Insulin-like growth factor 2 (IGF2), produced and secreted by adult beta-cells, functions as an autocrine activator of the beta-cell insulin-like growth factor 1 receptor signaling pathway. Whether this autocrine activity of IGF2 plays a physiological role in beta-cell and whole-body physiology is not known. Here, we studied mice with beta-cell-specific inactivation of Igf2 (beta IGF2K0 mice) and assessed beta-cell mass and function in aging, pregnancy, and acute induction of insulin resistance. We showed that glucose-stimulated insulin secretion (GSIS) was markedly reduced in old female beta IGF2K0 mice; glucose tolerance was, however, normal because of increased insulin sensitivity. While on a high-fat diet, both male and female beta IGF2K0 mice displayed lower GSIS compared with control mice, but reduced beta-cell mass was observed only in female beta IGF2K0 mice. During pregnancy, there was no increase in beta-cell proliferation and mass in beta IGF2K0 mice. Finally, beta-cell mass expansion in response to acute induction of insulin resistance was lower in beta IGF2K0 mice than in control mice. Thus, the autocrine action of IGF2 regulates adult beta-cell mass and function to preserve in vivo GSIS in aging and to adapt beta-cell mass in response to metabolic stress, pregnancy hormones, and acute induction of insulin resistance.