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Updated: Aug 6, 2026
09:35
A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
Increased pancreatic beta-cell proliferation mediated by CREB binding protein gene activation
Mehboob A Hussain1, Delia L Porras, Matthew H Rowe
1Metabolism Division, Department of Pediatrics and Medicine, Johns Hopkins University, 600 N. Wolfe Street, CMSC 10-113, Baltimore, MD 21287, USA. mhussai4@jhmi.edu
Molecular and Cellular Biology
|August 16, 2006
Summary
Altering the cyclic AMP (cAMP) pathway in pancreatic beta cells increases beta-cell mass but reduces glucose-stimulated insulin secretion. This occurs due to sustained activation of CBP-responsive genes, including pgc1a.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Biology
Background:
- The cyclic AMP (cAMP) signaling pathway regulates pancreatic beta-cell function.
- Protein kinase A (PKA) phosphorylates CREB, recruiting transcriptional coactivators p300 and CREB binding protein (CBP).
- Insulin action causes serine 436 phosphorylation of CBP, disrupting CREB-CBP interaction and reducing nuclear cAMP signaling.
Purpose of the Study:
- To investigate the nuclear role of the cAMP-PKA-CREB-CBP pathway in pancreatic beta cells.
- To examine the effects of a mutation preventing insulin-dependent CBP phosphorylation on beta-cell function and mass.
Main Methods:
- Utilized mutant mice lacking the insulin-dependent phosphorylation site of CBP.
- Assessed islet and beta-cell mass, proliferation (in vivo and in vitro), and insulin secretion (glucose-stimulated and KCl-induced).
- Analyzed gene expression, specifically focusing on pgc1a transcripts.
Main Results:
- Mutant mice exhibited a twofold increase in islet and beta-cell mass with enhanced beta-cell proliferation.
- Glucose-stimulated insulin secretion was reduced in mutant islets, despite normal insulin synthesis and storage.
- Transcripts of pgc1a, a gene that impairs glucose-stimulated insulin secretion, were significantly elevated in mutant islets.
Conclusions:
- Sustained activation of CBP-responsive genes leads to increased beta-cell proliferation.
- In these beta cells, elevated pgc1a expression, mediated by CREB-CBP, diminishes glucose-stimulated insulin secretion.
- The study highlights a critical role for nuclear CBP phosphorylation in balancing beta-cell mass and function.
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