NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin 300070, PR China.
NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin 300070, PR China.
J Diabetes Complications. 2019 Apr;33(4):267-277. doi: 10.1016/j.jdiacomp.2018.12.013. Epub 2019 Jan 2.
High glucose (HG)-induced pancreatic β-cell apoptosis may be a major contributor to the progression of diabetes mellitus (DM). NADPH oxidase (NOX2) has been considered a crucial regulator in β-cell apoptosis. This study was designed to evaluate the impact of GLP-1 receptor agonist (GLP-1Ra) liraglutide on pancreatic β-cell apoptosis in diabetes and the underlying mechanisms involved.
The diabetic rat models induced by streptozotocin (STZ) and a high fat diet (HFD) received 12 weeks of liraglutide treatment. Hyperglycemic clamp test was carried out to evaluate β-cell function in vivo. Flow cytometry analysis was used to measure apoptosis rates in vitro. DCFH-DA method was used to detected ROS level in vivo and in vitro.
Liraglutide significantly improved islet function and morphology in diabetic rats and decreased cell apoptosis rates. Thr183/Thr185 p-JNK1/2 and NOX2 levels reduced in diabetic rats and HG-induced INS-1 cell following liraglutide treatment. In addition, liraglutide upregulated the phosphorylation of AMPKα (p-AMPKα), which prevented NOX2 activation and alleviated HG-induced β-cell apoptosis.
The p-AMPKα/NOX2/JNK1/2 pathway is essential for liraglutide to attenuate HG-induced β-cell apoptosis, which further proves that GLP-1Ras may become promising therapeutics for diabetes mellitus.
高葡萄糖（HG）诱导的胰岛β细胞凋亡可能是糖尿病（DM）进展的主要原因。NADPH 氧化酶（NOX2）被认为是β细胞凋亡的关键调节因子。本研究旨在评估 GLP-1 受体激动剂（GLP-1Ra）利拉鲁肽对糖尿病中胰岛β细胞凋亡的影响及其潜在机制。
采用链脲佐菌素（STZ）和高脂饮食（HFD）诱导的糖尿病大鼠模型进行 12 周利拉鲁肽治疗。通过高血糖钳夹试验评估体内β细胞功能。采用流式细胞术分析体外细胞凋亡率。采用 DCFH-DA 法检测体内和体外 ROS 水平。
利拉鲁肽显著改善了糖尿病大鼠的胰岛功能和形态，降低了细胞凋亡率。糖尿病大鼠和 HG 诱导的 INS-1 细胞中 Thr183/Thr185 p-JNK1/2 和 NOX2 水平降低，利拉鲁肽处理后降低。此外，利拉鲁肽上调 AMPKα 的磷酸化（p-AMPKα），从而阻止 NOX2 的激活并减轻 HG 诱导的β细胞凋亡。
p-AMPKα/NOX2/JNK1/2 通路是利拉鲁肽减轻 HG 诱导的β细胞凋亡的关键，这进一步证明 GLP-1Ras 可能成为治疗糖尿病的有前途的药物。
