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.
背景: 使用GABA或者胰高血糖素样肽-1(GLP-1)治疗可以维持胰腺β细胞的数量并且预防糖尿病。最近，我们报道了小鼠联合使用GABA与西格列汀(一种可以增加内源性GLP-1的二肽基肽酶-4抑制剂)治疗后，在减少药物诱导的β-细胞损伤以及促进β-细胞再生方面比单独使用这两种药物治疗更加有效。然而，在人类胰岛中目前尚未明确GABA与GLP-1是否能够发挥类似的作用。 方法: 为了研究GABA与GLP-1之间的相互作用，对人类胰岛或者INS-1细胞进行GABA和/或艾塞那肽(一种临床上正在使用的GLP-1受体激动剂，GLP-1RA)处理，并且用细胞因子混合物培养了24小时。分别使用蛋白质印迹法与流式细胞分析法，检测分离的细胞凋亡蛋白酶-3与膜联蛋白V结合力对细胞因子诱导凋亡的影响。 结果: 单独使用GABA或者艾塞那肽治疗都可以减少细胞因子诱导的凋亡。联合使用GABA与艾塞那肽治疗后更加显著地改善了这一点，从而逆转了细胞凋亡。联合治疗可以显著加强Akt通路的信号传导。此外，有研究报道，sirtuin-1(sirt1)与α-klotho对β细胞都具有保护作用，联合治疗后两者的浓度都增加了。重要的是，联合使用这两种药物治疗后人类β细胞的胰岛素分泌功能得到了改善。 结论: 联合使用GABA与GLP-1RA治疗对β细胞的存活以及功能具有叠加效应，提示在治疗糖尿病患者时这种联合治疗方案可能要优于单用这两种药物。.
Keywords: GABA; GLP-1; apoptosis; human islets; β-cells; β-细胞。; 人类胰岛; 凋亡.
© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.