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Differential Mitogenic Signaling in Insulin Receptor-Deficient Fetal Pancreatic ß-Cells

Institute of Biochemistry/Department of Biochemistry and Molecular Biology, Joint Center Consejo Superior Investigacion Cientifica/Universidad Complutense, School of Pharmacy, Complutense University, 28040 Madrid, Spain

Address all correspondence and requests to: M. Benito, Instituto de Bioquímica/Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Ciudad Universitaria, 28040 Madrid, Spain. E-mail: benito{at}farm.ucm.es.

Insulin receptor (IR) may play an essential role in the development of ß-cell mass in the mouse pancreas. To further define the function of this signaling system in ß-cell development, we generated IR-deficient ß-cell lines. Fetal pancreata were dissected from mice harboring a floxed allele of the insulin receptor (IRLoxP) and used to isolate islets. These islets were infected with a retrovirus to express simian virus 40 large T antigen, a strategy for establishing ß-cell lines (ß-IRLoxP). Subsequently, these cells were infected with adenovirus encoding cre recombinase to delete insulin receptor (ß-IR^–/–). ß-Cells expressed insulin and Pdx-1 mRNA in response to glucose. In ß-IRLoxP ß-cells, p44/p42 MAPK and phosphatidylinositol 3 kinase pathways, mammalian target of rapamycin (mTOR), and p70S₆K phosphorylation and ß-cell proliferation were stimulated in response to insulin. Wortmannin or PD98059 had no effect on insulin-mediated mTOR/p70S₆K signaling and the corresponding mitogenic response. However, the presence of both inhibitors totally impaired these signaling pathways and mitogenesis in response to insulin. Rapamycin completely blocked insulin-activated mTOR/p70S₆K signaling and mitogenesis. Interestingly, in ß-IR^–/– ß-cells, glucose failed to stimulate phosphatidylinositol 3 kinase activity but induced p44/p42 MAPKs and mTOR/p70S₆K phosphorylation and ß-cell mitogenesis. PD98059, but not wortmannin, inhibited glucose-induced mTOR/p70S₆K signaling and mitogenesis in those cells. Finally, rapamycin blocked glucose-mediated mitogenesis of ß-IR^–/– cells. In conclusion, independently of glucose, insulin can mediate mitogenesis in fetal pancreatic ß-cell lines. However, in the absence of the insulin receptor, glucose induces ß-cell mitogenesis.

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