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[摘要]：Signaling by receptor tyrosine kinases regulates pancreatic beta cell function. Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in beta cells impairs insulin secretion. Conversely, Irs2 ablation impairs beta cell replication. In this study, we examined aspects of the Igf1r regulatory signaling cascade in beta cells. To examine genetically the involvement of Irs1 and Irs2 in Igf1r signaling, we generated double mutant mice lacking Igf1r specifically in pancreatic beta cells in an Irs1-or Irs2-null background. We show that Igf1r/Irs1 double mutants do not differ phenotypically from Irs1 single mutants and exhibit hyperinsulinemia, while maintaining normal beta cell mass and glucose tolerance. In contrast, lack of Igf1r function in beta cells aggravates the consequences of Irs2 ablation in double mutants and results in lethal diabetes by 6 weeks of age. This additivity of phenotypic manifestations indicates that Irs2 serves a pathway that is largely independent of Igf1r signaling. Consistent with the view that the latter is the InsR pathway, we show that combined beta cell-specific knock-out of both Insr and Igf1r results in a phenocopy of double mutants lacking Igf1r and Irs2. We conclude that Igf1r signals primarily through Irs1 and affects insulin secretion, whereas beta cell proliferation is mainly regulated by InsR using Irs2 as a downstream signaling effector. The insulin and IGF pathways appear to control beta cell functions independently and selectively. |
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