ABSTRACT
Signaling by receptor tyrosine kinases regulates pancreatic ß cell function. Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in ß cells impairs insulin secretion. Conversely, Irs2 ablation impairs ß cell replication. In this study, we examined aspects of the Igf1r regulatory signaling cascade in ß cells. To examine genetically the involvement of Irs1 and Irs2 in Igf1r signaling, we generated double mutant mice lacking Igf1r specifically in pancreatic ß 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 ß cell mass and glucose tolerance. In contrast, lack of Igf1r function in ß 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 ß 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 ß cell proliferation is mainly regulated by InsR using Irs2 as a downstream signaling effector. The insulin and IGF pathways appear to control ß cell functions independently and selectively.
