Vascular-derived connective tissue growth factor (Ctgf) is critical for pregnancy-induced β cell hyperplasia in adult mice

Abstract

During pregnancy, maternal β 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 β cell development and promotes regeneration after partial β cell ablation. During embryogenesis, Ctgf is expressed in pancreatic ducts, vasculature, and β cells. In the adult pancreas, Ctgf is expressed only in the vasculature. Here, we report that pregnant mice with global Ctgf haploinsufficiency (Ctgf) have an impairment in maternal β cell proliferation, while β cell proliferation in virgin Ctgf females is unaffected. Additionally, α-cell proliferation, β cell size, and GSIS were unaffected in Ctgf mice, suggesting that vascular-derived Ctgf has a specific role in islet compensation during pregnancy.

Features of Connective Tissue Metabolism and Microelements in Blood Serum of Pregnant Women With Cervical Insufficiency

“…It suggests that there is a disturbance in the ratio between connective and muscle tissues, which are characteristic for UCTD. Similar changes in the form of reduction of the collagen amount and increased mass of muscle tissue are observed in a case of cervical insufficiency [3,11].…”

“…Cervical insufficiency (CI) is one of the leading reasons of extremely early and early preterm deliveries. Clinically CI happens at 22-28 weeks of pregnancy leading to premature deliveries and such newborns have indicators of perinatal morbidity and mortality [3,4].…”

“…At the same time, modern studies show numerous pregnancy complications in patients with UCTD such as miscarriage and premature delivery, preeclampsia, placental dysfunction, premature rupture of amniotic membranes [9,11]. The process of delivery and the postpartum period are mostly complicated by abnormalities of labor activity, birth trauma, bleeding and disorders of wound repair after surgery [3,4]. It suggests that there is a disturbance in the ratio between connective and muscle tissues, which are characteristic for UCTD.…”

High glucose alters fetal rat islet transcriptome and induces progeny islet dysfunction

“…Both these genes are expressed only in late embryonic beta cell development and emerging islets (Arnaud-Dabernat et al 2007, Crawford et al 2009). Particularly, Ctgf inactivation during embryogenesis caused decreased insulin-positive cells (Crawford et al 2009), while Ctgf haploinsufficiency mice had decreased beta cell proliferation during pregnancy (Pasek et al 2017).…”

Regulation and bioactivity of the CCN family of genes and proteins in obesity and diabetes

“…Current published data addressing CCNs in pancreatic islets, and specifically in pancreatic beta-cells, suggests multiple roles of the CCNs in differing stages of pancreatic beta-cell development and pathology. While the original studies of CCN2 homozygous global gene knockout did not find an overt pancreatic abnormality (Ivkovic et al 2003), more recent publications have interrogated and found an important role for CCN2 in endocrine pancreatic development prenatally, indicating it is required for beta-cell proliferation, differentiation, and islet morphogenesis during development (Charrier and Brigstock 2013), (Crawford et al 2009), as well as beta-cell function gestationally (Pasek et al 2016), (Pasek et al 2017). CCN2 also mediated adult beta-cell proliferation in the setting of a murine model of partial beta-cell ablation in a macrophage dependent manner, suggesting CCN2 may have a role in preventing persistent adult islet dysfunction linked to inflammation (Riley et al 2015).…”