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

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 2

β Cell Notch activation prevents normal GSIS, leading to glucose intolerance.

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β Cell Notch activation prevents normal GSIS, leading to glucose intoler...
(A) GTT in chow-fed, adult β-NICD, and Cre– control mice (n = 7–8 mice/group). (B) GTT in chow-fed, 1 year-old β-NICD mice and Cre– control mice (n = 7–8 mice/group). (C) GTT in β-NICD and Cre– control mice fed HFD for 8 weeks (n = 8–10 mice/group). (D) GTT in chow-fed, adult β-NICD/Rbpj and Cre– control mice (n = 7 mice/group). (E) Plasma insulin postintraperitoneal glucose injection in chow-fed β-NICD and Cre– control mice (n = 5 mice/group). (F) GSIS in islets isolated from β-NICD and Cre– control mice, adjusted for islet insulin content (n = 4 mice/group). (G) Insulin content in islets isolated from β-NICD and Cre– control mice, adjusted for islet DNA content (n = 4 mice/group). (H) Gene expression in islets isolated from chow-fed β-NICD and Cre– control mice (n = 5 mice/group). (I) Representative images of pancreatic sections from β-NICD and Cre– control mice stained with antibodies directed against Hes1 (left) or Slc2a2 (right) (n = 5 mice/group). Scale bars: 20 μm. (J) Representative electron micrographs from 1-year-old β-NICD mice and Cre– control mice (top). Arrows represent immature vesicles, and arrowheads show mature vesicles. Scale bars: 500 nm. Quantitation of mature (over total) dense-core insulin vesicles (bottom left) and cytoplasmic area occupied by insulin vesicles (bottom right) (n = 2 mice/group). All data are shown with group means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed t test.