The aim of the present study was to investigate the protective effect of the glucagon-Like peptide-1 receptor agonist exendin-4 on the interleukin (IL)-1 beta-induced impairment of glucose-stimulated insulin secretion (GSIS) in (beta-TC-6 cells. beta-TC-6 cells were pretreated with various concentrations of IL-beta (0.15, 1.5 or 15 ng/ml) and exendin-4 (0.1 or 1 mM). Exendin-4 was administered to beta-TC-6 cells prior to, during and following pretreatment. Cells were stimulated with various concentrations of glucose (0, 1.38, 5.5 and 11.1 mM), and insulin was measured via radioimmunoassay of the supernatant; furthermore, western blot analysis was used to detect phosphorylated extracellular receptor kinase (ERK)1/2. The insulin levels (151.08 +/- 14.34 mu IU/ml) and ERK1/2 phosphorylation in beta-TC-6 cells peaked in response to 1.38 mM glucose stimulation compared with 0, 5.5 and 11.1 mM glucose stimulation. IL-113 inhibited GSIS in a dose-dependent manner: Insulin levels were 83.76 +/- 1.16 mu IU/ml when 0.15 ng/ml IL-1 beta was added under GSIS, 59.46 +/- 3.20 mu IU/ml when 1.5 ng/ml IL-1 beta was added under GSIS, and 56.98 +/- 1.19 mu IU/ml when 15 ng/ml IL-1 beta was added under GSIS. Exendin-4 exerted a protective effect against IL-1 beta-induced GSIS inhibition in a dose-dependent manner. The greatest protective effect was observed when exendin-4 was added prior to IL-1 beta pretreatment, which was statistically significant (P<0.05). These findings suggested that exendin-4 was able to reverse the IL-1 beta-induced inhibition of ERK1/2 phosphorylation and serves a protective role by impairing GSIS induced by IL-beta in beta-TC-6 cells. This mechanism may be associated with the recovery of ERK1/2 activation.