Articles

Notch signaling dynamically regulates adult β cell proliferation and maturity

Bartolomé, Alberto; Zhu, Changyu; Sussel, Lori; Pajvani, Utpal B.

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.

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Also Published In

Title
The Journal of Clinical Investigation
DOI
https://doi.org/10.1172/JCI98098

More About This Work

Academic Units
Medicine
Published Here
February 4, 2025