Journal Article

Gestational Diabetes Mellitus Resulting From Impaired β-Cell Compensation in the Absence of FoxM1, a Novel Downstream Effector of Placental Lactogen

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

2010

Overview

Gestational Diabetes Mellitus Resulting From Impaired β-Cell Compensation in the Absence of FoxM1, a Novel Downstream Effector of Placental Lactogen Hongjie Zhang 1 , Jia Zhang 2 , Christine F. Pope 1 , Laura A. Crawford 3 , Rupangi C. Vasavada 4 , Shubhada M. Jagasia 1 and Maureen Gannon 1 , 2 , 3 1 Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee; 2 Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; 3 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee; 4 Department of Medicine, Division of Endocrinology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Corresponding author: Maureen Gannon, maureen.gannon{at}vanderbilt.edu . H.Z. and J.Z. contributed equally to this work. 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 (FoxM1 Δpanc ). 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. FoxM1 Δpanc females developed gestational diabetes mellitus as pregnancy progressed. After parturition, euglycemia was restored in FoxM1 Δpanc 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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received January 9, 2009. Accepted September 23, 2009. © 2010 American Diabetes Association

• Publisher: American Diabetes Association
• Subject: Animals / Biological and medical sciences / Blotting, Western / Cell Division / Diabetes / Diabetes in pregnancy / Diabetes, Gestational - genetics / Diabetes. Impaired glucose tolerance / DNA Primers / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Female / Forkhead Box Protein M1 / Forkhead Transcription Factors - deficiency / Forkhead Transcription Factors - genetics / Gene Deletion / Gene Expression Regulation, Developmental / Glucose - metabolism / Glucose Tolerance Test / Health aspects / Insulin-Secreting Cells - cytology / Insulin-Secreting Cells - pathology / Insulin-Secreting Cells - physiology / Islets of Langerhans - physiology / Medical sciences / Mice / Mice, Transgenic / Original / Pancreatic beta cells / Placental Lactogen - physiology / Pregnancy / Pregnant women / Reverse Transcriptase Polymerase Chain Reaction / RNA - genetics / RNA - isolation & purification / Somatotropin