Gestational diabetes mellitus resulting from impaired beta-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen.

OBJECTIVE: The objectives of the study were to determine whether the cell cycle transcription factor, FoxM1, is required for glucose homeostasis and beta-cell mass expansion in maternal islets during pregnancy and whether FoxM1 is essential for placental lactogen (PL)-induced beta-cell proliferation. RESEARCH DESIGN AND METHODS: beta-Cell mass, beta-cell proliferation, and glucose homeostasis were assessed in virgin, pregnant, and postpartum mice with a pancreas-wide Foxm1 deletion (FoxM1(Deltapanc)). Wild-type islets were cultured with or without PL and examined for Foxm1 induction. Transgenic mice overexpressing PL in beta-cells were bred with FoxM1(Deltapanc) mice, and beta-cell proliferation was examined. RESULTS: Foxm1 was upregulated in maternal islets during pregnancy. In contrast to controls, beta-cell proliferation did not increase in pregnant FoxM1(Deltapanc) females. Mutant islets showed increased Menin and nuclear p27. FoxM1(Deltapanc) females developed gestational diabetes mellitus as pregnancy progressed. After parturition, euglycemia was restored in FoxM1(Deltapanc) females, but islet size was significantly reduced. Strikingly, beta-cell mass was normal in postpartum FoxM1(Deltapanc) pancreata due to a combination of increased beta-cell size and islet neogenesis. Evidence for neogenesis included increased number of endocrine clusters, increased proportion of smaller islets, and increased neurogenin 3 or insulin expression in cells adjacent to ducts. PL induced Foxm1 expression in cultured islets, and FoxM1 was essential for PL-mediated increases in beta-cell proliferation in vivo. CONCLUSIONS: FoxM1 is essential for beta-cell compensation during pregnancy. In the absence of increased beta-cell proliferation, neogenesis is induced in postpartum FoxM1(Deltapanc) pancreata. Our results suggest that FoxM1 functions downstream of PL to mediate its effects on beta-cell proliferation.

Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation.

Within the developing pancreas Hepatic Nuclear Factor 6 (HNF6) directly activates the pro-endocrine transcription factor, Ngn3. HNF6 and Ngn3 are each essential for endocrine differentiation and HNF6 is also required for embryonic duct development. Most HNF6(-/-) animals die as neonates, making it difficult to study later aspects of HNF6 function. Here, we describe, using conditional gene inactivation, that HNF6 has specific functions at different developmental stages in different pancreatic lineages. Loss of HNF6 from Ngn3-expressing cells (HNF6(Delta endo)) resulted in fewer multipotent progenitor cells entering the endocrine lineage, but had no effect on beta cell terminal differentiation. Early, pancreas-wide HNF6 inactivation (HNF6(Delta panc)) resulted in endocrine and ductal defects similar to those described for HNF6 global inactivation. However, all HNF6(Delta panc) animals survived to adulthood. HNF6(Delta panc) pancreata displayed increased ductal cell proliferation and metaplasia, as well as characteristics of pancreatitis, including up-regulation of CTGF, MMP7, and p8/Nupr1. Pancreatitis was most likely caused by defects in ductal primary cilia. In addition, expression of Prox1, a known regulator of pancreas development, was decreased in HNF6(Delta panc) pancreata. These data confirm that HNF6 has both early and late functions in the developing pancreas and is essential for maintenance of Ngn3 expression and proper pancreatic duct morphology.