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

Hongjie Zhang, Jia Zhang, Christine F. Pope, Laura A. Crawford, Rupangi C. Vasavada, Shubhada M. Jagasia, Maureen Gannon

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

OBJECTIVE - The objectives of the study were to determine whether the cell cycle transcription factor, FoxM1, is required for glucose homeostasis and β-cell mass expansion in maternal islets during pregnancy and whether FoxM1 is essential for placental lactogen (PL)-induced β-cell proliferation. RESEARCH DESIGN AND METHODS - β-Cell mass, β-cell proliferation, and glucose homeostasis were assessed in virgin, pregnant, and postpartum mice with a pancreas-wide Foxm1 deletion (FoxM1Δpanc). Wild-type islets were cultured with or without PL and examined for Foxm1 induction. Transgenic mice overexpressing PL in β-cells were bred with FoxM1 Δpanc mice, and β-cell proliferation was examined. RESULTS - Foxm1 was upregulated in maternal islets during pregnancy. In contrast to controls, β-cell proliferation did not increase in pregnant FoxM1 Δpanc females. Mutant islets showed increased Menin and nuclear p27. FoxM1Δpanc females developed gestational diabetes mellitus as pregnancy progressed. After parturition, euglycemia was restored in FoxM1Δpanc females, but islet size was significantly reduced. Strikingly, β-cell mass was normal in postpartum FoxM1 Δpanc pancreata due to a combination of increased β-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 β-cell proliferation in vivo. CONCLUSIONS - FoxM1 is essential for β-cell compensation during pregnancy. In the absence of increased β-cell proliferation, neogenesis is induced in postpartum FoxM1 Δpanc pancreata. Our results suggest that FoxM1 functions downstream of PL to mediate its effects on β-cell proliferation.

Original languageEnglish (US)
Pages (from-to)143-152
Number of pages10
JournalDiabetes
Volume59
Issue number1
DOIs
StatePublished - Jan 2010

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