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Notch signaling dynamically regulates adult β cell proliferation and maturity
Alberto Bartolome, … , Lori Sussel, Utpal B. Pajvani
Alberto Bartolome, … , Lori Sussel, Utpal B. Pajvani
Published January 2, 2019; First published October 30, 2018
Citation Information: J Clin Invest. 2019;129(1):268-280. https://doi.org/10.1172/JCI98098.
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Categories: Research Article Endocrinology Metabolism

Notch signaling dynamically regulates adult β cell proliferation and maturity

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Abstract

Notch signaling regulates differentiation of the pancreatic endocrine lineage during embryogenesis, but the role of Notch in mature β cells is unclear. We found that islets derived from lean mice show modest β cell Notch activity, which increases in obesity and in response to high glucose. This response appeared maladaptive, as mice with β cell–specific–deficient Notch transcriptional activity showed improved glucose tolerance when subjected to high-fat diet feeding. Conversely, mice with β cell–specific Notch gain of function (β-NICD) had a progressive loss of β cell maturity, due to proteasomal degradation of MafA, leading to impaired glucose-stimulated insulin secretion and glucose intolerance with aging or obesity. Surprisingly, Notch-active β cells had increased proliferative capacity, leading to increased but dysfunctional β cell mass. These studies demonstrate a dynamic role for Notch in developed β cells for simultaneously regulating β cell function and proliferation.

Authors

Alberto Bartolome, Changyu Zhu, Lori Sussel, Utpal B. Pajvani

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Figure 5

Notch activation and reduced maturity in proliferating β cells.

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Notch activation and reduced maturity in proliferating β cells.
(A) Repr...
(A) Representative images of pancreatic sections from day 15 (D15) pregnant (D15) WT mice and quantitation expressed as average MafA fluorescence intensity of BrdU+ and BrdU– populations (n = 5 mice/group). Individual cells are plotted in Supplemental Figure 6A. (B) Representative images of pancreatic sections from pregnant (D15) mice stained for BrdU as well as antibodies directed against insulin and Pdx1, Neurod1, or Ucn3 (n = 5 mice/group). (C) Representative images of pancreatic sections from virgin and pregnant (D15) TNR mice, with quantitation of percentage of GFP+ β cells (n = 4–5 mice/group). (D) Representative images of pancreatic sections from pregnant (D15) TNR mice showing Ki67, insulin, and GFP reporter staining (top), with increased magnification of the boxed region (bottom). Arrows indicate Ki67+ β cells. Quantitation of percentage of GFP+ β cells or percentage of GFP+Ki67+ β cells (n = 5 mice/group; overall count of 3995 total β cells and 188 Ki67+ β cells). (E) Quantitation of average MafA fluorescence intensity in GFP– and GFP+ β cells from chow-fed TNR mice, normalized to average value in GFP– cells (n = 5 mice). Approximately 1000 cells quantified per pancreas. Scale bars: 20 μm. All data are shown with group means. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed t test.
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