Abstract:
:Exendin-4 (Ex-4), a long-acting agonist of glucagon-like peptide-1 receptor, is a novel anti-diabetic drug that prevents β-cells against various toxicities. However, the mechanism and molecules mediating the protection procession of Ex-4 are not fully understood. We investigated the protective effect of Ex-4 against lipotoxicity, mediated by a repression of sterol regulatory element-binding protein (SREBP)-1c, a regulator of genes expression involved in fat and cholesterol synthesis. To observe the effect of Ex-4, we evaluated glucose-stimulated insulin secretion (GSIS) and apoptosis in the MIN6 pancreatic β-cell line, which were cultured in DMEM medium containing 500 μM palmitate, with or without 10 nM Ex-4. We also examined the roles of SREBP-1c in lipotoxicity model by knockdown with si-RNA. Treatment with Ex-4 improved insulin secretion and survival as well as reduced SREBP-1c expression and activity in palmitate-treated MIN6 cells. This improvement was accompanied with an upregulation of PI3K/Akt signaling pathway, and LY294.002, a specific inhibitor of PI3 kinase, abrogated effects of Ex-4 on insulin secretion. Moreover, SREBP-1c in nuclei was increased by the inhibition of PI3 kinase. Lipotoxic effects of palmitate in the insulin secretion and apoptosis were significantly prevented by SREBP-1 knockdown. In conclusion, Ex-4 protects β-cell against palmitate-induced β-cell dysfunction and apoptosis, by inhibiting SREBP-1c expression and activity through the PI3K/Akt signaling pathway.
journal_name
Mol Cell Endocrinoljournal_title
Molecular and cellular endocrinologyauthors
Hong SW,Lee J,Park SE,Rhee EJ,Park CY,Oh KW,Park SW,Lee WYdoi
10.1016/j.mce.2012.07.004subject
Has Abstractpub_date
2012-10-15 00:00:00pages
242-52issue
1-2eissn
0303-7207issn
1872-8057pii
S0303-7207(12)00355-3journal_volume
362pub_type
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