Horm Metab Res 2008; 40(3): 172-180
DOI: 10.1055/s-2008-1042426
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

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

D. Tews 1 , U. Werner 2 , J. Eckel 1
  • 1Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany
  • 2Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany
Further Information

Publication History

received 22.02.2007

accepted 15.08.2007

Publication Date:
17 March 2008 (online)

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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.

References

Correspondence

Prof. Dr. J. Eckel

German Diabetes Center

Auf'm Hennekamp 65

40225 Düsseldorf

Germany

Phone: +49/211/338 25 61

Fax: +49/211/338 26 97

Email: eckel@uni-duesseldorf.de