ABSTRACT
During pregnancy, maternal ß cells undergo compensatory changes including hypertrophy, hyperplasia, and increased glucose-stimulated insulin secretion (GSIS). Failure of these adaptations to occur can result in gestational diabetes mellitus. The secreted protein, Connective tissue growth factor (Ctgf), is critical for normal ß cell development and promotes regeneration after partial ß cell ablation. During embryogenesis, Ctgf is expressed in pancreatic ducts, vasculature, and ß cells. In the adult pancreas, Ctgf is expressed only in the vasculature. Here, we report that pregnant mice with global Ctgf haploinsufficiency (CtgfLacZ/+) have an impairment in maternal ß cell proliferation, while ß cell proliferation in virgin CtgfLacZ/+ females is unaffected. Additionally, α-cell proliferation, ß cell size, and GSIS were unaffected in CtgfLacZ/+ mice, suggesting that vascular-derived Ctgf has a specific role in islet compensation during pregnancy.
Subject(s)
Connective Tissue Growth Factor/metabolism , Diabetes, Gestational/metabolism , Endothelium, Vascular/metabolism , Insulin-Secreting Cells/metabolism , Insulin/metabolism , Pancreas/blood supply , Animals , Blood Glucose/analysis , Cell Proliferation , Connective Tissue Growth Factor/genetics , Diabetes, Gestational/blood , Diabetes, Gestational/pathology , Endothelium, Vascular/pathology , Female , Genes, Reporter , Haploinsufficiency , Heterozygote , Immunohistochemistry , Insulin Secretion , Insulin-Secreting Cells/pathology , Loss of Function Mutation , Mice, Inbred C57BL , Mice, Transgenic , Pancreas/metabolism , Pancreas/pathology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Pregnancy , Up-RegulationABSTRACT
During pregnancy, maternal ß-cells undergo compensatory changes, including increased ß-cell mass and enhanced glucose-stimulated insulin secretion. Failure of these adaptations to occur results in gestational diabetes mellitus. The secreted protein connective tissue growth factor (CTGF) is critical for normal ß-cell development and promotes regeneration after partial ß-cell ablation. During embryogenesis, CTGF is expressed in pancreatic ducts, vasculature, and ß-cells. In adult pancreas, CTGF is expressed only in the vasculature. Here we show that pregnant mice with global Ctgf haploinsufficiency (Ctgf(LacZ/+)) have an impairment in maternal ß-cell proliferation; no difference was observed in virgin Ctgf(LacZ/+) females. Using a conditional CTGF allele, we found that mice with a specific inactivation of CTGF in endocrine cells (Ctgf(ΔEndo)) develop gestational diabetes during pregnancy, but this is due to a reduction in glucose-stimulated insulin secretion rather than impaired maternal ß-cell proliferation. Moreover, virgin Ctgf(ΔEndo) females also display impaired GSIS with glucose intolerance, indicating that underlying ß-cell dysfunction precedes the development of gestational diabetes in this animal model. This is the first time a role for CTGF in ß-cell function has been reported.
