Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway

被引：69

作者：

Natalicchio, Annalisa ^{[1
]}

Labarbuta, Rossella ^{[1
]}

Tortosa, Federica ^{[1
]}

Biondi, Giuseppina ^{[1
]}

Marrano, Nicola ^{[1
]}

Peschechera, Alessandro ^{[1
]}

Carchia, Emanuele ^{[2
]}

Orlando, Maura Roberta ^{[1
]}

Leonardini, Anna ^{[1
]}

Cignarelli, Angelo ^{[1
]}

Marchetti, Piero ^{[3
]}

Perrini, Sebastio ^{[1
]}

Laviola, Luigi ^{[1
]}

Giorgino, Francesco ^{[1
]}

机构：

[1] Univ Bari Aldo Moro, Dept Emergency & Organ Transplantat, Sect Internal Med Endocrinol Androl & Metab Dis, I-70124 Bari, Italy

[2] Biogem Sc Ar L, Ist Ric Genet Gaetano Salvatore, Ariano Irpino, AV, Italy

[3] AOU Pisana, Endocrinol & Metab Transplantat, Pisa, Italy

来源：

DIABETOLOGIA | 2013年 / 56卷 / 11期

关键词：

Beta cell apoptosis; Exendin-4; G-protein-coupled receptor 40; JNK; p38; MAPK; Palmitate; INSULIN-SECRETING CELLS; ACID-INDUCED APOPTOSIS; FREE FATTY-ACIDS; ENDOPLASMIC-RETICULUM STRESS; INHIBITS APOPTOSIS; ISLET CELLS; ACTIVATION; GLUCAGON; DEATH; GLUCOSE;

D O I：

10.1007/s00125-013-3028-4

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The mechanisms of the protective effects of exendin-4 on NEFA-induced beta cell apoptosis were investigated. The effects of exendin-4 and palmitate were evaluated in human and murine islets, rat insulin-secreting INS-1E cells and murine glucagon-secreting alpha-TC1-6 cells. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting or immunofluorescence, respectively. Small interfering (si)RNAs for Ib1 and Gpr40 were used. Cell apoptosis was quantified by two independent assays. Insulin release was assessed with an insulin ELISA. Exposure of human and murine primary islets and INS-1E cells, but not alpha-TC1-6 cells, to exendin-4 inhibited phosphorylation of the stress kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and prevented apoptosis in response to palmitate. Exendin-4 increased the protein content of islet-brain 1 (IB1), an endogenous JNK blocker; however, siRNA-mediated reduction of IB1 did not impair the ability of exendin-4 to inhibit JNK and prevent apoptosis. Exendin-4 reduced G-protein-coupled receptor 40 (GPR40) expression and inhibited palmitate-induced phosphorylation of mitogen-activated kinase kinase (MKK)4 and MKK7. The effects of exendin-4 were abrogated in the presence of the protein kinase A (PKA) inhibitors, H89 and KT5720. Knockdown of GPR40, as well as use of a specific GPR40 antagonist, resulted in diminished palmitate-induced JNK and p38 MAPK phosphorylation and apoptosis. Furthermore, inhibition of JNK and p38 MAPK activity prevented palmitate-induced apoptosis. Exendin-4 counteracts the proapoptotic effects of palmitate in beta cells by reducing GPR40 expression and inhibiting MKK7- and MKK4-dependent phosphorylation of the stress kinases, JNK and p38 MAPK, in a PKA-dependent manner.

引用

页码：2456 / 2466

页数：11

共 49 条

[21] Free fatty acids and Cytokines induce pancreatic β-cell apoptosis by different mechanisms:: Role of nuclear factor-κB and endoplasmic reticulum stress [J].