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Notch signaling dynamically regulates adult β cell proliferation and maturity
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Notch signaling dynamically regulates adult β cell proliferation and maturity
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Journal Article
Notch signaling dynamically regulates adult β cell proliferation and maturity
2019
Overview
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.
Publisher
American Society for Clinical Investigation
Subject
/ Aging
/ Animals
/ Diabetes
/ Diet
/ Glucose
/ Glucose Intolerance - genetics
/ Glucose Intolerance - metabolism
/ Glucose Intolerance - pathology
/ Insulin
/ Insulin Secretion - drug effects
/ Insulin Secretion - genetics
/ Insulin-Secreting Cells - metabolism
/ Insulin-Secreting Cells - pathology
/ Ligands
/ Mice
/ Obesity
/ Pancreas
/ Receptors, Notch - metabolism
/ Rodents
