Enhanced protection against cytokine- and fatty acid-induced apoptosis in pancreatic beta cells by combined treatment with glucagon-like peptide-1 receptor agonists and insulin analogues

We recently showed that Insulin analogues exhibit a beta-cell protective function. The aim of this study was to test if the anti-apoptotic activity of GLP-1 agonists and Insulin analogues is mediated by different pathways and if combined treatment may provide augmented protection against beta-cell death. Incubation of INS-1 cells with cytokines or fatty acids increased the number of apoptotic cells and Caspase 3 activity, which was reduced by pretreatment with GLP-1 and its receptor agonists exendin-4 and AVE0010 by 50-60%. Similar effects (about 40% reduction) were observed after pretreatment with several Insulin analogues. Combined treatment revealed additive activity and resulted in prevention of both cytokine- and fatty acid-induced Apoptosis by up to 80%. No acute Akt-phosphorylation in response to GLP-1 Receptor agonists could be observed, however, it became detectable after 24-hour stimulation. Gene silencing of Akt2 increased cytokine-induced Apoptosis 2-fold. Under these conditions the beta-cell protective activity of AVE0010 remained completely unaltered. We show here that the anti-apoptotic activity of GLP-1 and its receptor agonists AVE0010 and exendin-4 is enhanced by addition of Insulin analogues and that the anti-apoptotic action of GLP-1 mimetics is mostly unrelated to Akt2 signaling. It is suggested that combination of GLP-1 Receptor agonists and Insulin analogues, specifically Insulin glargine, may represent a new therapeutic option for preservation of beta-cell mass in type 2 diabetic patients.