Beyond modulating beta cell survival, cytokines inhibit insulin promoter activity, which likely contributes to islet dysfunction following islet transplant. This effect appears to be mediated, in part, via altered expression of transcription factors important for insulin gene expression.
A progressive decline in islet function is a major obstacle to the success of islet transplantation. The cause of this decline in islet function is unclear, but immunosuppressive agents may contribute. Insulin-like growth factor-I (IGF-I) and betacellulin are important for islet cell survival and/or proliferation. In the present study, we performed studies in INS-1 cells and murine islets to define the effect of IGF-I and betacellulin on progression of islet cells through the cell cycle and the impact of immunosuppressive agents. Treatment of INS-1 cells for 24 hrs with 20 ng/ml betacellulin or 50 ng/ml IGF-I increased cells in S phase by ~2-fold. Treatment of INS-1 cells with IGF-I or betacellulin also increased cyclin D1 expression and nuclear exclusion of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1. In INS-1 cells and islets, betacellulin- and IGF-I increased Akt, ERK, and p70S6 kinase phosphorylation. Rapamycin, an immunosuppressant which inhibits mTOR, inhibited the increase in p70S6 kinase phosphorylation stimulated by betacellulin- and IGF-I in INS-1 cells. Rapamycin also inhibited betacellulin- and IGF-I-induced entry of cells into S phase and BrdU incorporation as well as the effect of betacellulin and IGF-I on cyclin D1 expression and nuclear exclusion of p21Cip1 and p27Kip1. Together, these data suggest that the effect of betacellulin and IGF-I on islet cell growth and proliferation is mediated, in part, via signaling through mTOR. As rapamycin is used to treat islet transplant recipients, these results suggest that rapamycin could have deleterious effects on islet proliferation and function over time.
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