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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.
Author Information (click to view)

Billiard F, Karaliota S, Wang B, Stellas D, Serafimidis I, Manousopoulou A, Koutmani Y, Ninou E, Golubov J, DaNave A, Tsakanikas P, Xin Y, Zhang W, Sleeman M, Yancopoulos GD, Murphy AJ, Garbis SD, Karalis K, Skokos D,


Billiard F, Karaliota S, Wang B, Stellas D, Serafimidis I, Manousopoulou A, Koutmani Y, Ninou E, Golubov J, DaNave A, Tsakanikas P, Xin Y, Zhang W, Sleeman M, Yancopoulos GD, Murphy AJ, Garbis SD, Karalis K, Skokos D, (click to view)

Billiard F, Karaliota S, Wang B, Stellas D, Serafimidis I, Manousopoulou A, Koutmani Y, Ninou E, Golubov J, DaNave A, Tsakanikas P, Xin Y, Zhang W, Sleeman M, Yancopoulos GD, Murphy AJ, Garbis SD, Karalis K, Skokos D,

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Cell reports 2018 01 2822(4) 895-904 pii S2211-1247(17)31913-7
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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