Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication.
A key goal of diabetes research is to develop treatments to safely promote human ß-cell replication. It has recently become appreciated that activation of γ-aminobutyric acid receptors (GABA-Rs) on ß-cells can promote their survival and replication. A number of positive allosteric modulators (PAMs) that enhance GABA's actions on neuronal GABAA-Rs are in clinical use. Repurposing these GABAA-R PAMs to help treat diabetes is theoretically appealing because of their safety and potential to enhance the ability of GABA, secreted from ß-cells, or exogenously administered, to promote ß-cell replication and survival. Here, we show that clinically applicable GABAA-R PAMs can increase significantly INS-1 ß-cell replication, which is enhanced by exogenous GABA application. Furthermore, a GABAA-R PAM promoted human islet cell replication in vitro. This effect was abrogated by a GABAA-R antagonist. The combination of a PAM and low levels of exogenous GABA further increased human islet cell replication. These findings suggest that PAMs may potentiate the actions of GABA secreted by islet ß-cells on GABAA-Rs and provide a new class of drugs for diabetes treatment. Finally, our findings may explain a past clinical observation of a GABAA-R PAM reducing HbA1c levels in diabetic patients.
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA. jtian@mednet.ucla.edu.
Jide
J
Tian
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA.
Hoa
H
Dang
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA.
Blake
B
Middleton
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA. dkaufman@mednet.ucla.edu.
Daniel L
DL
Kaufman
D000494:Allosteric Regulation; D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002998:Clonazepam / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008874:Midazolam / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000096:biosynthesis*
D002352:Carrier Proteins; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C069997:Tspo protein, rat; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; D008874:Midazolam; D000525:Alprazolam