Research Article Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication Jide Tian, Hoa Dang, Angela Hu, Willem Xu, and Daniel L. Kaufman Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA Correspondence should be addressed to Daniel L. Kaufman; dkaufman@mednet.ucla.edu Received 12 May 2017; Accepted 26 July 2017; Published 5 September 2017 Academic Editor: Peter Thule Copyright © 2017 Jide Tian et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The activation of β-cell’s A- and B-type gamma-aminobutyric acid receptors (GABA A -Rs and GABA B -Rs) can promote their survival and replication, and the activation of α-cell GABA A -Rs promotes their conversion into β-cells. However, GABA and the most clinically applicable GABA-R ligands may be suboptimal for the long-term treatment of diabetes due to their pharmacological properties or potential side-effects on the central nervous system (CNS). Lesogaberan (AZD3355) is a peripherally restricted high-affinity GABA B -R-specific agonist, originally developed for the treatment of gastroesophageal reflux disease (GERD) that appears to be safe for human use. This study tested the hypothesis that lesogaberan could be repurposed to promote human islet cell survival and β-cell replication. Treatment with lesogaberan significantly enhanced replication of human islet cells in vitro, which was abrogated by a GABA B -R antagonist. Immunohistochemical analysis of human islets that were grafted into immune-deficient mice revealed that oral treatment with lesogaberan promoted human β-cell replication and islet cell survival in vivo as effectively as GABA (which activates both GABA A -Rs and GABA B -Rs), perhaps because of its more favorable pharmacokinetics. Lesogaberan may be a promising drug candidate for clinical studies of diabetes intervention and islet transplantation. 1. Introduction A major goal in diabetes research is to develop agents that can safely promote human β-cell survival and replication. Most mitogens and growth factors that have been shown to promote rodent β-cell replication fail to promote human β-cell replication (reviewed in [1, 2]). β-Cells have been long known to express the GABA synthetic enzyme glutamic acid decarboxylase (GAD), as well as GABA A -Rs and GABA B -Rs [3–7]. Although GABA A -Rs and GABA B -Rs share GABA as an agonist, these receptors are encoded by distinct gene families and their activation induces different pathways; GABA A -Rs are fast-acting chloride channels and GABA B -Rs are slow-acting G-protein-coupled receptors [8, 9]. Recently, GABA administration has been shown to protect rodent and human β-cells from apoptosis and to promote their replica- tion both in vitro and in vivo [10–14]. This response is medi- ated by both GABA A -R and GABA B -Rs [10–12, 14, 15]. GABA-mediated enhancement of β-cell replication did not attenuate after five weeks of GABA treatment and led to an eventual increase in β-cell mass in a nonautoimmune context [14]. Notably, GABA treatment enhanced β-cell replication and survival in newly diabetic NOD mice [11, 16, 17], indicat- ing that GABA-R activation can be beneficial in an autoim- mune context even when little β-cell mass remains. β-Cells express GABA A -Rs and GABA B -Rs [3, 4, 7, 18, 19]. α-Cells express GABA A -Rs but may not express functional GABA B -Rs, while PCR detects GABA B -R transcripts in iso- lated α-cells (but not the α-cell line α-TC9), a GABA B -R agonist failed to modulate any of the tested α-cell functions [3, 18–21]. We are unaware of any evidence of functional GABA B -Rs on δ or PP islet cells. Very recently, long- term treatment with antimalarial drugs that target gephyrin (a protein that participates in GABA A -R transport to the membrane), or treatment with GABA, was shown to pro- mote islet α-cell transdifferentiation into β-cells [22, 23]. Hindawi Journal of Diabetes Research Volume 2017, Article ID 6403539, 7 pages https://doi.org/10.1155/2017/6403539