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.


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.
Zhang
Hongjie
H
Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Zhang
Jia
J
Pope
Christine F
CF
Crawford
Laura A
LA
Vasavada
Rupangi C
RC
Jagasia
Shubhada M
SM
Gannon
Maureen
M
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D017931:DNA Primers; D016640:Diabetes, Gestational / Q000235:genetics*; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000473:pathology / Q000502:physiology; D007515:Islets of Langerhans / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010928:Placental Lactogen / Q000502:physiology*; D011247:Pregnancy; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D012313:RNA; D010928:Placental Lactogen; D005947:Glucose