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D iabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing β cells. The mechanisms governing replication of terminally differentiated β cells and neogenesis from progenitor cells are unclear. Mice lacking insulin receptor substrate-2 (Irs2) develop β cell failure, suggesting that insulin signaling is required to maintain an adequate β cell mass. We report that haploinsufficiency for the forkhead transcription factor Foxo1 reverses β cell failure in Irs2^–/– mice through partial restoration of β cell proliferation and increased expression of the pancreatic transcription factor pancreas/duodenum homeobox gene-1 (Pdx1). Foxo1 and Pdx1 exhibit mutually exclusive patterns of nuclear localization in β cells, and constitutive nuclear expression of a mutant Foxo1 is associated with lack of Pdx1 expression. We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3β–dependent) expression from the Pdx1 promoter. We propose that insulin/IGFs regulate β cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts.