Epidermal growth factor (EGF)-receptor signalling is needed for murine beta cell mass expansion in response to high-fat diet and pregnancy but not after pancreatic duct ligation

Abstract

Aims/hypothesis Epidermal growth factor receptor (EGFR) signalling is essential for the proper fetal development of pancreatic islets and in the postnatal formation of an adequate beta cell mass. In this study we investigated the role of EGFR signalling in the physiological states of beta cell mass expansion in adults during metabolic syndrome and pregnancy, as well as in regeneration after pancreatic duct ligation. Methods Heterozygous Pdx1-EGFR-dominant-negative (E1-DN) mice, which have a kinase-negative EGFR under the Pdx1 promoter, and wild-type mice were both subjected to a high-fat diet, pregnancy and pancreatic duct ligation. Results The beta cell mass of wild-type mice fed the highfat diet increased by 70% and the mice remained normoglycaemic; the E1-DN mice became diabetic and failed to show any compensatory beta cell mass expansion. Similarly, pregnant wild-type mice had four times more proliferating beta cells and a 75% increase in beta cell mass at mid-gestation, in contrast to the pregnant E1-DN mice, which did not show any significant beta cell compensation and were hyperglycaemic in an intraperitoneal glucose tolerance test. However, after pancreatic duct ligation, both the wild-type and E1-DN mice showed similar expression of Ngn3 (also known as Neurog3) and beta cell proliferation increased to a similar level in the ligated part of pancreas. Conclusions/interpretations EGFR signalling is essential in beta cell mass expansion during a high-fat diet and pregnancy where replication is the primary mechanism for compensatory beta cell mass expansion. In contrast, EGFR signalling appears not to be crucial to increased beta cell proliferation after pancreatic duct ligation.

Proteomic characterisation reveals active Wnt-signalling by human multipotent stromal cells as a key regulator of beta cell survival and proliferation

“…First, MSC R showed increased secretion of EGF previously shown to increase beta cell mass in rodents by stimulating beta cell replication [42]. However, EGF receptor signalling was required for expansion of murine beta cell mass in response to a high-fat diet, but was not crucial for neoislet formation after pancreatic ductal ligation [43]. Second, the CCN family of extracellular matrix-associated, heparin-binding proteins has been shown to modulate cell growth and repair in many tissues by increasing the bioavailability of BMPs, VEGF, Wnt and TGF ligands [44].…”

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

“…EGFR signaling pathways are essential for ␤-cell mass expansion in response to a high-fat diet and in pregnancy (200). EGF is synthesized in the pancreas and increases insulin secretion in mouse pancreatic islets; EGF expression levels are decreased in diabetic animals (285).…”

The negative cell cycle regulators, p27Kip1, p18Ink4c, and GSK-3, play critical role in maintaining quiescence of adult human pancreaticβ-cells and restrict their ability to proliferate

“…In 2004, another independent group revealed that β-cell proliferation is the primary mechanism for maintaining postnatal β-cell mass in mice 42 . Subsequently, numerous studies demonstrated using animal models of β-cell ablation, insulin resistance, high fat diet/obesity and pregnancy that β-cell proliferation is a major mechanism for restoring adequate β-cell mass resulting in maintenance of normal glucose homeostasis in both pathological and physiological conditions 2 - 5 , 43 , 44 . However, knowledge of human β-cell proliferation was obscure until an elegant study published in 2008 37 .…”

“…Additionally, our studies have revealed that siRNA-mediated downregulation of p27(Kip1) along with either of the GSK-3 isoforms does not stimulate INS-1 cell proliferation any further relative to individual knockdown of each of the GSK-3 isoforms, indicating GSK-3 as an upstream modulator of p27(Kip1) in β-cells. Studies have shown that adaptive growth of β-cell mass occurs via increased proliferation of β-cells for compensating elevated insulin demand during pregnancy and also, in response to high fat diet/obesity 43 , 44 , 51 . Studies have also demonstrated that decreased levels of p27(Kip1) and p18(Ink4c) are required for increased β-cell proliferation during pregnancy and hyperphagic obesity 51 .…”