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

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.

Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies

“…However, whereas a treatment with long lasting analogues such as liraglutide or dulaglutide are able to promote pancreatic beta-cell proliferation in diabetic db / db mice [ 151 , 152 ], in high-fat-fed and streptozotocin-induced [ 153 ] or alloxan-induced [ 154 ] mouse model of T2D, it is well accepted that adult human beta-cells have a limited capacity to proliferate [ 155 ]. On the contrary, many studies have identified in rodent and human that GLP-1RA alleviate beta-cell apoptosis [ 151 , 156 , 157 , 158 , 159 ] induced by several stressors such as gluco/lipotoxicity [ 160 , 161 , 162 , 163 ], which may trigger oxidative [ 164 ] and ER stress [ 162 , 165 ], or by cytokines [ 166 , 167 , 168 , 169 ]. A reduced beta-cell apoptosis was also observed in diabetic db / db [ 152 ] and Akita [ 170 , 171 ] mice or prediabetic GK rats [ 172 ] chronically treated with GLP1-RA.…”

GABAergic regulation of pancreatic islet cells: Physiology and antidiabetic effects

“…It was superior at inducing regeneration as manifested by an increased number of small islets, and greater Ki67 + and PDX-1 + β-cell counts. Recently, in isolated human islets, we found that a combination of GABA and a GLP-1 receptor agonist (Exendin-4) was superior to either agents alone in T A B L E 2 GABA-mediated protection against β-cell apoptosis protecting human β cells against cytokine-induced apoptosis, and in stimulating insulin secretion (Son et al, 2018). Interestingly, in that study, the combination of these mediators increased Akt signaling, as well as SIRT1 and Klotho expression, in an additive way.…”

Single-cell RNA-seq with spike-in cells enables accurate quantification of cell-specific drug effects in pancreatic islets

“…Recent studies have demonstrated that artemether indeed improves glucose tolerance in multiple in vivo models [37][38][39][40][41][42]. Similarly, GABA has been reported to improve glucose homeostasis by alpha cell transdifferentiation or beta cell proliferation [43][44][45][46][47][48][49][50][51][52]. However, the mechanisms of artemether and GABA have been controversial, as two recent studies have not detected an increase in alpha cell-derived beta cells using lineage tracing models [8,41].…”