{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:08:10Z","timestamp":1791205690953,"version":"4.1.0"},"reference-count":51,"publisher":"American Diabetes Association","issue":"10","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,10,1]]},"abstract":"<jats:p>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 \u03b2-cell growth nonadditively with glucose in a phosphatidylinositol-3 kinase (PI-3K)\u2013dependent 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 \u03b2-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 \u03b2(INS 832\/13) cells. GLP-1 also caused nuclear translocation of the atypical protein kinase C (aPKC) \u03b6 isoform in INS as well as in dissociated normal rat \u03b2-cells as shown by immunolocalization and Western immunoblotting analysis. Tritiated thymidine incorporation measurements showed that the p38 MAPK inhibitor SB203580 suppressed GLP-1\u2013induced \u03b2-cell proliferation. Further investigation was performed using isoform-specific pseudosubstrates of classical (\u03b1, \u03b2, and \u03b3) or \u03b6 aPKC isoforms. The PKC\u03b6 pseudosubstrate suppressed the proliferative action of GLP-1, whereas the inhibitor of classical PKC isoforms had no effect. Overexpression of a kinase-dead PKC\u03b6 acting as a dominant negative protein suppressed GLP-1\u2013induced proliferation. In addition, ectopic expression of a constitutively active PKC\u03b6 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\u2013induced activation of PKC\u03b6 is implicated in the \u03b2-cell proliferative signal of the insulinotropic hormone. The results are consistent with a model in which GLP-1\u2013induced PI-3K activation results in PKC\u03b6 translocation to the nucleus, which may play a role in the pleiotropic effects (DNA synthesis, metabolic enzymes, and insulin gene expression) of the glucoincretin.<\/jats:p>","DOI":"10.2337\/diabetes.50.10.2237","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"2237-2243","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":216,"title":["Protein Kinase C\u03b6 Activation Mediates Glucagon-Like Peptide-1\u2013Induced Pancreatic \u03b2-Cell Proliferation"],"prefix":"10.2337","volume":"50","author":[{"given":"Jean","family":"Buteau","sequence":"first","affiliation":[{"name":"Molecular Nutrition Unit, Department of Nutrition, University of Montreal, the Centre de Recherche du CHUM and Institut du Cancer, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Foisy","sequence":"additional","affiliation":[{"name":"Molecular Nutrition Unit, Department of Nutrition, University of Montreal, the Centre de Recherche du CHUM and Institut du Cancer, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Pacific Northwest Research Institute & Department of Pharmacology, University of Washington, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor J.","family":"Biden","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Prentki","sequence":"additional","affiliation":[{"name":"Molecular Nutrition Unit, Department of Nutrition, University of Montreal, the Centre de Recherche du CHUM and Institut du Cancer, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031212272483700_R1","doi-asserted-by":"crossref","unstructured":"Fehmann HC, Goke R, Goke B: Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. 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