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Delta-like ligand-4-notch signaling inhibition regulates pancreatic islet function and insulin secretion

Delta-like ligand-4-notch signaling inhibition regulates pancreatic islet function and insulin secretion
Delta-like ligand-4-notch signaling inhibition regulates pancreatic islet function and insulin secretion
Although Notch signaling has been proposed as a therapeutic target for type-2 diabetes, liver steatosis, and atherosclerosis, its direct effect on pancreatic islets remains unknown. Here, we demonstrated a function of Dll4-Notch signaling inhibition on the biology of insulin-producing cells. We confirmed enhanced expression of key Notch signaling genes in purified pancreatic islets from diabetic NOD mice and showed that treatment with anti-Dll4 antibody specifically abolished Notch signaling pathway activation. Furthermore, we showed that Notch inhibition could drive proliferation of β-islet cells and confer protection from the development of STZ-induced diabetes. Importantly, inhibition of the Dll4 pathway in WT mice increased insulin secretion by inducing the differentiation of pancreatic β-islet cell progenitors, as well as the proliferation of insulin-secreting cells. These findings reveal a direct effect of Dll4-blockade on pancreatic islets that, in conjunction with its immunomodulatory effects, could be used for unmet medical needs hallmarked by inefficient insulin action.
2211-1247
895-904
Billard, Fabienne
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Karalis, Katia P.
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Karaliota, Sevasti
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Wing, Bei
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Stellas, Dimitrios
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Serafimidis, Ioannis
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Manousopoulou, Antigoni
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Koutmani, Yiassemi
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Ninou, Elpiniki
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Golubov, Jacquelynn
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DaNave, Amanda
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Tsakanikas, Panagiotis
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Xin, Yurong
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Zhang, Wen
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Sleeman, Matthew
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Yancopoulos, George D.
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Murphy, Andrew
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Garbis, Spiros D.
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Karalis, Katia P.
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Skokos, Dimitris
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Billard, Fabienne
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Karalis, Katia P.
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Karaliota, Sevasti
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Wing, Bei
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Stellas, Dimitrios
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Serafimidis, Ioannis
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Manousopoulou, Antigoni
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Koutmani, Yiassemi
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Ninou, Elpiniki
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Golubov, Jacquelynn
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DaNave, Amanda
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Tsakanikas, Panagiotis
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Xin, Yurong
cea55508-6b8f-4ce2-8cee-51d683c38185
Zhang, Wen
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Sleeman, Matthew
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Yancopoulos, George D.
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Murphy, Andrew
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Garbis, Spiros D.
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Karalis, Katia P.
6f2e686f-a238-4c9e-9801-05fab311f0af
Skokos, Dimitris
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Billard, Fabienne, Karalis, Katia P., Karaliota, Sevasti, Wing, Bei, Stellas, Dimitrios, Serafimidis, Ioannis, Manousopoulou, Antigoni, Koutmani, Yiassemi, Ninou, Elpiniki, Golubov, Jacquelynn, DaNave, Amanda, Tsakanikas, Panagiotis, Xin, Yurong, Zhang, Wen, Sleeman, Matthew, Yancopoulos, George D., Murphy, Andrew, Garbis, Spiros D., Karalis, Katia P. and Skokos, Dimitris (2018) Delta-like ligand-4-notch signaling inhibition regulates pancreatic islet function and insulin secretion. Cell Reports, 22 (4), 895-904. (doi:10.1016/j.celrep.2017.12.076).

Record type: Article

Abstract

Although Notch signaling has been proposed as a therapeutic target for type-2 diabetes, liver steatosis, and atherosclerosis, its direct effect on pancreatic islets remains unknown. Here, we demonstrated a function of Dll4-Notch signaling inhibition on the biology of insulin-producing cells. We confirmed enhanced expression of key Notch signaling genes in purified pancreatic islets from diabetic NOD mice and showed that treatment with anti-Dll4 antibody specifically abolished Notch signaling pathway activation. Furthermore, we showed that Notch inhibition could drive proliferation of β-islet cells and confer protection from the development of STZ-induced diabetes. Importantly, inhibition of the Dll4 pathway in WT mice increased insulin secretion by inducing the differentiation of pancreatic β-islet cell progenitors, as well as the proliferation of insulin-secreting cells. These findings reveal a direct effect of Dll4-blockade on pancreatic islets that, in conjunction with its immunomodulatory effects, could be used for unmet medical needs hallmarked by inefficient insulin action.

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Billiard et al_NOTCH-Insulin Signaling_2018-Cell Reports - Version of Record
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Accepted/In Press date: 21 December 2017
e-pub ahead of print date: 28 January 2018
Published date: January 2018

Identifiers

Local EPrints ID: 417701
URI: http://eprints.soton.ac.uk/id/eprint/417701
ISSN: 2211-1247
PURE UUID: c176ede4-67ab-4da7-8fea-89bbaf4a006f
ORCID for Spiros D. Garbis: ORCID iD orcid.org/0000-0002-1050-0805

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Date deposited: 12 Feb 2018 17:30
Last modified: 15 Mar 2024 18:16

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Contributors

Author: Fabienne Billard
Author: Katia P. Karalis
Author: Sevasti Karaliota
Author: Bei Wing
Author: Dimitrios Stellas
Author: Ioannis Serafimidis
Author: Antigoni Manousopoulou
Author: Yiassemi Koutmani
Author: Elpiniki Ninou
Author: Jacquelynn Golubov
Author: Amanda DaNave
Author: Panagiotis Tsakanikas
Author: Yurong Xin
Author: Wen Zhang
Author: Matthew Sleeman
Author: George D. Yancopoulos
Author: Andrew Murphy
Author: Spiros D. Garbis ORCID iD
Author: Katia P. Karalis
Author: Dimitris Skokos

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