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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Research Article Endocrinology Metabolism

Notch signaling dynamically regulates adult β cell proliferation and maturity

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 6

Notch activation increases β cell proliferative capacity.

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Notch activation increases β cell proliferative capacity. (A) Quantitati...
(A) Quantitation of β cell mass in adult β-NICD and Cre– control mice (n = 5–7 mice/group). **P < 0.01, 2-tailed t test. (B) Representative images and quantitation of BrdU+ β cells in pancreatic sections from adult β-NICD and Cre– control mice (n = 5 mice/group). **P < 0.01, 2-tailed t test. (C) Quantitation of Ki67+ β cells in pancreatic sections from adult β-NICD and Cre– control mice (n = 5 mice/group). *P < 0.05, 2-tailed t test. (D) Representative images and quantitation of Ki67+ β cells in P14 pancreas in β-NICD and Cre– control mice (n = 6–8 mice/group). **P < 0.01, 2-tailed t test. (E) Quantitation of β cell mass in 1-year old β-NICD and Cre– mice (n = 5–6 mice/group). **P < 0.01, 2-tailed t test. (F) Representative images and quantitation of Ki67+ β cells in P14 pancreas in β-DNMAML and Cre– control mice (n = 4–5 mice/group). **P < 0.01, 2-tailed t test. (G) Quantitation of Ki67+Pdx1+ cells in islet cells dispersed from control (MIP-Cre–), DNMAML1 (MIP-CreERT+; R26-DNMAML/+), or NICD (MIP-CreERT+; R26-NICD/+) mice, grown in full medium containing 22 mM glucose and 1 μM 4-OHT for 4 days (n = 5–7 mice/group). *P < 0.05; ***P < 0.001, 1-way ANOVA and Dunnett’s multiple comparisons post hoc test. Representative images are shown in Supplemental Figure 6D. (H) Representative images and quantitation of Ki67+ β cells in pancreatic sections from pregnant (D15) β-NICD and Cre– control females (n = 4–6 mice/group). **P < 0.01, 2-tailed t test. (I) Quantitation of Ki67+ β cells in pancreatic sections of pregnant (D15) β-Rbpj and Cre– control females (n = 4–5 mice/group). *P < 0.05, 2-tailed t test. Scale bars: 20 μm. All data are shown with group means.