Exendin-4, a glucagon-like peptide-1 receptor agonist, suppresses pancreatic β-cell destruction induced by encephalomyocarditis virus

Viral infection is one of the important factors for the pathogenesis of type 1 diabetes. Particularly, in fulminant type 1 diabetes, rapid beta-cell destruction is suggested to be triggered by viral infection. Recently, glucagon-like peptide 1 (GLP-1) receptor agonists have been reported to have direct beneficial effects on beta-cells, such as anti-apoptotic effect, increasing beta-cell mass, and improvement of beta-cell function. However, their effects on beta-cell destruction induced by viral infections have not been elucidated. In this study, we used an encephalomyocarditis virus (EMCV)-induced diabetic model mouse to show that a GLP-1 receptor agonist, exendin-4, prevents beta-cell destruction. Nine-week-old male DBA/2 mice were intraperitoneally injected with EMCV (200 plaque forming units (PFU) mouse(-1)). Low (20 nmol kg(-1) d(-1)) or high (40 nmol kg(-1) d(-1)) doses of exendin-4 were administered for 10 d, starting from 2 d before the infection, and the rate of diabetic onset was evaluated. In addition, the number of infiltrating macrophage per islet and the ratio of beta-cell area to islet area were determined. The effects of exendin-4 on infected beta-cells and macrophages were investigated by using MIN6 and RAW264 mouse macrophages. The incidence of diabetes was significantly lower in the high-dose exendin-4-treated group than in the control group. Furthermore, the beta-cell area was significantly more preserved in the high-dose exendin-4-treated group than in the control. In addition, the number of macrophages infiltrating into the islets was significantly less in the high-dose exendin-4-treated group than in the control group. In vitro, exendin-4 reduced beta-cell apoptosis, and tumor necrosis factor alpha (TNF alpha), interleukin beta (IL-beta), and inducible nitric oxide synthase (iNOS) production of infected or lipopolysaccharide (LPS)-stimulated macrophages. These results suggested that exendin-4 limits beta-cell destruction by protecting beta cells and reducing the inflammatory response of macrophages. (C) 2010 Elsevier Inc. All rights reserved.