Effect of epiregulin on pancreatic beta cell growth and insulin secretion

Kuntz, Emmanuelle; Broca, Christophe; Komurasaki, Toshi; Kaltenbacher, Marie-Christine; Gross, René; Pinget, M.; Damgé, Christiane

doi:10.1080/08977190500233367

Cited by 12 publications

(9 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although HB-EGF was essential for the glucose response, whether HB-EGF is the sole endogenous EGFR ligand acting during b-cell compensation to metabolic stress remains an open question. BTC (41), epiregulin (43), transforming growth factor-a, and EGF (41,44) exert mitogenic effects on the b-cell and are expressed in developing (45) and adult (38) rodent islets and during b-cell neogenesis (46). Hence, different EGFR ligands likely contribute to b-cell compensation in a context-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

HB-EGF Signaling Is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

et al. 2020

View full text Add to dashboard Cite

The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β-cells in response to glucose in a carbohydrate-response element–binding protein (ChREBP)–dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.

show abstract

Section: Discussionmentioning

confidence: 99%

HB-EGF Signaling Is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

et al. 2020

View full text Add to dashboard Cite

show abstract

“…However, other ERBB ligands could be involved in regulating ERBB activation in db/db mice. Indeed, other ligands, which have been involved in metabolic disorders, can modulate ERBB phosphorylation state 25 , such as NRG4 26, 27 , betacellulin 28, 29 , epiregulin 30 or proheparin-binding EGF-like growth factor (HB-EGF) 31, 32 . As many biological processes can be regulated through ERBB, the functional consequences of the modified ERBB abundance and phosphorylation state in diabetes are difficult to predict.…”

Section: Discussionmentioning

confidence: 99%

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

Ennequin

Capel

Caillaud

et al. 2017

Sci Rep

View full text Add to dashboard Cite

It has been reported that neuregulin1 (NRG1) improves glucose tolerance in healthy and diabetic rodents. In vitro studies also suggest that NRG1 regulates myocyte oxidative capacity. To confirm this observation in vivo, we evaluated the effect on mitochondrial function of an 8-week treatment with NRG1 in db/db diabetic mice and C57BL/6JRJ healthy controls. NRG1 treatment improved complex 2-mediated mitochondrial respiration in the gastrocnemius of both control and diabetic mice and increased mitochondrial complex 2 subunit content by 2-fold. This effect was not associated with an increase in mitochondrial biogenesis markers. Enhanced ERBB4 phosphorylation could mediate NRG1 effects on mitochondrial function through signalling pathways, independently of ERK1/2, AKT or AMPK.

show abstract

“…For example, EGF alone or combination with gastrin increased insulin secretion and beta cell numbers [33], and EGF treatment increased serum insulin levels and lowered blood glucose levels in diabetic mice [34]. Transforming growth factor-α increased beta cell growth and differentiation [35], and epiregulin, another EGF receptor ligand, stimulated beta cell proliferation and insulin release in pancreatic beta cell lines [36]. The functional redundancies of various EGF ligands suggest that EGF receptor binding with ligands via a conserved motif might be important mediators of beta cell mass regulation.…”

Section: Discussionmentioning

confidence: 99%

Betacellulin-Induced Beta Cell Proliferation and Regeneration Is Mediated by Activation of ErbB-1 and ErbB-2 Receptors

Shin

Lee

et al. 2011

PLoS ONE

View full text Add to dashboard Cite

BackgroundBetacellulin (BTC), a member of the epidermal growth factor family, is known to play an important role in regulating growth and differentiation of pancreatic beta cells. Growth-promoting actions of BTC are mediated by epidermal growth factor receptors (ErbBs), namely ErbB-1, ErbB-2, ErbB-3 and ErbB-4; however, the exact mechanism for beta cell proliferation has not been elucidated. Therefore, we investigated which ErbBs are involved and some molecular mechanisms by which BTC regulates beta cell proliferation.Methodology/Principal FindingsThe expression of ErbB-1, ErbB-2, ErbB-3, and ErbB-4 mRNA was detected by RT-PCR in both a beta cell line (MIN-6 cells) and C57BL/6 mouse islets. Immunoprecipitation and western blotting analysis showed that BTC treatment of MIN-6 cells induced phosphorylation of only ErbB-1 and ErbB-2 among the four EGF receptors. BTC treatment resulted in DNA synthetic activity, cell cycle progression, and bromodeoxyuridine (BrdU)-positive staining. The proliferative effect was blocked by treatment with AG1478 or AG825, specific tyrosine kinase inhibitors of ErbB-1 and ErbB-2, respectively. BTC treatment increased mRNA and protein levels of insulin receptor substrate-2 (IRS-2), and this was blocked by the ErbB-1 and ErbB-2 inhibitors. Inhibition of IRS-2 by siRNA blocked cell cycle progression induced by BTC treatment. Streptozotocin-induced diabetic mice injected with a recombinant adenovirus expressing BTC and treated with AG1478 or AG825 showed reduced islet size, reduced numbers of BrdU-positive cells in the islets, and did not attain BTC-mediated remission of diabetes.Conclusions/SignificanceThese results suggest that BTC exerts proliferative activity on beta cells through the activation of ErbB-1 and ErbB-2 receptors, which may increase IRS-2 expression, contributing to the regeneration of beta cells.

show abstract

Effect of epiregulin on pancreatic beta cell growth and insulin secretion

Cited by 12 publications

References 35 publications

HB-EGF Signaling Is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

HB-EGF Signaling Is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

Betacellulin-Induced Beta Cell Proliferation and Regeneration Is Mediated by Activation of ErbB-1 and ErbB-2 Receptors

Contact Info

Product

Resources

About