Loss of HGF/c-Met Signaling in Pancreatic β-Cells Leads to Incomplete Maternal β-Cell Adaptation and Gestational Diabetes Mellitus

Abstract

Hepatocyte growth factor (HGF) is a mitogen and insulinotropic agent for the β-cell. However, whether HGF/c-Met has a role in maternal β-cell adaptation during pregnancy is unknown. To address this issue, we characterized glucose and β-cell homeostasis in pregnant mice lacking c-Met in the pancreas (PancMet KO mice). Circulating HGF and islet c-Met and HGF expression were increased in pregnant mice. Importantly, PancMet KO mice displayed decreased β-cell replication and increased β-cell apoptosis at gestational day (GD)15. The decreased β-cell replication was associated with reductions in islet prolactin receptor levels, STAT5 nuclear localization and forkhead box M1 mRNA, and upregulation of p27. Furthermore, PancMet KO mouse β-cells were more sensitive to dexamethasone-induced cytotoxicity, whereas HGF protected human β-cells against dexamethasone in vitro. These detrimental alterations in β-cell proliferation and death led to incomplete maternal β-cell mass expansion in PancMet KO mice at GD19 and early postpartum periods. The decreased β-cell mass was accompanied by increased blood glucose, decreased plasma insulin, and impaired glucose tolerance. PancMet KO mouse islets failed to upregulate GLUT2 and pancreatic duodenal homeobox-1 mRNA, insulin content, and glucose-stimulated insulin secretion during gestation. These studies indicate that HGF/c-Met signaling is essential for maternal β-cell adaptation during pregnancy and that its absence/attenuation leads to gestational diabetes mellitus.

Insulin demand regulates β cell number via the unfolded protein response

“…Since the rate of β cell proliferation is strongly influenced by the metabolic environment of the host (14)(15)(16), in some cases trumping islet-intrinsic factors (17,18), the working model in the field has been that circulating factors regulate β cell proliferation. Many different signals have been proposed to drive β cell proliferation in response to insulin demand, principally nutrients (14,15,19,20) and growth factors (8,(21)(22)(23). However, no circulating signal explains all the observations, and models in which a distant organ senses insulin demand and directs β cells to proliferate are complicated and indirect.…”

The Placental Secretome: Identifying Potential Cross-Talk Between Placenta and Islet β-Cells

“…Islet β-cell adaptive responses occur after placentation and are rapidly reversed post-partum, consistent with placental signals playing a major role in informing β-cells of the gestational stage via circulating mediators. It is well established that the placental lactogens and prolactin play important roles in metabolic adaptations during pregnancy, but these cannot account for all of the β-cell adaptive responses because the time-course of elevations in their circulating levels does not match that of increases in β-cell mass [7-11]. The current study aimed to identify other placentally-derived mediators with the potential to influence β-cells to facilitate future functional studies into changes in the endocrine capacity of islets in pregnancy.…”

Expression mechanism of tryptophan hydroxylase 1 in mouse islets during pregnancy

“…The insufficient compensation of insulin secretion contributes to the development of gestational diabetes. Meanwhile, numerous studies performed in pregnant mice have shown that proliferation of b cells is augmented in response to pregnancy (Zhang et al 2010, Demirci et al 2012, Jacovetti et al 2012. The prolactin receptor is the target of prolactin and placental lactogen, and is expressed in pancreatic b cells to contribute for augmentation of insulin release during pregnancy (Buchanan & Xiang 2005).…”