Dong Ok Son1,2, Wenjuan Liu1,3, Xiaoming Li1, Gerald J Prud'homme4,5, Qinghua Wang1,3,6,7. 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
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.
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.