The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits beta-cell apoptosis in vitro.
We here show that GLP-1 and the long-acting GLP-1 analogue, liraglutide, interfere with diabetes-associated apoptotic processes in the beta-cell. Studies using primary neonatal rat islets showed that native GLP-1 and liraglutide inhibited both cytokine- and free fatty acid-induced apoptosis in a dose-dependent manner. The anti-apoptotic effect of liraglutide was mediated by the GLP-1 receptor as the specific GLP-1 receptor antagonist, exendin(9-39), blocked the effects. The adenylate cyclase activator, forskolin, had an anti-apoptotic effect similar to those of GLP-1 and liraglutide indicating that the effect was cAMP-mediated. Blocking the PI3 kinase pathway using wortmannin but not the MAP kinase pathways by PD98059 inhibited the effects of liraglutide. In conclusion, GLP-1 receptor activation has anti-apoptotic effect on both cytokine, and free fatty acid-induced apoptosis in primary islet-cells, thus suggesting that the long-acting GLP-1 analogue, liraglutide, may be useful for retaining beta-cell mass in both type 1 and type 2 diabetic patients.
Bregenholt
Søren
S
Novo Nordisk A/S, Novo Alle, DK-2880 Bagsaerd, Denmark.
Møldrup
Annette
A
Blume
Niels
N
Karlsen
Allan E
AE
Nissen Friedrichsen
Birgitte
B
Tornhave
Ditte
D
Knudsen
Lotte Bjerre
LB
Petersen
Jacob S
JS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005934:Glucagon / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects*; D000069450:Liraglutide; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011498:Protein Precursors / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D016207:Cytokines; D005230:Fatty Acids, Nonesterified; D010446:Peptide Fragments; D011498:Protein Precursors; D009569:Nitric Oxide; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D019869:Phosphatidylinositol 3-Kinases