HCV-Induced Beta Cell Dysfunction Contributes to HCV-Associated Type-2 Diabetes

Chronic hepatitis C virus (HCV) infection has a close association with type 2 diabetes mellitus (T2DM). Although the mechanisms of insulin resistant in 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 found HCV could infected the beta cell directly and impair pancreatic beta cell function in CHC and mouse model. Both first-phase and second-phase insulin secretion was impaired, at least partially due to the reduction of exocytosis of secretory insulin-containing granules following HCV infection. Upregulated p38δ in HCV-infected beta cells resulted in inactivation of protein kinase D (PKD), which was responsible for impaired insulin secretory capacity of beta cells. These findings provided a new perspective into mechanism of HCV induced type 2 diabetes and a new inspiration for the important prognostic and therapeutic implications in the management of CHC patients with glucose intolerance. Funding Statement: This work was supported by grants from the National Natural Sciences Foundation of China [grant number 81770859, 81271828, 81471079, 31271268], the National Basic Research Program of China [grant number 2015CB554304], the Youth Innovation Promotion Association, Open Research Fund Program of the State Key Laboratory of Virology of China (grant number 2018IOV003) Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: Human studies were approved by the Ethics Committee of the First Hospital of Jilin University and the First Affiliated Hospital of Xinjiang Medical University. The written informed consents were received from participants prior to inclusion in the study. All animal experiments were approved by the Institutional Animal Ethical Committee of Wuhan Institute of Virology, Chinese Academy of Sciences (WIV, CAS).