, via activation of extracellular signal-related kinase 1/2 (ERK1/2) signaling pathway
We found that exendin-4 inhibited palmitate-induced apoptosis via activating ERK1/2 pathway and through inhibiting mitochondrial apoptosis pathway in the MIN6 cells
Summary
Type 2 diabetes is a heterogeneous disorder characterized by peripheral insulin resistance, defects in insulin secretion, and β-cell apoptosis. Prolonged exposure to elevated levels of FFAs has been shown to cause defective β-cell proliferation and increased β-cell apoptosis. GLP-1 can be used against hyperglycemia and obesity in most T2DM diabetic patients by stimulating insulin secretion, inhibiting glucagon secretion, slowing gastric emptying, and promoting satiety [2]. Among all these effects, the major target of GLP-1 actions is the pancreatic β-cell [3,4,5]. Recent data have shown that GLP-1 and its receptor agonists promote the survival of β-cell lines when challenged with various apoptotic stimulators, including hyperglycemia, inflammatory cytokines, oxidative stress, and endoplasmic reticulum stress [8,9,10]. Until now whether exendin-4, a GLP1 receptor agonist, exerts cytoprotective effects in pancreatic β-cells under lipotoxic condition had not been determined completely
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