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

ABSTRACT: 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 ?-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 GABA_A-Rs are in clinical use. Repurposing these GABA_A-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 GABA_A-R PAMs can increase significantly INS-1 ß-cell replication, which is enhanced by exogenous GABA application. Furthermore, a GABA_A-R PAM promoted human islet cell replication in vitro. This effect was abrogated by a GABA_A-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 GABA_A-Rs and provide a new class of drugs for diabetes treatment. Finally, our findings may explain a past clinical observation of a GABA_A-R PAM reducing HbA1c levels in diabetic patients.

SUBMITTER: Tian J 

PROVIDER: S-EPMC5428733 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature