Stimulation of pancreatic β-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways

• DOI: 10.1677/joe.1.06160
• Publication Date: 2006-03-07T16:02:46Z
• Authors: Birgitte N Friedr...; Nicole Neubauer; Ying C Lee; Vivian K Gram; Niels Blume; Jacob S Petersen; Jens H Nielsen; Annette Møldrup
• Keywords: Wortmannin

The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), have been suggested to act as β-cell growth factors may therefore be of critical importance for the maintenance a proper mass. We investigated molecular mechanism incretin-induced replication in primary monolayer cultures newborn rat islet cells. GLP-1, GIP long-acting GLP-1 derivative, lira-glutide, increased 50–80% at 10–100 nM upon 24 h stimulus, whereas glucagon similar concentration had no significant effect. stimulatory effect was efficiently mimicked by adenylate cyclase activator, forskolin, 10 (~90% increase) additive (~170–250% with response human hormone (hGH), indicating use distinct intracellular signalling pathways leading mitosis incretins cytokines, respectively. both completely blocked protein kinase A (PKA) inhibitor, H89. In addition, phosphoinositol 3-kinase (PI3K) inhibitor wortmannin mitogen-activated (MEK) PD98059, inhibited GLP-1- GIP-stimulated proliferation. p38 (MAPK) SB203580, inhibitory on either or stimulated Cyclin Ds switches G0/G1-S phase transition many cell types we previously demonstrated hGH-induced cyclin D2 expression insulinoma line, INS-1. time-dependently induced D1 mRNA levels INS-1E, were unaffected. However, minor stimulation observed D3 levels. Transient transfection promoter-luciferase reporter construct into cells INS-1 revealed approximately 2–3 fold increase transcriptional activity GIP, 4–7 forskolin. treatment type hGH promoter activity. H89, wortmannin, PD98059. conclude that is dependent cAMP/PKA, p42 MAPK PI3K activities, which involve induction D1. liraglutide potential humans would impact long-term diabetes treatment.