Author:
Niu Ben,Ma Lijing,Yao Lixuan,Zhang Yating,Su Heng
Abstract
Abstract
Purpose
To explore the mechanism of insulin secretion dysfunction in pancreatic beta cells induced by N-glycosylation mediated by an infection from the hepatitis C virus (HCV).
Methods
Min6 cell models infected with HCV and stimulated with glucose were constructed. Meanwhile, an HCV-infected animal model and a type 2 diabetes mellitus (T2DM) rat model were constructed. Glucose uptake in the Min6 cells was detected, and insulin secretion was detected by ELISA. Flow cytometry, immunofluorescence staining, Western blotting, RT-qPCR, and lectin blotting were used to detect the expression levels of related proteins and mRNA, as well as the level of N-glycosylation. HE staining was used to observe the pathological changes in the pancreatic tissue, and an oral glucose tolerance test (OGTT) was used to evaluate the glucose tolerance of the rats.
Results
Compared with the NC group, the expression levels of GnT-IVa, GLUT2, galectin-9, and voltage-dependent calcium channel 1.2 (Cav1.2) were significantly downregulated in the HCV-infected group. The ATP-sensitive potassium channel (KATP) component proteins SUR1 and Kir6.2 were significantly upregulated, while intracellular glucose intake and insulin secretion decreased, N-glycosylation levels and ATP levels significantly decreased, and the overexpression of GnT-IVa reversed the effect of the HCV infection. However, treatment with the glycosylation inhibitor kifunensine (KIF) or the KATP channel activator diazine (Dia) reversed the effects of the overexpression of GnT-IVa. In the animal experiments, HE staining revealed serious pathological injuries in the pancreatic tissue of the HCV-infected rats, with decreased glucose tolerance and glycosylation levels, decreased insulin secretion, downregulated expression of GnT-IVa, GLUT2, and Cav1.2, and upregulated expression of SUR1 and Kir6.2. The overexpression treatment of GnT-IVa or the KATP channel antagonist miglinide reversed the effects of HCV.
Conclusion
HCV infection inhibits GLUT2 N-glycosylation on the pancreatic β cell surface by downregulating the expression of GnT-IVa and then activates the KATP pathway, which ultimately leads to disturbances in insulin secretion.
Funder
The Regional Science Foundation Project of the National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Endocrinology,Endocrinology, Diabetes and Metabolism
Reference32 articles.
1. M.L. Shiffman, N.T. Gunn, Impact of hepatitis C virus therapy on metabolism and public health. Liver Int 37, 13–18 (2017)
2. S. Grimbert, P. Valensi, C. Levy-Marchal, G. Perret, J.P. Richardet, C. Raffoux et al. High prevalence of diabetes mellitus in patients with chronic hepatitis C. A case-control study. Gastroenterol Clin Biol 20, 544–548 (1996)
3. Y. Shintani, H. Fujie, H. Miyoshi, T. Tsutsumi, K. Tsukamoto, S. Kimura et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 126, 840–848 (2004)
4. L.F. Wang, C.H. Wu, Y. Shan, X.H. Fan, N. Huo, H.Y. Lu et al. Prevalence of abnormal glycometabolism in patients with chronic hepatitis C and related risk factors in China. Chin Med J 124, 183–188 (2011)
5. J.M. Hui, A. Sud, G.C. Farrell, P. Bandara, K. Byth, J.G. Kench et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 125, 1695–1704 (2003)