Protein kinase C zeta activation mediates glucagon-like peptide-1-induced pancreatic beta-cell proliferation

Glucagon-like peptide-1 (GLP-1), an insulinotropic and. glucoincretin hormo ne, is a potentially important then. apeutic agent in the treatment of diab etes. We previously provided evidence that GLP-1 induces pancreatic beta -c ell growth nonadditively with glucose in a phosphatidylinositol-3 kinase (P I-3K)-dependent manner. In the present study, we investigated the downstrea m effectors of PI-3K to determine the precise signal transduction pathways that mediate the action of GLP-1 on beta -cell. proliferation. GLP-1 increa sed extracellular signal-related kinase 1/2, p38 mitogen-activated protein kinase. (MAPK), and protein kinase B activities nonadditively with glucose in pancreatic beta (INS 832/13) cells. GLP-1 also caused nuclear translocat ion of the atypical protein kinase C aPKC isoform in INS as well as in. dis sociated normal rat beta -cells as shown by immunolocalization and Western immunoblotting analysis. Tritiated thymidine incorporation measurements sho wed that. the p38 MAPK inhibitor SB203580 suppressed GLP-1-. induced beta - cell proliferation. Further investigation was performed using isoform-speci fic pseudosubstrates of classical (alpha, beta, and gamma) or zeta aPKC iso forms. The PKC zeta pseudosubstrate suppressed the proliferative action oi GLP-1, whereas the inhibitor of classical PKC isoforms had no effect. Overe xpression of a kinase-dead PKC zeta acting as a dominant negative protein s uppressed GLP-1 -induced proliferation. In addition, ectopic expression of a constitutively active PKC zeta mutant stimulated tritiated thymidine inco rporation to the same extent as GLP-1, and the glucoincretin had no growth- promoting action under this condition. The data indicate that GLP-1-induced activation of PKC zeta is implicated in the beta -cell proliferative signa l of the insulinotropic hormone. The results are consistent with a model in which GLP-1-. induced PI-3K activation results in PKC zeta translocation t o the nucleus, which may play a role in the pleiotropic effects (DNA synthe sis, metabolic enzymes, and insulin gene expression) of the glucoineretin.