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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
64c4598c-29fc-4185-ac58-d46968881248
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
8e6c2f32-c700-451a-b9d1-7c91534cec99
Billard, Fabienne
64c4598c-29fc-4185-ac58-d46968881248
Karalis, Katia P.
6f2e686f-a238-4c9e-9801-05fab311f0af
Karaliota, Sevasti
8fe53657-8046-4143-8dca-cae54e00dee8
Wing, Bei
cb7b7d1a-2853-4237-81ad-4ff1e6f64180
Stellas, Dimitrios
14b5298b-a363-4e49-9b19-c859250ecadd
Serafimidis, Ioannis
57303540-9a3f-4e6b-849a-9f3125c50eb7
Manousopoulou, Antigoni
9a5e4e75-cea9-4d0b-91c8-0fa2af02632f
Koutmani, Yiassemi
d1c698f7-2233-4186-86c3-bcfbe5ec57dc
Ninou, Elpiniki
82ebd576-369c-4a43-82f2-13a422c8f24b
Golubov, Jacquelynn
2ec4cd0e-ea3a-4895-a092-54d73260c7b0
DaNave, Amanda
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Tsakanikas, Panagiotis
7434da65-d694-40d5-b80c-31ba682d80ab
Xin, Yurong
cea55508-6b8f-4ce2-8cee-51d683c38185
Zhang, Wen
f50628f4-242a-49cc-ab62-61b481a7ead8
Sleeman, Matthew
e748146f-38f5-4fb0-8965-64d409d5b70b
Yancopoulos, George D.
8318b2fd-fb61-4a9d-950d-c0be6401f46b
Murphy, Andrew
59d42076-5f3d-40f5-8b32-ce995fd67371
Garbis, Spiros D.
7067fd19-50c9-4d42-9611-f370289470bd
Karalis, Katia P.
6f2e686f-a238-4c9e-9801-05fab311f0af
Skokos, Dimitris
8e6c2f32-c700-451a-b9d1-7c91534cec99

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.

Text 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: https://eprints.soton.ac.uk/id/eprint/417701
ISSN: 2211-1247
PURE UUID: c176ede4-67ab-4da7-8fea-89bbaf4a006f

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Date deposited: 12 Feb 2018 17:30
Last modified: 27 Jun 2018 16:31

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