Delta-like Ligand-4-Notch Signaling Inhibition Regulates Pancreatic Islet Function and Insulin Secretion

• Published in: Cell reports (Cambridge) Vol. 22; no. 4; pp. 895 - 904
• Main Authors: Billiard, Fabienne, Karaliota, Sevasti, Wang, 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 J., Garbis, Spiros D., Karalis, Katia, Skokos, Dimitris
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.01.2018; Elsevier
• Subjects: delta-like ligand; diabetes; differentiation; insulin secretion; notch pathway; proliferation; β-cells; notch pathway; differentiation; proliferation; β-cells; insulin secretion; delta-like ligand; diabetes
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.12.076

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. [Display omitted] •Dll4-Notch signaling blockade preserves islets and reverses diabetes in NOD mice•Inhibition of the Dll4 pathway restores β-islet cell function in STZ-treated mice•Anti-Dll4 antibody enhances β-islet cell proliferation and differentiation•Islet Dll4-blockade may provide a target in compromised insulin-producing states The conserved Notch signaling pathway is required for adult tissue homeostasis. Billiard et al. show that Dll4-Notch signaling inhibition supports the health of β-islet cells and affects insulin production by driving differentiation of insulin-producing cell progenitors and blockade of islet apoptosis.