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

D Tews, U Werner, J Eckel - Hormone and metabolic research, 2008 - thieme-connect.com
D Tews, U Werner, J Eckel
Hormone and metabolic research, 2008thieme-connect.com
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 …
Abstract
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.
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