Chronic hepatitis C virus infection impairs insulin secretion by regulation of p38δ MAPK-dependent exocytosis in pancreatic β-cells
Chronic hepatitis C virus infection impairs insulin secretion by regulation of p38δ MAPK-dependent exocytosis in pancreatic β-cells
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DOI：
10.1042/cs20190900
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发表时间：
2020-03-01
期刊：
影响因子：
6
通讯作者：
Wang, Qian
中科院分区：
文献类型：
--
作者：
Chen, Jizheng;Wang, Fang;Wang, Qian
慢性丙型肝炎病毒（HCV）感染与2型糖尿病密切相关。虽然慢性丙型肝炎（CHC）患者胰岛素抵抗的机制已经被广泛研究，但很少有人关注β细胞功能在丙型肝炎相关糖尿病中的作用。在这里，我们分析了CHC患者和hcv感染小鼠模型的β细胞功能，发现除了胰岛素抵抗外，CHC患者和hcv感染的C/O-Tg小鼠的胰腺β细胞功能受损，不仅在糖尿病个体中，而且在空腹血糖水平受损的个体中。第一期和第二期胰岛素分泌均受损，至少部分原因是HCV感染后分泌的含胰岛素颗粒的胞吐减少。hcv感染的β细胞中p38 δ上调导致蛋白激酶D （PKD）失活，而PKD是导致β细胞胰岛素分泌能力受损的原因。因此，丙型肝炎病毒感染引起的β细胞胰岛素分泌受损导致丙型肝炎病毒相关的2型糖尿病。这些发现为空腹血糖受损的CHC患者的预后和治疗提供了新的启示。
Chronic hepatitis C virus (HCV) infection has a close association with type 2 diabetes mellitus. Although the mechanisms of insulin resistance in chronic hepatitis C (CHC) patients have been extensively studied, little attention has been given to the role of beta-cell function in HCV-associated diabetes. Here, we analysed beta-cell function in CHC patients and HCV-infected mouse model and found in addition to insulin resistance, impaired pancreatic beta-cell function occurred in CHC patients and HCV-infected C/O-Tg mice, not only in diabetic individuals but also in individuals with impaired fasting glucose levels. Both first-phase and second-phase insulin secretion were impaired, at least partially due to the reduction of exocytosis of secretory insulin-containing granules following HCV infection. Up-regulated p38 delta in HCV-infected beta-cells resulted in inactivation of protein kinase D (PKD), which was responsible for impaired insulin secretory capacity of beta-cells. Thus, impaired insulin secretion due to HCV infection in beta-cells contributes to HCV-associated type 2 diabetes. These findings provided a new inspiration for the important prognostic and therapeutic implications in the management of CHC patients with impaired fasting glucose.