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Effects of sustained GABA releasing implants on pancreatic islets in mice

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Abstract

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that is strongly and selectively synthesized in and secreted from pancreatic beta cells. Exogenously delivered GABA has been proposed to induce beta cell regeneration in type 1 diabetes, but these results have been difficult to replicate and may depend on the specifics of the animal model and drug delivery method used. Here, we developed a GABA-releasing ethylene-vinyl acetate polymer implant for sustained GABA delivery to the intraperitoneal space as an alternative to injected or oral GABA. We explored the effect of the GABA-releasing polymer implants compared to implanted osmotic pumps loaded with GABA on islet size in non-diabetic, outbred mice. We also attempted to monitor in vivo GABA release using HPLC on blood samples, but these measurements were confounded by high variability within treatment groups and unexpectedly high serum GABA levels in mice receiving GABA-negative implants. The ethylene-vinyl acetate polymer implants became heavily fibrosed with abdominal adhesion tissue, while the osmotic pumps had no macroscopic fibrosis. Histological analysis showed no significant effect of the sustained GABA delivery polymer or osmotic pumps on islet size, alpha cell to beta cell ratio, or the number of Ki67-positive islet cells. The GABA treatment time course was limited to two weeks due to the drug-release window of the polymer, while others reported islet-trophic effects of GABA after 10 to 12 weeks of treatment. In summary, our study is consistent with the concept that exogenous GABA administration does not significantly alter islet cell mass in non-diabetic CD-1 mice in the short-term. However, more data are needed including higher GABA doses and more prolonged treatment regimens for a better comparison with contrasting reports.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

We thank the Molecular Pathology Core, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, for tissue processing and staining service.

Funding

Funding support was provided by the intramural funding programs of the J. Crayton Pruitt Family Department of Biomedical Engineering and the Herbert Wertheim College of Engineering at the University of Florida (E.P.) and by the University of Florida Center for Undergraduate Research, University Scholars Program (K.L.).

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  1. J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA

    Kevin C. Ling, D. Walker Hagan, Jorge Santini-González & Edward A. Phelps

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  1. Kevin C. Ling
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  2. D. Walker Hagan
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Contributions

Data collection and analysis were performed by Kevin C. Ling, D. Walker Hagan, Jorge Santini-González, and Edward A. Phelps. The manuscript was written by Kevin C. Ling and Edward A. Phelps. All authors read and commented on previous versions of the manuscript and approved the final manuscript.

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Correspondence to Edward A. Phelps.

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Ling, K.C., Hagan, D.W., Santini-González, J. et al. Effects of sustained GABA releasing implants on pancreatic islets in mice. Drug Deliv. and Transl. Res. 11, 2198–2208 (2021). https://doi.org/10.1007/s13346-020-00886-2

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