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.