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© 2001 by the American Diabetes Association, Inc.
Protein Kinase C
Activation Mediates Glucagon-Like Peptide-1–Induced Pancreatic ß-Cell Proliferation
1 Molecular Nutrition Unit, Department of Nutrition, University of Montreal, the Centre de Recherche du CHUM and Institut du Cancer, Montreal, Quebec, Canada
2 Pacific Northwest Research Institute & Department of Pharmacology, University of Washington, Seattle, Washington
3 Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
Glucagon-like peptide-1 (GLP-1), an insulinotropic and glucoincretin hormone, is a potentially important therapeutic agent in the treatment of diabetes. We previously provided evidence that GLP-1 induces pancreatic ß-cell growth nonadditively with glucose in a phosphatidylinositol-3 kinase (PI-3K)–dependent manner. In the present study, we investigated the downstream effectors of PI-3K to determine the precise signal transduction pathways that mediate the action of GLP-1 on ß-cell proliferation. GLP-1 increased extracellular signal-related kinase 1/2, p38 mitogen-activated protein kinase (MAPK), and protein kinase B activities nonadditively with glucose in pancreatic ß(INS 832/13) cells. GLP-1 also caused nuclear translocation of the atypical protein kinase C (aPKC) 
isoform in INS as well as in dissociated normal rat ß-cells as shown by immunolocalization and Western immunoblotting analysis. Tritiated thymidine incorporation measurements showed that the p38 MAPK inhibitor SB203580 suppressed GLP-1–induced ß-cell proliferation. Further investigation was performed using isoform-specific pseudosubstrates of classical (
, ß, and 
) or aPKC isoforms. The PKC pseudosubstrate suppressed the proliferative action of GLP-1, whereas the inhibitor of classical PKC isoforms had no effect. Overexpression of a kinase-dead PKC acting as a dominant negative protein suppressed GLP-1–induced proliferation. In addition, ectopic expression of a constitutively active PKC mutant stimulated tritiated thymidine incorporation 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 is implicated in the ß-cell proliferative signal of the insulinotropic hormone. The results are consistent with a model in which GLP-1–induced PI-3K activation results in PKC translocation to the nucleus, which may play a role in the pleiotropic effects (DNA synthesis, metabolic enzymes, and insulin gene expression) of the glucoincretin.
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