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P38 plays an important role in glucolipotoxicity-induced apoptosis in INS-1 cells
Lingli Zhou1, Xiaoling Cai1, Xueyao Han1
1Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing 100044, China.
Objectives:
The mechanism underlying the regulation of glucolipotoxicity-induced apoptosis by MAPKs was examined in INS-1 cells.
Methods:
The rat insulinoma cell line INS-1 was cotreated with glucose (30 mM) and palmitic acid (0.2 mM) (GLU+PA). Apoptosis was assessed by cell morphology and detection of PARP cleavage. The activation of MAPKs was examined by Western blotting using specific antibodies against the phosphorylated forms of JNK, ERK1/2, and P38.
Results:
(1) Live cell imaging studies showed that treatment with GLU+PA for 72 h induced significant cell death, concomitant with PARP-1 cleavage and caspase-3 activation, which peaked at 96 h of treatment. (2) Western blot analysis of the activation of MAPKs during GLU+PA-induced INS-1 cell apoptosis showed that phosphorylation of P38 increased gradually and reached a peak at 96 h, which coincided with PARP-1 cleavage. A transient increase of ERK activation was followed by a rapid decline at 96 h, whereas JNK phosphorylation status remained unchanged in response to GLU+PA. (3) Phosphorylation of insulin receptor substrate (IRS)-2 at 48 h of treatment triggered its degradation, which coincided with P38 activation. (4) Inhibition of P38, but not JNK or ERK, blocked GLU+PA-induced INS-1 cell apoptosis.
Conclusions:
P38 may be involved in the regulation of glucolipotoxicity-induced apoptosis through the phosphorylation of IRS-2.
Insights
Glucolipotoxicity induces cell death in INS-1 cells via p38 MAPK activation, which phosphorylates IRS-2. Inhibiting p38 MAPK prevents this apoptosis, highlighting its role in regulating cell death.
Area of Science:
- Cell Biology
- Molecular Biology
- Endocrinology
Background:
- Glucolipotoxicity, a condition resulting from high glucose and fatty acid levels, is implicated in pancreatic beta-cell dysfunction and apoptosis.
- Mitogen-activated protein kinases (MAPKs) are critical signaling pathways involved in cellular responses to stress, including apoptosis.
Purpose of the Study:
- To investigate the role of MAPKs in regulating apoptosis induced by glucolipotoxicity in INS-1 cells.
- To elucidate the specific MAPK pathways involved and their downstream targets.
Main Methods:
- INS-1 cells were exposed to high glucose and palmitic acid (GLU+PA) to induce glucolipotoxicity.
- Apoptosis was assessed using cell morphology and poly(ADP-ribose) polymerase (PARP) cleavage.
- MAPK activation (JNK, ERK1/2, P38) was analyzed by Western blotting.
- Insulin receptor substrate (IRS)-2 phosphorylation and degradation were examined.
Main Results:
- GLU+PA treatment induced significant INS-1 cell death, PARP-1 cleavage, and caspase-3 activation.
- P38 MAPK phosphorylation increased and peaked at 96 hours, coinciding with PARP-1 cleavage.
- P38 inhibition, but not JNK or ERK inhibition, blocked GLU+PA-induced apoptosis.
- IRS-2 phosphorylation at 48 hours preceded its degradation and coincided with P38 activation.
Conclusions:
- P38 MAPK plays a critical role in mediating glucolipotoxicity-induced apoptosis in INS-1 cells.
- The mechanism involves p38-mediated phosphorylation and subsequent degradation of IRS-2.
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