Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication
The activation of β-cell’s A- and B-type gamma-aminobutyric acid receptors (GABAA-Rs and GABAB-Rs) can promote their survival and replication, and the activation of α-cell GABAA-Rs promotes their conversion into β-cells. However, GABA and the most clinically applicable GABA-R ligands may be suboptim...
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| Format: | Article |
| Language: | English |
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Wiley
2017-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2017/6403539 |
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| author | Jide Tian Hoa Dang Angela Hu Willem Xu Daniel L. Kaufman |
| author_facet | Jide Tian Hoa Dang Angela Hu Willem Xu Daniel L. Kaufman |
| author_sort | Jide Tian |
| collection | DOAJ |
| description | The activation of β-cell’s A- and B-type gamma-aminobutyric acid receptors (GABAA-Rs and GABAB-Rs) can promote their survival and replication, and the activation of α-cell GABAA-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 GABAB-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 GABAB-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 GABAA-Rs and GABAB-Rs), perhaps because of its more favorable pharmacokinetics. Lesogaberan may be a promising drug candidate for clinical studies of diabetes intervention and islet transplantation. |
| format | Article |
| id | doaj-art-0380ce1814274475932802055fa49923 |
| institution | Kabale University |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-0380ce1814274475932802055fa499232025-02-03T05:58:57ZengWileyJournal of Diabetes Research2314-67452314-67532017-01-01201710.1155/2017/64035396403539Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell ReplicationJide Tian0Hoa Dang1Angela Hu2Willem Xu3Daniel L. Kaufman4Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USADepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USADepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USADepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USADepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USAThe activation of β-cell’s A- and B-type gamma-aminobutyric acid receptors (GABAA-Rs and GABAB-Rs) can promote their survival and replication, and the activation of α-cell GABAA-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 GABAB-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 GABAB-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 GABAA-Rs and GABAB-Rs), perhaps because of its more favorable pharmacokinetics. Lesogaberan may be a promising drug candidate for clinical studies of diabetes intervention and islet transplantation.http://dx.doi.org/10.1155/2017/6403539 |
| spellingShingle | Jide Tian Hoa Dang Angela Hu Willem Xu Daniel L. Kaufman Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication Journal of Diabetes Research |
| title | Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication |
| title_full | Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication |
| title_fullStr | Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication |
| title_full_unstemmed | Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication |
| title_short | Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication |
| title_sort | repurposing lesogaberan to promote human islet cell survival and β cell replication |
| url | http://dx.doi.org/10.1155/2017/6403539 |
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