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      Connective tissue growth factor is critical for proper β-cell function and pregnancy-induced β-cell hyperplasia in adult mice

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          Abstract

          During pregnancy, maternal β-cells undergo compensatory changes, including increased β-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 β-cell development and promotes regeneration after partial β-cell ablation. During embryogenesis, CTGF is expressed in pancreatic ducts, vasculature, and β-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 β-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 β-cell proliferation. Moreover, virgin Ctgf ΔEndo females also display impaired GSIS with glucose intolerance, indicating that underlying β-cell dysfunction precedes the development of gestational diabetes in this animal model. This is the first time a role for CTGF in β-cell function has been reported.

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          Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes.

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            Method for the Isolation of Intact Islets of Langerhans from the Rat Pancreas

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              Expansion of beta-cell mass in response to pregnancy.

              Inadequate beta-cell mass can lead to insulin insufficiency and diabetes. During times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing beta-cell mass, both by increasing cell size and by changing the balance between beta-cell proliferation and apoptosis. In this paper, we review recent advances in our understanding of the mechanisms that control the adaptive expansion of beta-cell mass, focusing on the islet's response to pregnancy, a physiological state of insulin resistance. Functional characterization of factors controlling both beta-cell proliferation and survival might not only lead to the development of successful therapeutic strategies to enhance the response of the beta-cell to increased metabolic loads, but also improve islet transplantation regimens. Copyright 2009 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                American Journal of Physiology-Endocrinology and Metabolism
                American Journal of Physiology-Endocrinology and Metabolism
                American Physiological Society
                0193-1849
                1522-1555
                September 01 2016
                September 01 2016
                : 311
                : 3
                : E564-E574
                Affiliations
                [1 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;
                [2 ]Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee; and
                [3 ]School for Science and Math, Vanderbilt University, Nashville, Tennessee
                [4 ]Department of Veterans Affairs Tennessee Valley, Nashville, Tennessee;
                [5 ]Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee;
                Article
                10.1152/ajpendo.00194.2016
                5142004
                27460898
                b6afc2f4-d4d2-490c-b54e-99020b3ef62a
                © 2016
                History

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