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Insulin receptor (IR) may play an essential role in the development of [beta]-cell mass in the mouse pancreas. To further define the function of this signaling system in [beta]-cell development, we generated IR-deficient [beta]-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 [beta]-cell lines ([beta]-IRLoxP). Subsequently, these cells were infected with adenovirus encoding cre recombinase to delete insulin receptor ([beta]-IR-/-). [beta]-Cells expressed insulin and Pdx-1 mRNA in response to glucose. In [beta]-IRLoxP [beta]-cells, p44/p42 MAPK and phosphatidylinositol 3 kinase pathways, mammalian target of rapamycin (mTOR), and p70S6K phosphorylation and [beta]-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 [beta]-IR-/- [beta]-cells, glucose failed to stimulate phosphatidylinositol 3 kinase activity but induced p44/p42 MAPKs and mTOR/p70S6K phosphorylation and [beta]-cell mitogenesis. PD98059, but not wortmannin, inhibited glucose-induced mTOR/p70S6K signaling and mitogenesis in those cells. Finally, rapamycin blocked glucose-mediated mitogenesis of [beta]-IR-/- cells. In conclusion, independently of glucose, insulin can mediate mitogenesis in fetal pancreatic [beta]-cell lines. However, in the absence of the insulin receptor, glucose induces [beta]-cell mitogenesis.

Copyright (C) 2006 by The Endocrine Society