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J Diabetes. 2019 Jul;11(7):563-572. doi: 10.1111/1753-0407.12881. Epub 2019 Jan 1.

Combined effect of GABA and glucagon-like peptide-1 receptor agonist on cytokine-induced apoptosis in pancreatic β-cell line and isolated human islets.

Son DO1,2, Liu W1,3, Li X1, Prud'homme GJ4,5, Wang Q1,3,6,7.

Author information

1
Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.
2
Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Canada.
3
Department of Endocrinology, Huashan Hospital, Medical School, Fudan University, Shanghai, China.
4
Department of Laboratory Medicine, St. Michael's Hospital, Toronto.
5
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
6
Department of Physiology, University of Toronto, Toronto, Canada.
7
Department of Medicine, University of Toronto, Toronto, Canada.

Abstract

in English, Chinese

BACKGROUND:

Treatment with GABA or glucagon-like peptide-1 (GLP-1) can preserve pancreatic β-cell mass and prevent diabetes. Recently, we reported that the combination of GABA and sitagliptin (a dipeptidyl peptidase-4 inhibitor that increases endogenous GLP-1) was more effective than either agent alone in reducing drug-induced β-cell damage and promoting β-cell regeneration in mice. However, in human islets, it remains unclear whether GABA and GLP-1 exert similar effects.

METHODS:

To investigate GABA and GLP-1 interactions, human islets or INS-1 cells were treated with GABA and/or exendin-4, a GLP-1 receptor agonist (GLP-1RA) in clinical use, and incubated with a cytokine mixture for 24 hours. Cleaved caspase-3 and annexin V binding were measured by western blot and flow cytometry analysis, respectively, to investigate effects on cytokine-induced apoptosis.

RESULTS:

Cytokine-induced apoptosis was reduced by either GABA or exendin-4 alone. This was markedly improved by combining GABA and exendin-4, resulting in a reversal of apoptosis. The combination notably increased Akt pathway signaling. Furthermore, sirtuin-1 (SIRT1) and α-Klotho, both reported to have protective effects on β-cells, were increased. Importantly, the combination ameliorated insulin secretion by human β-cells.

CONCLUSIONS:

The combination of GABA and a GLP-1RA exerted additive effects on β-cell survival and function, suggesting that this combination may be superior to either drug alone in the treatment of diabetes.

KEYWORDS:

GABA; GLP-1; apoptosis; human islets; β-cells; β-细胞。; 人类胰岛; 凋亡

PMID:
30520247
DOI:
10.1111/1753-0407.12881

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