Exendin‐4 protects pancreatic beta cells from human islet amyloid polypeptide‐induced cell damage: potential involvement of AKT and mitochondria biogenesis

Jul 24, 2010Diabetes, obesity & metabolism

Exendin-4 may protect insulin-producing pancreatic cells from damage caused by amyloid protein through cell survival and energy production pathways

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Abstract

Glucagon-like peptide-1 receptor agonist exendin-4 partially protects beta cells from hIAPP-induced apoptosis.

hIAPP was shown to induce cell apoptosis and growth inhibition in clonal insulinoma cells.
Exendin-4 provided partial protection against hIAPP-induced apoptosis and recovery from AKT inhibition.
Constitutive activation of AKT reduced hIAPP-induced apoptosis, while inhibiting the PI3K/AKT pathway negated exendin-4's protective effects.
hIAPP increased FOXO1 expression and inhibited pdx-1 nuclear translocation, changes that were reversed by exendin-4.
Exendin-4 treatment enhanced mitochondrial biogenesis in the cells.

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AIM: Glucagon-like peptide-1 (GLP-1) stimulates beta-cell proliferation and enhances beta-cell survival, whereas oligomerization of human islet amyloid polypeptide (hIAPP) may induce beta-cell apoptosis and reduce beta-cell mass. Type 2 diabetes is associated with increased expression of IAPP. As GLP-1-based therapy is currently developed as a novel antidiabetic therapy, we examined the potential protective action of the GLP-1 receptor agonist exendin-4 on hIAPP-induced beta-cell apoptosis.

METHODS: The study was performed in clonal insulinoma (INS-1E) cells. Both method of transcriptional and translational and sulphorhodamine B (SRB) assays were used to evaluate cell viability and cell mass. Western blot analysis was applied to detect protein expression. Transfection of constitutively active protein kinase B (PKB/AKT) was performed to examine the role of AKT. Mitochondrial biogenesis was quantified by mitogreen staining and RT-PCR.

RESULTS: First, we confirmed that hIAPP induced cell apoptosis and growth inhibition in INS-1E cells. These effects were partially protected by exendin-4 in association with partial recovery of the hIAPP-mediated AKT inhibition. Furthermore, AKT constitutive activation attenuated hIAPP-induced apoptosis, whereas PI3K/AKT inhibition abrogated exendin-4-mediated effects. These findings suggest that the antiapoptotic and proliferative effects of exendin-4 in hIAPP-treated INS-1E cells were partially mediated through AKT pathway. Moreover, hIAPP induced FOXO1 but inhibited pdx-1 nucleus translocation. These effects were restored by exendin-4. Finally, mitogreen staining and RT-PCR revealed enhanced mitochondrial biogenesis by exendin-4 treatment.

CONCLUSIONS: Collectively, these results suggest that GLP-1 receptor agonist protects beta cells from hIAPP-induced cell death partially through the activation of AKT pathway and improved mitochondrial function.

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Exendin‐4 protects pancreatic beta cells from human islet amyloid polypeptide‐induced cell damage: potential involvement of AKT and mitochondria biogenesis

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