Both type 1 and type 2 diabetes are characterized by deficient insulin secretion and decreased beta-cell mass. Thus, regenerative strategies to increase beta-cell mass need to be developed. To characterize mechanisms of beta-cell plasticity, we studied a model of severe insulin resistance in the adult mouse and defined how beta-cells adapt. Chronic corticosterone (CORT) treatment was given to adult mice and led to rapid insulin resistance and adaptive increased insulin secretion. Adaptive and massive increase of beta-cell mass was observed during treatment up to 8 weeks. beta-Cell mass increase was partially reversible upon treatment cessation and reinduced upon subsequent treatment. beta-Cell neogenesis was suggested by an increased number of islets, mainly close to ducts, and increased Sox9 and Ngn3 mRNA levels in islets, but lineage-tracing experiments revealed that neoformed beta-cells did not derive from Sox9- or Ngn3-expressing cells. CORT treatment after beta-cell depletion partially restored beta-cells. Finally, beta-cell neogenesis was shown to be indirectly stimulated by CORT because serum from CORT-treated mice increased beta-cell differentiation in in vitro cultures of pancreatic buds. Altogether, the results present a novel model of beta-cell neogenesis in the adult mouse and identify the presence of neogenic factors in the serum of CORT-treated mice.