Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China.
Mol Cell Endocrinol. 2021 Jan 15;520:111070. doi: 10.1016/j.mce.2020.111070. Epub 2020 Oct 27.
Hyperuricaemia is a disorder of purine metabolism. Elevated serum uric acid is strongly associated with many diseases, including gout, abdominal obesity, insulin resistance, and cardiovascular and kidney disease. Our previous studies showed that high uric acid (HUA) induced insulin resistance in several peripheral organs, including the liver, myocardium and adipose tissue. However, whether HUA directly induces insulin resistance of pancreatic β cells, the only source of insulin in the body and also a sensitive insulin target, is unknown. In this study, pancreatic β cells pretreated with HUA showed impaired insulin expression/secretion, glucose uptake and the glycolytic pathway. RNA-seq revealed that HUA affected the biological processes of INS-1 cells broadly, including oxidoreduction coenzyme metabolic process, pyruvate metabolic process, and glycolytic process. In addition, HUA reduced mitochondrial membrane potential and increased the production of reactive oxygen species(ROS) in INS-1 cells. INS-1 cells pretreated with probenecid, an organic anion transporter inhibitor, protected INS-1 cells against HUA-induced insulin secretion decrease, Pretreatment with N-acetyl-L-cysteine(NAC), a globally used antioxidant, recovered HUA-decreased insulin secretion and glucose uptake by pancreatic β cells. Insulin-like growth factor 1 (IGF-1), the phosphatidylinositol 3-kinase (PI3K) activator, rescues HUA-decreased insulin secretion by re-activating AKT phosphorylation. Thus, HUA induce insulin resistance, impaired insulin secretion and glycolytic pathway of pancreatic ꞵ cell through IRS2/AKT pathway.
高尿酸血症是嘌呤代谢紊乱的一种疾病。血清尿酸升高与多种疾病密切相关，包括痛风、腹型肥胖、胰岛素抵抗以及心血管和肾脏疾病。我们之前的研究表明，高尿酸（HUA）可诱导肝脏、心肌和脂肪组织等多种外周器官发生胰岛素抵抗。然而，高尿酸是否直接诱导体内唯一胰岛素来源的胰岛β细胞发生胰岛素抵抗，以及是否是一个敏感的胰岛素靶标尚不清楚。在这项研究中，HUA 预处理的胰岛β细胞表现出胰岛素表达/分泌、葡萄糖摄取和糖酵解途径受损。RNA-seq 显示 HUA 广泛影响 INS-1 细胞的生物学过程，包括氧化还原辅酶代谢过程、丙酮酸代谢过程和糖酵解过程。此外，HUA 降低了 INS-1 细胞的线粒体膜电位并增加了活性氧（ROS）的产生。用有机阴离子转运体抑制剂丙磺舒预处理 INS-1 细胞可保护 INS-1 细胞免受 HUA 诱导的胰岛素分泌减少，用抗氧化剂 N-乙酰-L-半胱氨酸（NAC）预处理可恢复 HUA 降低的胰岛素分泌和葡萄糖摄取。胰岛素样生长因子 1（IGF-1），一种磷酸肌醇 3-激酶（PI3K）激活剂，通过重新激活 AKT 磷酸化来挽救 HUA 降低的胰岛素分泌。因此，HUA 通过 IRS2/AKT 通路诱导胰岛β细胞发生胰岛素抵抗、胰岛素分泌受损和糖酵解途径障碍。
