This study shows how Hnf1b inactivation in pancreatic ductal cells leads to chronic pancreatitis, neoplasia, and potentiates pancreatic intraepithelial neoplasia formation. This shows a cause of pancreatitis and identifies Hnf1b as a potential tumor suppressor for pancreatic cancer.

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