Combined use of GABA and sitagliptin promotes human β-cell proliferation and reduces apoptosis

in Journal of Endocrinology
Authors:
Wenjuan Liu Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China

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Harry Kevin Lau Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada

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Dong Ok Son Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada

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Tianru Jin Department of Physiology, University of Toronto, Toronto, Ontario, Canada
Division of Advanced Diagnostics, Toronto General Research Institutes, University Health Network, Toronto, Ontario, Canada
Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada

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Yehong Yang Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China

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Zhaoyun Zhang Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China

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Yiming Li Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China

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Gerald J Prud’homme Department of Laboratory Medicine and Pathobiology, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

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Qinghua Wang Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China

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Correspondence should be addressed to G J Prud’homme or Q Wang: gerald.prudhomme@utoronto.ca or Qinghua.Wang@unityhealth.to
DOI:
https://doi.org/10.1530/JOE-20-0315
Volume/Issue:
Volume 248: Issue 2
Article Type:
Research Article
Page Range:
133–143
Online Publication Date:
Feb 2021
Copyright:
© 2021 Society for Endocrinology 2021
Collections:
Top-cited articles of 2023
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γ-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent β-cell survival and function. In human β-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic β-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human β-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human β-cell counts and plasma human insulin levels. Importantly, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ β-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on β cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of β-cell proliferation and a decrease in apoptosis.

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Sept 2018 onwards Past Year Past 30 Days
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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
11
Article Type:
Research Article
Received Date:
21 Sep 2020
Accepted Date:
25 Nov 2020
Print Publication Date:
01 Feb 2021
Online Publication Date:
Feb 2021
Keywords:
GABA; sitagliptin; human islet; β-cell; type 1 diabetes

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