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)...

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Autores principales:	Jide Tian, Hoa Dang, Blake Middleton, Daniel L. Kaufman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/699c7694478c4951878f8b73c833f82b
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spelling	oai:doaj.org-article:699c7694478c4951878f8b73c833f82b2021-12-02T16:06:38ZClinically applicable GABA receptor positive allosteric modulators promote ß-cell replication10.1038/s41598-017-00515-y2045-2322https://doaj.org/article/699c7694478c4951878f8b73c833f82b2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00515-yhttps://doaj.org/toc/2045-2322A 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.Jide TianHoa DangBlake MiddletonDaniel L. KaufmanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-7 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jide Tian Hoa Dang Blake Middleton Daniel L. Kaufman Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication
description	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.
format	article
author	Jide Tian Hoa Dang Blake Middleton Daniel L. Kaufman
author_facet	Jide Tian Hoa Dang Blake Middleton Daniel L. Kaufman
author_sort	Jide Tian
title	Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication
title_short	Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication
title_full	Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication
title_fullStr	Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication
title_full_unstemmed	Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication
title_sort	clinically applicable gaba receptor positive allosteric modulators promote ß-cell replication
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/699c7694478c4951878f8b73c833f82b
work_keys_str_mv	AT jidetian clinicallyapplicablegabareceptorpositiveallostericmodulatorspromoteßcellreplication AT hoadang clinicallyapplicablegabareceptorpositiveallostericmodulatorspromoteßcellreplication AT blakemiddleton clinicallyapplicablegabareceptorpositiveallostericmodulatorspromoteßcellreplication AT daniellkaufman clinicallyapplicablegabareceptorpositiveallostericmodulatorspromoteßcellreplication
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Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication

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