State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, China.
Clin Sci (Lond). 2020 Mar 13;134(5):529-542. doi: 10.1042/CS20190900.
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 β-cell function in HCV-associated diabetes. Here, we analysed β-cell function in CHC patients and HCV-infected mouse model and found in addition to insulin resistance, impaired pancreatic β-cell function occurred in CHC patients and HCV-infected C/OTg 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 p38δ in HCV-infected β-cells resulted in inactivation of protein kinase D (PKD), which was responsible for impaired insulin secretory capacity of β-cells. Thus, impaired insulin secretion due to HCV infection in β-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.
慢性丙型肝炎病毒（HCV）感染与 2 型糖尿病密切相关。尽管慢性丙型肝炎（CHC）患者胰岛素抵抗的机制已被广泛研究，但人们对 HCV 相关糖尿病中β细胞功能的作用关注甚少。在这里，我们分析了 CHC 患者和 HCV 感染的小鼠模型中的β细胞功能，发现除了胰岛素抵抗外，CHC 患者和 HCV 感染的 C/OTg 小鼠中还存在受损的胰腺β细胞功能，不仅发生在糖尿病个体中，也发生在空腹血糖受损的个体中。第一相和第二相胰岛素分泌均受损，至少部分原因是 HCV 感染后分泌胰岛素的颗粒的胞吐作用减少。HCV 感染的β细胞中 p38δ 的上调导致蛋白激酶 D（PKD）失活，这是导致β细胞胰岛素分泌能力受损的原因。因此，HCV 感染导致β细胞胰岛素分泌受损，导致 HCV 相关 2 型糖尿病。这些发现为管理空腹血糖受损的 CHC 患者提供了新的启示，具有重要的预后和治疗意义。
