School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland BT52 1SA, UK.
School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland BT52 1SA, UK.
Biochem Pharmacol. 2022 May;199:115019. doi: 10.1016/j.bcp.2022.115019. Epub 2022 Mar 28.
Poorly controlled diabetes is characterised by a partial or complete loss of pancreatic islet β-cells, which deprives the remaining islet cells of important β-cell-derived soluble signals, such as insulin or GABA. We aimed to dissect the role of the two signals in the development of islet α-cells, focusing specifically on α-/β-cell transdifferentiation and using the stem cell differentiation factor nicotinamide as a comparator.
Streptozotocin (STZ)-treated diabetic mice expressing a fluorescent reporter in pancreatic islet α-cells were injected with GABA (10 mg/kg once daily), nicotinamide (150 mg/kg once daily) or insulin (1U/kg three times daily) for 10 days. The impact of the treatment on metabolic status of the animals as well as the morphology, proliferative potential and transdifferentiation of pancreatic islet cells was assessed using biochemical methods and immunofluorescence.
Metabolic status of STZ-diabetic mice was not dramatically altered by the treatment interventions, although GABA therapy did reduce circulating glucagon and augment pancreatic insulin stores. The effects of the exogenous agents on islet β-cells ranged from the attenuation of apoptosis (insulin, nicotinamide) to enhancement of proliferation (GABA). Furthermore, insulin and GABA but not nicotinamide enhanced the differentiation of α-cells into β-cells and increased relative number of 'bihormonal' cells, expressing both insulin and glucagon.
Our data suggest a role for endogenous insulin and GABA signalling in α-cell plasticity, which is likely to bypass the common nicotinamide-sensitive stem cell differentiation pathway.
未得到良好控制的糖尿病的特征是胰岛β细胞的部分或完全丧失，这剥夺了剩余胰岛细胞重要的β细胞衍生的可溶性信号，如胰岛素或 GABA。我们旨在剖析这两种信号在胰岛α细胞发育中的作用，特别关注α-/β细胞转分化，并使用干细胞分化因子烟酰胺作为比较。
用表达荧光报告基因的胰岛α细胞的链脲佐菌素（STZ）处理的糖尿病小鼠，每日一次腹腔注射 GABA（10mg/kg）、烟酰胺（150mg/kg）或胰岛素（1U/kg，每日三次），共 10 天。通过生化方法和免疫荧光评估治疗对动物代谢状态以及胰岛细胞形态、增殖潜力和转分化的影响。
治疗干预并未显著改变 STZ 糖尿病小鼠的代谢状态，尽管 GABA 治疗确实降低了循环胰高血糖素并增加了胰腺胰岛素储存。外源性物质对胰岛β细胞的影响范围从抑制细胞凋亡（胰岛素、烟酰胺）到促进增殖（GABA）。此外，胰岛素和 GABA 但不是烟酰胺增强了α细胞向β细胞的分化，并增加了表达胰岛素和胰高血糖素的“双激素”细胞的相对数量。
我们的数据表明内源性胰岛素和 GABA 信号在α细胞可塑性中起作用，这可能绕过常见的烟酰胺敏感的干细胞分化途径。
