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A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
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Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication.
Jide Tian1, Hoa Dang2, Blake Middleton2
1Department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA. jtian@mednet.ucla.edu.
Scientific Reports
|March 25, 2017
Summary
Positive allosteric modulators (PAMs) for gamma-aminobutyric acid receptors (GABA-Rs) promote beta-cell replication in vitro. These findings suggest GABA-R PAMs as a potential new class of diabetes drugs.
Area of Science:
- Endocrinology
- Neuroscience
- Pharmacology
Background:
- Human beta-cell replication is crucial for diabetes treatment.
- Gamma-aminobutyric acid receptors (GABA-Rs) on beta-cells influence their survival and replication.
- Existing GABA-A receptor positive allosteric modulators (PAMs) are clinically approved.
Purpose of the Study:
- To investigate the potential of repurposing GABA-A receptor PAMs for diabetes treatment.
- To determine if GABA-A receptor PAMs can enhance beta-cell replication.
- To explore the combination therapy of PAMs and exogenous GABA.
Main Methods:
- In vitro studies using INS-1 beta-cells and human islet cells.
- Application of clinically available GABA-A receptor PAMs.
- Assessment of cell replication rates with and without GABA-A receptor antagonists and exogenous GABA.
Main Results:
- Clinically applicable GABA-A receptor PAMs significantly increased INS-1 beta-cell replication.
- A GABA-A receptor PAM promoted human islet cell replication in vitro.
- The combination of a PAM and low-dose exogenous GABA further enhanced human islet cell replication.
- The observed effects were blocked by a GABA-A receptor antagonist.
Conclusions:
- GABA-A receptor PAMs can potentiate the effects of GABA on beta-cells, promoting replication.
- These PAMs represent a potential new therapeutic class for diabetes.
- Findings may explain previous clinical observations of reduced HbA1c levels with GABA-A receptor PAMs.
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