IGF2 produced and secreted by adult β cells, functions as an autocrine activator of the β cell IGF1R signaling pathway. Whether this autocrine activity of IGF2 plays a physiological role in β cell and whole body physiology is not known. Here, we studied mice with β cell-specific inactivation of Igf2 (βIGF2KO mice) and assessed β cell mass and function in ageing, pregnancy, and acute induction of insulin resistance. We showed that glucose-stimulated insulin secretion (GSIS) was markedly reduced in old female βIGF2KO mice; glucose tolerance was, however, normal because of increased insulin sensitivity. On high fat diet, both male and female βIGF2KO mice displayed lower GSIS as compared to control mice but reduced β cell mass was observed only in female βIGF2KO mice. During pregnancy, there was no increase in β cell proliferation and mass in βIGF2KO mice. Finally, β cell mass expansion in response to acute induction of insulin resistance was lower in βIGF2KO than in control mice. Thus, the autocrine action of IGF2 regulates adult β cell mass and function to preserve in vivo GSIS in ageing, and to adapt β cell mass in response to metabolic stress, pregnancy hormones, and acutely induced insulin resistance.

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