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01.11.2013 | Article

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

verfasst von: Annalisa Natalicchio, Rossella Labarbuta, Federica Tortosa, Giuseppina Biondi, Nicola Marrano, Alessandro Peschechera, Emanuele Carchia, Maura Roberta Orlando, Anna Leonardini, Angelo Cignarelli, Piero Marchetti, Sebastio Perrini, Luigi Laviola, Francesco Giorgino

Erschienen in: Diabetologia | Ausgabe 11/2013

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Abstract

Aims/hypothesis

The mechanisms of the protective effects of exendin-4 on NEFA-induced beta cell apoptosis were investigated.

Methods

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.

Results

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.

Conclusions/interpretation

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.

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Titel: Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway
verfasst von: Annalisa Natalicchio
Rossella Labarbuta
Federica Tortosa
Giuseppina Biondi
Nicola Marrano
Alessandro Peschechera
Emanuele Carchia
Maura Roberta Orlando
Anna Leonardini
Angelo Cignarelli
Piero Marchetti
Sebastio Perrini
Luigi Laviola
Francesco Giorgino
Publikationsdatum: 01.11.2013
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 11/2013
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-013-3028-4

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