Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication

Sci Rep. 2017 Mar 23;7(1):374. doi: 10.1038/s41598-017-00515-y.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Alprazolam / pharmacology
  • Animals
  • Benzodiazepines / pharmacology*
  • Carrier Proteins / metabolism
  • Cell Division / drug effects*
  • Cell Proliferation / drug effects*
  • Clonazepam / pharmacology
  • GABA Modulators / pharmacology
  • GABA-A Receptor Antagonists / administration & dosage
  • Humans
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / physiology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / physiology
  • Mice
  • Midazolam / pharmacology
  • Rats
  • Receptors, GABA-A / metabolism
  • Receptors, GABA-A / physiology*
  • gamma-Aminobutyric Acid / administration & dosage
  • gamma-Aminobutyric Acid / biosynthesis*


  • Carrier Proteins
  • GABA Modulators
  • GABA-A Receptor Antagonists
  • Receptors, GABA-A
  • Benzodiazepines
  • Tspo protein, rat
  • gamma-Aminobutyric Acid
  • Clonazepam
  • Midazolam
  • Alprazolam