Abstract：
:Hyperglycemia and hyperlipidemia (glycolipotoxicity)-triggered islet β-cell dysfunction is known to drive the progression of obesity-related type 2 diabetes, however the underlying mechanisms have not been clearly elucidated. The current study aimed to investigate the role of mitogen-activated protein kinase phosphatase 5 (MKP-5) in islet cells under glucolipotoxic conditions. Using gene overexpression and knockdown approaches, we demonstrated that MKP-5 could alleviate glucolipotoxicity-induced apoptosis via the endoplasmic reticulum (ER) stress and mitochondrial apoptosis pathways owing to the altered regulation of caspase family members and ER stress-related molecules in MIN6 and primary islet cells. Overexpression of MKP-5 reversed the glucose and palmitic acid (GP)-induced impairment of insulin secretion as well as the abnormal decreases in the expression of islet functional genes, thereby maintaining the normal insulin secretory functionality, whereas the absence of MKP-5 aggravated islet cell dysfunction. In parallel, the production of ROS and increased inflammation-associated genes in response to GP were also reduced upon MKP-5 overexpression. Further, inhibition of JNK or P38 MAPK pathways resisted to glucolipotoxicity observed in MKP-5 knockdown MIN6 cells. These findings indicate that MKP-5 is an important mediator for glucolipotoxicity-induced islet cell dysfunction and apoptosis, with JNK and P38 as the critical downstream pathways.
journal_name
Exp Cell Resjournal_title
Experimental cell researchauthors
Song Z,Ma J,Lu Y,Zhou C,Zhao T,Ai X,Wei X,Lin J,Wang W,Yan W,Jiao Pdoi
10.1016/j.yexcr.2019.06.012subject
Has Abstractpub_date
2019-09-01 00:00:00pages
111467issue
1eissn
0014-4827issn
1090-2422pii
S0014-4827(19)30307-6journal_volume
382pub_type
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